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Abstract Background Diffractive intraocular lenses (IOLs) could affect visual acuity in patients with macular pathologies such as epiretinal membrane (ERM) and could influence the results of pars plana vitrectomy (PPV) for ERM removal in pseudophakic eyes with these IOLs. The aim of this study is to evaluate the effect on visual outcomes of a diffractive trifocal IOL in PPV for ERM peeling. Methods This is a retrospective cohort study on 20 eyes with a single model of trifocal IOL that underwent PPV for removal of ERM between January 2015 and September 2018 in our clinics. Follow up was at least 1 year. Primary outcome measure was mean change in visual acuity. Secondary outcome measures were mean change in central macular thickness (CMT), recovery of the external retinal layers, and change in spherical equivalent (SE). Results Mean corrected distance visual acuity (CDVA) was 0.03 ± 0.03 logMAR after phacoemulsification; this worsened to 0.23 ± 0.10 logMAR with ERM, improving to 0.10 ± 0.04 log MAR 12 months after PPV (p = 0.001). Mean uncorrected near visual acuity (UNVA) was Jaeger 2.62 ± 0.51 after lensectomy. This worsened to Jaeger 5.46 ± 1.67 with ERM and improved to the initial Jaeger 2.69 ± 0.84 after PPV (p = 0.005). CMT decreased significantly, from 380.15 ± 60.50 μm with the ERM to 313.70 ± 36.98 μm after PPV. Mean SE after lensectomy was − 0.18 ± 0.38 D, which minimally changed to – 0.18 ± 0.47 D after PPV (p = 0.99). The only complication recorded after PPV was a case of cystoid macular edema. No difficulties in visualization due to IOL design were reported during PPV. Conclusion PPV for ERM in eyes with this trifocal IOL seems to be safe and effective, and allows recovery of the loss of UNVA.

Substitution of fish-based ingredients may alter the nutritional profile of the feeds, including the vitamin contents, ultimately leading to unbalanced vitamin supply. Vitamin A plays an essential role in epithelium preservation, cell differentiation, reproduction, and vision. It also intervenes in skeletogenesis through chondrocytes development. Therefore, low levels of vitamin A may cause poor growth and abnormal bone development among other symptoms. Besides, in gilthead seabream excess vitamin A altered bone structure and homeostasis, indicating that an upper level for vitamin A in feeds for this species must be defined. For this purpose, a practical plant-based diet (FM 10% and FO 6%) containing five increasing levels of vitamin A (24,000, 26,000, 27,000, 31,000, and 37,000 IU/kg) supplemented as retinyl acetate was formulated to identify the effects of high levels of vitamin A for gilthead seabream juveniles. The trial was conducted with 450 total fish distributed into 15 tanks, where each diet was tested in triplicates for 70 days. At the end of the trial, samples were taken for analyses of vitamin A—relevant markers. At the end of the trial the high levels of vitamin A supplementation did not cause a reduction in growth, whereas no significant effect was observed for the feed efficiency, specific growth rate, and feed convertion ratio. Although not significant, retinol content in liver showed a tendency to increase with the elevation of dietary vitamin A levels. Although minor, the highest level of vitamin A dietary content (37,000 IU/kg) caused a significant increase in caudal vertebrae partial fusion as well as caudal vertebrae malformations. Increasing dietary vitamin A was related to a reduction in the occurrence of microhemorrhages in the liver and a reduction in the presence of eosinophils associated to the pancreas. Overall, the results of the present study suggested that gilthead seabream juveniles fed a plant-based diet are able to tolerate very high levels of vitamin A supplementation when supplemented as retinyl acetate. Nevertheless, further supplementation should be avoided in order to reduce the prevalence of anomalies affecting the caudal vertebrae.

The aggressiveness of melanoma and lack of effective therapies incite the discovery of novel strategies. Recently, a new dual acting hybrid molecule (HM), combining a triazene and a ʟ-tyrosine analogue, was synthesized. HM was designed to specifically be activated by tyrosinase, the enzyme involved in melanin biosynthesis and overexpressed in melanoma. HM displayed remarkable superior antiproliferative activity towards various cancer cell lines compared with temozolomide (TMZ), a triazene drug in clinical use, that acts through DNA alkylation. In B16-F10 cells, HM induced a cell cycle arrest at phase G0/G1 with a 2.8-fold decrease in cell proliferation index. Also, compared to control cells, HM led to a concentration-dependent reduction in tyrosinase activity and increase in caspase 3/7 activity. To maximize the therapeutic performance of HM in vivo, its incorporation in long blood circulating liposomes, containing poly(ethylene glycol) (PEG) at their surface, was performed for passively targeting tumour sites. HM liposomes (LIP HM) exhibited high stability in biological fluids. Preclinical studies demonstrated its safety for systemic administration and in a subcutaneous murine melanoma model, significantly reduced tumour progression. In a metastatic murine melanoma model, a superior antitumour effect was also observed for mice receiving LIP HM, with markedly reduction of lung metastases compared to positive control group (TMZ). Biodistribution studies using 111In-labelled LIP HM demonstrated its ability for passively targeting tumour sites, thus correlating with the high therapeutic effect observed in the two experimental murine melanoma models. Overall, our proposed nanotherapeutic strategy was validated as an effective and safe alternative against melanoma.

Background SARS-CoV-2 is continuously disseminating worldwide. The development of strategies to break transmission is mandatory. Aim of the study To investigate the potential of cetylpyridinium chloride (CPC) as a viral inhibitor. Methods SARS-CoV-2 Virus Like-Particles (VLPs) were incubated with CPC, a potent surfactant routinely included in mouthwash preparations. Results Concentrations of 0.05% CPC (w/v) commonly used in mouthwash preparations are sufficient to promote the rupture of SARS-CoV-2 VLP membranes. Conclusion Including CPC in mouthwashes could be a prophylactic strategy to keep SARS-CoV-2 from spreading.

Dravet syndrome is a genetic encephalopathy characterized by severe epilepsy combined with motor, cognitive, and behavioral abnormalities. Current antiepileptic drugs achieve only partial control of seizures and provide little benefit on the patient’s neurological development. In >80% of cases, the disease is caused by haploinsufficiency of the SCN1A gene, which encodes the alpha subunit of the Nav1.1 voltage-gated sodium channel. Novel therapies aim to restore SCN1A expression in order to address all disease manifestations. We provide evidence that a high-capacity adenoviral vector harboring the 6-kb SCN1A cDNA is feasible and able to express functional Nav1.1 in neurons. In vivo, the best biodistribution was observed after intracerebral injection in basal ganglia, cerebellum, and prefrontal cortex. SCN1A A1783V knockin mice received the vector at 5 weeks of age, when most neurological alterations were present. Animals were protected from sudden death, and the epileptic phenotype was attenuated. Improvement of motor performance and interaction with the environment was observed. In contrast, hyperactivity persisted, and the impact on cognitive tests was variable (success in novel object recognition and failure in Morris water maze tests). These results provide proof of concept for gene supplementation in Dravet syndrome and indicate new directions for improvement.

Marginal and peripheral populations are important for biodiversity conservation. Their original situation in a species’ geographic and ecological space often confers them genetic diversity and traits of high adaptive value. Yet theoretical hypotheses related to marginality are difficult to test because of confounding factors that influence marginality, namely environment, geography, and history. There is an urgent need to develop metrics to disentangle these confounding factors. We designed nine quantitative indices of marginality and peripherality that define where margins lie within species distributions, from a geographical, an environmental and a historical perspective. Using the distribution maps of eight European forest tree species, we assessed whether these indices were idiosyncratic or whether they conveyed redundant information. Using a database on marginal and peripheral populations based on expert knowledge, we assessed the capacity of the indices to predict the marginality status of a population. There was no consistent pattern of correlation between indices across species, confirming that the indices conveyed different information related to the specific geometry of the species distributions. Contrasting with this heterogeneity of correlation patterns across species, the relative importance of the indices to predict the marginality status of populations was consistent across species. However, there was still a significant country effect in the marginality status, showing a variation in expert opinion of marginality vis-á-vis the species distribution. The marginality indices that we developed are entirely based on distribution maps and can be used for any species. They pave the way for testing hypotheses related to marginality and peripherality, with important implications in quantitative ecology, genetics, and biodiversity conservation.

Este artigo tem como objetivo discutir o alcance da práxis educativa relativa à cidadania e à cultura da paz, dando ênfase ao pensamento de Paulo Freire. Na compreensão freiriana é a vida e a humanidade dos sujeitos que pulsam e se colocam em evidência quando se ensina e aprende e, assim sendo, a efetividade da tarefa educativa se dá pelo nível de compromisso com a transformação do mundo, que passa necessariamente por um processo de re-humanização dos oprimidos e dos opressores e só se torna possível pelo enfrentamento direto de situações de injustiça, opressão, violência e desigualdade. Duas questões nos foram significativas: a - Freire confronta e desmantela a compreensão comum de educação, que a toma como prática que converte, dogmatiza, põe na forma, defendendo, em perspectiva contrária, a educação emancipatória, engajada com e na mudança do mundo, onde o educador e os educandos podem pensar, falar e agir, compartilhando um mundo entre si; b- em Freire, a opressão é um artifício de desumanização implicado à ausência de cidadania e, consecutivamente, à negação de uma cultura da paz, e somente a educação pode alterar o curso dessa história.

BackgroundChagas disease (CD) is caused by Trypanosoma cruzi and affects 6-7 million people worldwide. Approximately 30% of chronic patients develop chronic chagasic cardiomyopathy (CCC) after decades. Benznidazole (BNZ), one of the first-line chemotherapy used for CD, induces toxicity and fails to halt the progression of CCC in chronic patients. The recombinant parasite-derived antigens, including Tc24, Tc24-C4, TSA-1, and TSA-1-C4 with Toll-like receptor 4 (TLR-4) agonist-adjuvants reduce cardiac parasite burdens, heart inflammation, and fibrosis, leading us to envision their use as immunotherapy together with BNZ. Given genetic immunization (DNA vaccines) encoding Tc24 and TSA-1 induce protective immunity in mice and dogs, we propose that immunization with the corresponding recombinant proteins offers an alternative and feasible strategy to develop these antigens as a bivalent human vaccine. We hypothesized that a low dose of BNZ in combination with a therapeutic vaccine (TSA-1-C4 and Tc24-C4 antigens formulated with a synthetic TLR-4 agonist-adjuvant, E6020-SE) given during early chronic infection, could prevent cardiac disease progression and provide antigen-specific T cell immunity.Methodology/ principal findingsWe evaluated the therapeutic vaccine candidate plus BNZ (25 mg/kg/day/7 days) given on days 72 and 79 post-infection (p.i) (early chronic phase). Fibrosis, inflammation, and parasite burden were quantified in heart tissue at day 200 p.i. (late chronic phase). Further, spleen cells were collected to evaluate antigen-specific CD4+ and CD8+ T cell immune response, using flow cytometry. We found that vaccine-linked BNZ treated mice had lower cardiac fibrosis compared to the infected untreated control group. Moreover, cells from mice that received the immunotherapy had higher stimulation index of antigen-specific CD8+Perforin+ T cells as well as antigen-specific central memory T cells compared to the infected untreated control.ConclusionsOur results suggest that the bivalent immunotherapy together with BNZ treatment given during early chronic infection protects BALB/c mice against cardiac fibrosis progression and activates a strong CD8+ T cell response by in vitro restimulation, evidencing the induction of a long-lasting T. cruzi-immunity.

Introduction Breast cancer is the most common malignant tumour in women, with more than 2 million new cases annually worldwide. One of the most frequent and well-known surgical and post-actinic sequelae is post-mastectomy lymphoedema. The axillary web syndrome is another sequela that limits the functionality of the patient and delays the protocol time of administering cancer treatments; and in many cases, this sequela is misdiagnosed. This surgical sequela usually disappears spontaneously after the third month of appearance, but this implies a long period of discomfort and limitations for the patient, at the same time, it may delay the application of radiotherapy within the indicated protocol deadline (due to a need for body posture).Methods and analysis With the present quasi-experimental study, we intend to show the application of physiotherapy and stretching from the beginning of the appearance of the axillary cord, in a controlled and scheduled way by the physiotherapist. It is possible to reduce the time in which the lymphatic thrombus is present and, therefore, recover functionality and mobility, reduce pain and be able to apply treatments within the established deadline. We intend to apply this therapy into the intervention group and compare thrombus evolution time with the control group.Ethics and dissemination This trial has the approval of the Andalucía Ethics Committee (PEIBA code 1909-N1-21, reg. number 171.21).Trial registration number ClinicalTrials.gov Registry (NCT05115799).

The functional and neurophysiological distinction between the dorsal and ventral hippocampus affects also GABAergic inhibition. In line with this notion, ventral CA1 pyramidal cells displayed a more dynamic and effective response to inhibitory input compared to their dorsal counterparts. We posit that this difference is effected by the dorsal–ventral gradient of activin A, a member of the transforming growth factor-β family, which is increasingly recognized for its modulatory role in brain regions involved in cognitive functions and affective behavior. Lending credence to this hypothesis, we found that in slices from transgenic mice expressing a dominant-negative mutant of activin receptor IB (dnActRIB), inhibitory transmission was enhanced only in CA1 neurons of the dorsal hippocampus, where the basal activin A level is much higher than in the ventral hippocampus. We next asked how a rise in endogenous activin A would affect GABAergic inhibition along the longitudinal axis of the hippocampus. We performed ex vivo recordings in wild-type and dnActRIB mice after overnight exposure to an enriched environment (EE), which engenders a robust increase in activin A levels in both dorsal and ventral hippocampi. Compared to control mice from standard cages, the behaviorally induced surge in activin A produced a decline in ventral inhibition, an effect that was absent in slices from dnActRIB mice. Underscoring the essential role of activin in the EE-associated modulation of ventral inhibition, this effect was mimicked by acute application of recombinant activin A in control slices. In summary, both genetic and behavioral manipulations of activin receptor signaling affected the dorsal–ventral difference in synaptic inhibition, suggesting that activin A regulates the strength of GABAergic inhibition in a region-specific fashion.

We present the case of a 62-year-old patient who developed melenas and in whom conventional endoscopic tests could not detect any bleeding lesion. In our case, capsule endoscopy and enteroscopy were the pivotal elements in establishing the diagnosis of a neuroendocrine tumour with an atypical location. As a result, it was possible to surgically remove the lesions at an early stage of the malignancy without metastatic disease and without the need for adjuvant therapy. Our case demonstrates the need for these new techniques in tumours of atypical location and aggressive course. Otherwise, this malignancy may be underdiagnosed until an advanced stage.

Background: Cancer, being a highly widespread disease on a global scale, has prompted researchers to explore innovative treatment approaches. In this regard, blood flow restriction has emerged as a promising procedure utilized in diverse clinical populations with favorable results including improvements in muscle strength, cardiovascular function, and postoperative recovery. The aim of this systematic review was to assess the efficacy of blood flow restriction in cancer survivors. Methods: An investigation was carried out using various databases until February 2023: PubMed, Scientific Electronic Library Online, Physiotherapy Evidence Database, Scopus, Web of Science, Cochrane Plus, SPORTDiscus, Physiotherapy and Podiatry of the Complutense University of Madrid, ScienceDirect, ProQuest, Research Library, Cumulative Index of Nursing and Allied Literature Complete Journal Storage, and the gray literature. To assess the methodological quality of the studies, the PEDro scale was utilized, and the Cochrane Collaboration tool was employed to evaluate the risk of bias. Results: Five articles found that blood flow restriction was beneficial in improving several factors, including quality of life, physical function, strength, and lean mass, and in reducing postoperative complications and the length of hospital stay. Conclusion: Blood flow restriction can be a viable and effective treatment option. It is important to note that the caution with which one should interpret these results is due to the restricted quantity of articles and significant variation, and future research should concentrate on tailoring the application to individual patients, optimizing load progression, ensuring long-term follow-up, and enhancing the methodological rigor of studies, such as implementing sample blinding.

Long COVID syndrome has been recognized as a public health problem. Digital physiotherapy practice is an alternative that can better meet the needs of patients. The aim of this review was to synthesize the evidence of digital physiotherapy practice in Long COVID patients. A systematic review was carried out until December 2022. The review was complemented by an assessment of the risk of bias and methodological quality. A narrative synthesis of results was conducted, including subgroup analyses by intervention and clinical outcomes. Six articles, including 540 participants, were selected. Five articles were considered of high enough methodological quality. Parallel-group, single-blind, randomized controlled trials were the most commonly used research design. Tele-supervised home-based exercise training was the most commonly used intervention. Great heterogeneity in clinical outcomes and measurement tools was found. A subgroup analysis showed that digital physiotherapy is effective in improving clinical outcomes. Significant differences in favor of digital interventions over usual care were reported. Nevertheless, discrepancies regarding effectiveness were found. Improvements in clinical outcomes with digital physiotherapy were found to be at least non-inferior to usual care. This review provides new evidence that digital physiotherapy practice is an appropriate intervention for Long COVID patients, despite the inherent limitations of the review. Registration: CRD42022379004.

The present study aimed to evaluate the effect of dipyridamole, an indirect adenosine 2A receptors (A2AR), on the osseointegration of titanium implants in a large, translational pre-clinical model. Sixty tapered, acid-etched titanium implants, treated with four different coatings ((i) Type I Bovine Collagen (control), (ii) 10 μM dipyridamole (DIPY), (iii) 100 μM DIPY, and (iv) 1000 μM DIPY), were inserted in the vertebral bodies of 15 female sheep (weight ~65 kg). Qualitative and quantitative analysis were performed after 3, 6, and 12 weeks in vivo to assess histological features, and percentages of bone-to-implant contact (%BIC) and bone area fraction occupancy (%BAFO). Data was analyzed using a general linear mixed model analysis with time in vivo and coating as fixed factors. Histomorphometric analysis after 3 weeks in vivo revealed higher BIC for DIPY coated implant groups (10 μM (30.42% ± 10.62), 100 μM (36.41% ± 10.62), and 1000 μM (32.46% ± 10.62)) in comparison to the control group (17.99% ± 5.82). Further, significantly higher BAFO was observed for implants augmented with 1000 μM of DIPY (43.84% ± 9.97) compared to the control group (31.89% ± 5.46). At 6 and 12 weeks, no significant differences were observed among groups. Histological analysis evidenced similar osseointegration features and an intramembranous-type healing pattern for all groups. Qualitative observation corroborated the increased presence of woven bone formation in intimate contact with the surface of the implant and within the threads at 3 weeks with increased concentrations of DIPY. Coating the implant surface with dipyridamole yielded a favorable effect with regard to BIC and BAFO at 3 weeks in vivo. These findings suggest a positive effect of DIPY on the early stages of osseointegration.

Abstract Escovopsis is a diverse group of fungi, which are considered specialized parasites of the fungal cultivars of fungus-growing ants. The lack of a suitable taxonomic framework and phylogenetic inconsistencies have long hampered Escovopsis research. The aim of this study is to reassess the genus Escovopsis using a taxonomic approach and a comprehensive multilocus phylogenetic analysis, in order to set the basis of the genus systematics and the stage for future Escovopsis research. Our results support the separation of Escovopsis into three distinct genera. In light of this, we redefine Escovopsis as a monophyletic clade whose main feature is to form terminal vesicles on conidiophores. Consequently, E. kreiselii and E. trichodermoides were recombined into two new genera, Sympodiorosea and Luteomyces, as S. kreiselii and L. trichodermoides, respectively. This study expands our understanding of the systematics of Escovopsis and related genera, thereby facilitating future research on the evolutionary history, taxonomic diversity, and ecological roles of these inhabitants of the attine ant colonies.

Abstract Venous thromboembolism is the third common cardiovascular disease and is composed of two entities, deep vein thrombosis (DVT) and its potential fatal form, pulmonary embolism (PE). While PE is observed in ~ 40% of patients with documented DVT, there is limited biomarkers that can help identifying patients at high PE risk. To fill this need, we implemented a two hidden-layers artificial neural networks (ANN) on 376 antibodies and 19 biological traits measured in the plasma of 1388 DVT patients, with or without PE, of the MARTHA study. We used the LIME algorithm to obtain a linear approximate of the resulting ANN prediction model. As MARTHA patients were typed for genotyping DNA arrays, a genome wide association study (GWAS) was conducted on the LIME estimate. Detected single nucleotide polymorphisms (SNPs) were tested for association with PE risk in MARTHA. Main findings were replicated in the EOVT study composed of 143 PE patients and 196 DVT only patients. The derived ANN model for PE achieved an accuracy of 0.89 and 0.79 in our training and testing sets, respectively. A GWAS on the LIME approximate identified a strong statistical association peak (rs1424597: p = 5.3 × 10–7) at the PLXNA4 locus. Homozygote carriers for the rs1424597-A allele were then more frequently observed in PE than in DVT patients from the MARTHA (2% vs. 0.4%, p = 0.005) and the EOVT (3% vs. 0%, p = 0.013) studies. In a sample of 112 COVID-19 patients known to have endotheliopathy leading to acute lung injury and an increased risk of PE, decreased PLXNA4 levels were associated (p = 0.025) with worsened respiratory function. Using an original integrated proteomics and genetics strategy, we identified PLXNA4 as a new susceptibility gene for PE whose exact role now needs to be further elucidated.

Abstract Aims Maximum oxygen uptake (VO2max) is an essential parameter to assess functional capacity of patients with heart failure (HF). We aimed to identify clinical factors that determine its value, as they have not been well characterized yet. Methods We conducted a retrospective, observational, single‐centre study of 362 consecutive patients with HF who underwent cardiopulmonary exercise testing (CPET) as part of standard clinical assessment since 2009–2019. CPET was performed on treadmill, according to Bruce's protocol (n = 360) or Naughton's protocol (n = 2). We performed multivariable linear regression analyses in order to identify independent clinical predictors associated with peak VO2max. Results Mean age of study patients was 57.3 ± 10.9 years, mean left ventricular ejection fraction was 32.8 ± 14.2%, and mean VO2max was 19.8 ± 5.2 mL/kg/min. Eighty‐nine (24.6%) patients were women, and 114 (31.5%) had ischaemic heart disease. Multivariable linear regression analysis identified six independent clinical predictors of VO2max, including NYHA class (B coefficient = −2.585; P

Abstract Tumor progression and metastatic dissemination are driven by cell-intrinsic and biomechanical cues that favor the growth of life-threatening secondary tumors. We recently identified pro-metastatic vascular regions with blood flow profiles that are permissive for the arrest of circulating tumor cells. We have further established that such flow profiles also control endothelial remodeling, which favors extravasation of arrested CTCs. Yet, how shear forces control endothelial remodeling is unknown. In the present work, we aimed at dissecting the cellular and molecular mechanisms driving blood flow-dependent endothelial remodeling. Transcriptomic analysis of endothelial cells revealed that blood flow enhanced VEGFR signaling, among others. Using a combination of in vitro microfluidics and intravital imaging in zebrafish embryos, we now demonstrate that the early flow-driven endothelial response can be prevented upon specific inhibition of VEGFR tyrosine kinase and subsequent signaling. Inhibitory targeting of VEGFRs reduced endothelial remodeling and subsequent metastatic extravasation. These results confirm the importance of VEGFR-dependent endothelial remodeling as a driving force of CTC extravasation and metastatic dissemination. Furthermore, the present work suggests that therapies targeting endothelial remodeling might be a relevant clinical strategy in order to impede metastatic progression.

During the last decades, global interest in learning English as a foreign language has increased, encouraging countries to include it in school education. This trend was followed by the Chilean Ministry of Education, which suggests teaching English based on a communicative approach starting in early childhood education. To foster students' learning, it is imperative to acknowledge that children learn differently than older learners and that English as a foreign language teachers should be able to identify their needs and implement age-appropriate strategies. This article reports the action research findings that explore the contribution of board games, memory, and bingo on pre-kindergarten students' oral expression when participating in English lessons. A group of 19 children aged four from a private school in Concepción, Chile, took part in this study by playing online and board bingo, and memory games. Data were gathered by qualitative methods, such as an observation checklist, a semi-structured interview applied to thein co-teacher, and group interviews carried out with students at the end of the intervention. The group and semi-structured interview data were analyzed through the thematic data analysis technique, along with frequency data analysis used to process the observational checklists. The results show that students increased their English oral production when games were implemented in their lessons.

Tuberculosis (TB) still represents a major global health problem affecting over 10 million people worldwide. The gold-standard procedures for TB diagnosis are culture and nucleic acid amplification techniques. In this context, both lipoarabinomannan (LAM) urine test and rapid molecular tests have been major game changers. However, the low sensitivity of the former and the cost and the prohibitive infrastructure requirements to scale-up in endemic regions of the latter, make the improvement of the TB diagnostic landscape a priority. Most forms of life produce extracellular vesicles (EVs), including bacteria despite differences in bacterial cell envelope architecture. We demonstrated that Mycobacterium tuberculosis (Mtb), the causative agent of TB, produces EVs in vitro and in vivo as part of a sophisticated mechanism to manipulate host cellular physiology and to evade the host immune system. In a previous serology study, we showed that the recognition of several mycobacterial extracellular vesicles (MEV) associated proteins could have diagnostic properties. In this study, we pursued to expand the capabilities of MEVs in the context of TB diagnostics by analyzing the composition of MEVs isolated from Mtb cultures submitted to iron starvation and, testing their immunogenicity against a new cohort of serum samples derived from TB+ patients, latent TB-infected (LTBI) patients and healthy donors. We found that despite the stringent condition imposed by iron starvation, Mtb reduces the number of MEV associated proteins relative to iron sufficient conditions. In addition, TB serology revealed three new MEV antigens with specific biomarker capacity. These results suggest the feasibility of developing a point-of-care (POC) device based on selected MEV-associated proteins.

Abstract Background To determine the state of current practice and to reach a consensus on recommendations for the management of advanced ovarian cancer using a Delphi survey with a group of Spanish gynecologists and medical oncologists specially dedicated to gynecological tumors. Methods The questionnaire was developed by the byline authors. All questions but one were answered using a 9-item Likert-like scale with three types of answers: frequency, relevance and agreement. We performed two rounds between December 2018 and July 2019. A consensus was considered reached when at least 75% of the answers were located within three consecutive points of the Likert scale. Results In the first round, 32 oncologists and gynecologists were invited to participate, and 31 (96.9%) completed the online questionnaire. In the second round, 27 (87.1%) completed the online questionnaire. The results for the questions on first-line management of advanced disease, treatment of patients with recurrent disease for whom platinum might be the best option, and treatment of patients with recurrent disease for whom platinum might not be the best option are presented. Conclusions This survey shows a snapshot of current recommendations by this selected group of physicians. Although the majority of the agreements and recommendations are aligned with the recently published ESMO-ESGO consensus, there are some discrepancies that can be explained by differences in the interpretation of certain clinical trials, reimbursement or accessibility issues.

Abstract Background To determine whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, the cause of COVID-19 disease) exposure in pregnancy, compared to non-exposure, is associated with infection-related obstetric morbidity. Methods We conducted a multicentre prospective study in pregnancy based on a universal antenatal screening program for SARS-CoV-2 infection. Throughout Spain 45 hospitals tested all women at admission on delivery ward using polymerase-chain-reaction (PCR) for COVID-19 since late March 2020. The cohort of positive mothers and the concurrent sample of negative mothers was followed up until 6-weeks post-partum. Multivariable logistic regression analysis, adjusting for known confounding variables, determined the adjusted odds ratio (aOR) with 95% confidence intervals (95% CI) of the association of SARS-CoV-2 infection and obstetric outcomes. Main outcome measures: Preterm delivery (primary), premature rupture of membranes and neonatal intensive care unit admissions. Results Among 1009 screened pregnancies, 246 were SARS-CoV-2 positive. Compared to negative mothers (763 cases), SARS-CoV-2 infection increased the odds of preterm birth (34 vs 51, 13.8% vs 6.7%, aOR 2.12, 95% CI 1.32–3.36, p = 0.002); iatrogenic preterm delivery was more frequent in infected women (4.9% vs 1.3%, p = 0.001), while the occurrence of spontaneous preterm deliveries was statistically similar (6.1% vs 4.7%). An increased risk of premature rupture of membranes at term (39 vs 75, 15.8% vs 9.8%, aOR 1.70, 95% CI 1.11–2.57, p = 0.013) and neonatal intensive care unit admissions (23 vs 18, 9.3% vs 2.4%, aOR 4.62, 95% CI 2.43–8.94, p

Arthrogryposis multiplex congenita is a condition characterised by contractures and deformity in two or more body areas. Physiotherapy may be an appropriate treatment. The aim was to systematically review the evidence for rehabilitation in arthrogryposis multiplex congenita. A systematic review was performed following the PRISMA 2020 criteria. The search was conducted in PubMed, ScienceDirect, Scielo, Scopus, Web of Science, ENFISPO, JSTOR, Google Scholar, ProQuest, Cochrane Library and PEDro from inception until October 2022. To assess the methodological quality, we used the different aspects of the critical appraisal tool JBI. We included 14 studies (6 case reports, 5 case series, 2 cross-sectional and 1 qualitative study). Sample sizes ranged from 1 to 50 participants, with an age range between 11 days and 35 years. Most studies employed multicomponent therapy, mainly kinesitherapy, massage therapy, use of physical agents and stretching, some combined it with orthopaedic therapy, or it was complementary to surgical treatment. The key to improving the clinical picture was early and individualised care, tailored to the characteristics of the patients. Regarding methodological quality, the main conflicts encountered were in the reporting of participant characteristics and experimental interventions. Rehabilitation provides satisfactory results in the treatment of arthrogryposis multiplex congenita. More scientific production and randomised clinical trials are needed.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial, wide-spectrum liver disorder. Small intestinal bacterial overgrowth (SIBO) is characterized by an increase in the number and/or type of colonic bacteria in the upper gastrointestinal tract. SIBO, through energy salvage and induction of inflammation, may be a pathophysiological factor for NAFLD development and progression. Aim/Methods: Consecutive patients with histological, biochemical, or radiological diagnosis of any stage of NAFLD (non-alcoholic fatty liver [NAFL], non-alcoholic steatohepatitis [NASH], cirrhosis) underwent upper gastrointestinal endoscopy. Duodenal fluid (2cc) was aspirated from the 3rd–4th part of duodenum into sterile containers. SIBO was defined as ≥103 aerobic colony-forming units (CFU)/mL of duodenal aspirate and/or the presence of colonic-type bacteria. Patients without any liver disease undergoing gastroscopy due to gastroesophageal reflux disease (GERD) comprised the healthy control (HC) group. Concentrations (pg/mL) of tumor necrosis factor alpha (TNFα), interleukin (IL)-1β, and IL-6 were also measured in the duodenal fluid. The primary endpoint was to evaluate the prevalence of SIBO in NAFLD patients, while the comparison of SIBO prevalence among NAFLD patients and healthy controls was a secondary endpoint. Results: We enrolled 125 patients (51 NAFL, 27 NASH, 17 cirrhosis, and 30 HC) aged 54 ± 11.9 years and with a weight of 88.3 ± 19.6 kg (NAFLD vs. HC 90.7 ± 19.1 vs. 80.8 ± 19.6 kg, p = 0.02). Overall, SIBO was diagnosed in 23/125 (18.4%) patients, with Gram-negative bacteria being the predominant species (19/23; 82.6%). SIBO prevalence was higher in the NAFLD cohort compared to HC (22/95; 23.2% vs. 1/30; 3.3%, p = 0.014). Patients with NASH had higher SIBO prevalence (6/27; 22.2%) compared to NAFL individuals (8/51; 15.7%), but this difference did not reach statistical significance (p = 0.11). Patients with NASH-associated cirrhosis had a higher SIBO prevalence compared to patients with NAFL (8/17; 47.1% vs. 8/51; 15.7%, p = 0.02), while SIBO prevalence between patients with NASH-associated cirrhosis and NASH was not statistically different (8/17; 47.1% vs. 6/27; 22.2%, p = 0.11). Mean concentration of TNF-α, IL-1β, and IL-6 did not differ among the different groups. Conclusion: The prevalence of SIBO is significantly higher in a cohort of patients with NAFLD compared to healthy controls. Moreover, SIBO is more prevalent in patients with NASH-associated cirrhosis compared to patients with NAFL.

Photodynamic therapy is a non-invasive therapeutic strategy that combines external light with a photosensitizer (PS) to destroy abnormal cells. Despite the great progress in the development of new photosensitizers with improved efficacy, the PS’s photosensitivity, high hydrophobicity, and tumor target avidity still represent the main challenges. Herein, newly synthesized brominated squaraine, exhibiting intense absorption in the red/near-infrared region, has been successfully incorporated into Quatsome (QS) nanovesicles at different loadings. The formulations under study have been characterized and interrogated in vitro for cytotoxicity, cellular uptake, and PDT efficiency in a breast cancer cell line. The nanoencapsulation of brominated squaraine into QS overcomes the non-water solubility limitation of the brominated squaraine without compromising its ability to generate ROS rapidly. In addition, PDT effectiveness is maximized due to the highly localized PS loadings in the QS. This strategy allows using a therapeutic squaraine concentration that is 100 times lower than the concentration of free squaraine usually employed in PDT. Taken together, our results reveal the benefits of the incorporation of brominated squaraine into QS to optimize their photoactive properties and support their applicability as photosensitizer agents for PDT.

In fish, most hormonal productions of the pituitary gland display daily and/or seasonal rhythmic patterns under control by upstream regulators, including internal biological clocks. The pineal hormone melatonin, one main output of the clocks, acts at different levels of the neuroendocrine axis. Melatonin rhythmic production is synchronized mainly by photoperiod and temperature. Here we aimed at better understanding the role melatonin plays in regulating the pituitary hormonal productions in a species of scientific and economical interest, the euryhaline European sea bass Dicentrarchus labrax. We investigated the seasonal variations in mRNA abundance of pituitary hormones in two groups of fish raised one in sea water (SW fish), and one in brackish water (BW fish). The mRNA abundance of three melatonin receptors was also studied in the SW fish. Finally, we investigated the in vitro effects of melatonin or analogs on the mRNA abundance of pituitary hormones at two times of the year and after adaptation to different salinities. We found that (1) the reproductive hormones displayed similar mRNA seasonal profiles regardless of the fish origin, while (2) the other hormones exhibited different patterns in the SW vs. the BW fish. (3) The melatonin receptors mRNA abundance displayed seasonal variations in the SW fish. (4) Melatonin affected mRNA abundance of most of the pituitary hormones in vitro; (5) the responses to melatonin depended on its concentration, the month investigated and the salinity at which the fish were previously adapted. Our results suggest that the productions of the pituitary are a response to multiple factors from internal and external origin including melatonin. The variety of the responses described might reflect a high plasticity of the pituitary in a fish that faces multiple external conditions along its life characterized by marked daily and seasonal changes in photoperiod, temperature and salinity.

Abstract Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer’s disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [β AVROH (CI 95%) = 0.070 (0.037–0.104); P = 3.91 × 10−5; β FROH (CI95%) = 0.043 (0.009–0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p

Abstract Background HIV infection has become a chronic disease and well-being of people living with HIV (PLHIV) is now of particular concern. The objectives of this paper were to describe self-rated health among PLHIV, on ART and on ART virally suppressed and to analyse its determinants. Methods Data were obtained from a second-generation surveillance system based on a cross-sectional one-day survey in public hospitals. Epidemiological and clinical data were collected among HIV-infected inpatients and outpatients receiving HIV-related care the day of the survey in 86 hospitals in 2019. Self-rated health was measured using a question included in the National Health Survey: “In the last 12 months, how would you rate your health status?” an ordinal variable with five categories (very good, good, moderate, bad and very bad). For the analysis, these responses were dichotomized into two categories: 1 = very good/good and 0 = moderate, bad or very bad health status. Factors associated with very good/good self-rated health were estimated using logistic regression. Results Of 800 PLHIV, 67.5% perceived their health as very good/good, 68.4% among PLHIV on ART and 71.7% of those virally suppressed. Having university education (adjusted odds ratio (aOR):2.1), being unemployed (aOR:0.3) or retired (aOR:0.2), ever being diagnosed of AIDS (aOR:0.6), comorbidities (aOR:0.3), less than 2 year since HIV diagnosis (aOR:0.3) and not receiving ART (aOR:0.3) were associated with good self-rated health. Moreover, among PLHIV on ART, viral load less than 200 copies (aOR:3.2) were related to better perceived health. Bad adherence was inversely associated with good self-rated health among PLHIV on ART (aOR:0.5) and of those virally suppressed (aOR:0.4). Conclusions Nearly seven in 10 PLHIV in Spain considered their health status as very good/good, being higher among virally suppressed PLHIV. Both demographic and clinical determinants affect quality of life.

In the last years, educational community is asking for a change by introducing social tools in formal learning contexts. Besides, although meaningful research on the effects of social learning can be found in the literature, all authors agree that further research is needed. Social Network Analysis (SNA) has been proven to be a useful tool for both researchers and teachers. However, both standard SNA tools and the most popular social network sites are external to the Learning Management Systems (LMS) anda, therefore, they are hard to integrate by teachers into their educational designs. This study shows MSocial, a novel tool integrated into the Moodle LMS, that allows students interact in their social networks without losing their presence in the LMS. MSocial monitors student activity in social networks (both inside and outside of Moodle), calculates SNA metrics and shows the results promptly in the Moodle course site. Therefore, teachers can easily understand, visualize, and analyze the social participation and interaction of students and incorporate these results to improve the learning process.

Abstract The Senegalese sole (Solea senegalensis) is an economically important flatfish species. In this study, a genome draft was analyzed to identify microsatellite (SSR) markers for whole-genome genotyping. A subset of 224 contigs containing SSRs were preselected and validated by using a de novo female hybrid assembly. Overall, the SSR density in the genome was 886.7 markers per megabase of genomic sequences and the dinucleotide motif was the most abundant (52.4%). In silico comparison identified a set of 108 SSRs (with di-, tetra- or pentanucleotide motifs) widely distributed in the genome and suitable for primer design. A total of 106 markers were structured in thirteen multiplex PCR assays (with up to 10-plex) and the amplification conditions were optimized with a high-quality score. Main genetic diversity statistics and genotyping reliability were assessed. A subset of 40 high polymorphic markers were selected to optimize four supermultiplex PCRs (with up to 11-plex) for pedigree analysis. Theoretical exclusion probabilities and real parentage allocation tests using parent–offspring information confirmed their robustness and effectiveness for parental assignment. These new SSR markers were combined with previously published SSRs (in total 229 makers) to construct a new and improved integrated genetic map containing 21 linkage groups that matched with the expected number of chromosomes. Synteny analysis with respect to C. semilaevis provided new clues on chromosome evolution in flatfish and the formation of metacentric and submetacentric chromosomes in Senegalese sole.

Activin A, a member of the TGF-β family, is recognized as a multifunctional protein in the adult brain with a particular impact on neuronal circuits associated with cognitive and affective functions. Activin receptor signaling in mouse hippocampus is strongly enhanced by the exploration of an enriched environment (EE), a behavioral paradigm known to improve performance in learning and memory tasks and to ameliorate depression-like behaviors. To interrogate the relationship between EE, activin signaling, and cellular excitability in the hippocampus, we performed ex vivo whole-cell recordings from dentate gyrus (DG) granule cells (GCs) of wild type mice and transgenic mice expressing a dominant-negative mutant of activin receptor IB (dnActRIB), which disrupts activin signaling in a forebrain-specific fashion. We found that, after overnight EE housing, GC excitability was strongly enhanced in an activin-dependent fashion. Moreover, the effect of EE on GC firing was mimicked by pre-treatment of hippocampal slices from control mice with recombinant activin A for several hours. The excitatory effect of activin A was preserved when canonical SMAD-dependent signaling was pharmacologically suppressed but was blocked by inhibitors of ERK-MAPK and PKA signaling. The involvement of a non-genomic signaling cascade was supported by the fact that the excitatory effect of activin A was already achieved within minutes of application. With respect to the ionic mechanism underlying the increase in intrinsic excitability, voltage-clamp recordings revealed that activin A induced an apparent inward current, which resulted from the suppression of a standing G protein-gated inwardly rectifying K+ (GIRK) current. The link between EE, enhanced activin signaling, and inhibition of GIRK current was strengthened by the following findings: (i) The specific GIRK channel blocker tertiapin Q (TQ) occluded the characteristic electrophysiological effects of activin A in both current- and voltage-clamp recordings. (ii) The outward current evoked by the GIRK channel activator adenosine was significantly reduced by preceding EE exploration as well as by recombinant activin A in control slices. In conclusion, our study identifies GIRK current suppression via non-canonical activin signaling as a mechanism that might at least in part contribute to the beneficial effects of EE on cognitive performance and affective behavior.

ABSTRACT We assessed the impacts of the biological invasion of Azadirachta indica on the quality of plant species native to a Seasonally Dry Tropical Forest. We planted Amburana cearensis, Libidibia ferrea, Mimosa caesalpiniifolia, and Cenostigma pyramidale individuals alone and interacting with the exotic species. We measured their diameters at ground level and heights for four months, calculating their monthly and general average. After this period, seedlings were destroyed to obtain their number of leaves, leaf area, specific leaf area, length and primary root area, wood density, wood dry matter, leaf dry matter, shoot dry matter, primary root dry matter, secondary root dry matter, root system dry matter, and total dry matter. The presence of the exotic species affected the functional characteristics of native species in different ways. We observed negative effects in M. caesalpiniifolia and A. cearensis, positive effects in C. pyramidale, and mixed effects in L. ferrea. In addition, we identified conflicting demands between pairs of characteristics of the interacting species A. cearensis and M. caesalpiniifolia. Based on the results, it is possible to conclude that A. indica decreases the quality of individuals of most native species studied, which may have consequences for their establishment and the local biodiversity.

The main objective of the current study was to analyze how parents' sociodemographic characteristics, mode of commuting and physical activity (PA) act as indicators of active commuting to school (ACS) in their children and adolescents. A total of 684 paired parents (52.8% mothers) and their respective offspring (33.7% girls) were included. The participants self-reported their sociodemographic characteristics, mode of commuting, and PA. Logistic regression analyses were performed using a stepwise approach, including, as indicators, parental characteristics, mode of commuting and PA. The main outcome was child and adolescent ACS. The odds ratio (OR) and R2 of Nagelkerke were obtained for each step. Parental sociodemographic characteristics were greater indicators of child ACS than the parental mode of commuting and PA. In children, the greatest predictive variables of ACS explained 38% of the variance and were as follows: car availability (OR = 0.24), father's educational level (OR = 0.47), mother's educational level (OR = 1.95), mother's active commuting to work (OR = 4.52) and mother's salary/month (OR = 0.67). In adolescents, the greatest predictive variables of ACS explained 40% of the variance and were as follows: socioeconomic level (OR = 0.43) and father's active commuting (OR = 10.6). In conclusion, sociodemographic factors are better indicators of ACS than parents' physical activity and active commuting to work.

Le succès des programmes d'élevage des petits ruminants dépend des modèles appropriés d'évaluation génétique des reproducteurs sur des caractères présentant une association génétique entre les différents phénotypes reproductifs. L’objectif de ce travail est de déterminer les composantes environnementales et génétiques qui synthétisent les performances de reproduction des chèvres locales élevées dans des conditions arides afin de jalonner les bases d’une future amélioration génétique de cette population. Deux caractères de reproduction ont été étudiés : l'intervalle entre mise bas et la taille de la portée à la naissance. Trois modèles ont été utilisés pour chaque cas, des analyses uni et bi-variées, qui différaient par les effets aléatoires inclus dans le modèle, uniquement les effets génétiques additifs, uniquement les effets environnementaux permanents ou les deux effets simultanément. Les résultats obtenus suggèrent que le modèle Bi-variée incluant uniquement les effets environnementaux permanents de la chèvre est le plus adéquat pour modéliser les performances de reproduction de la chèvre locale. Les variances génétiques directes sont principalement plus élevées en utilisant le model uni-varié que le modèle Bi-varié. Les estimations de la variance environnementale obtenues sont les mêmes pour les deux modèles. Les héritabilités enregistrées à partir du modèle uni-varié sont légèrement inférieures aux estimations issues du modèle Bi-varié. Il parait impératif de considérer qu’au niveau du modèle animale, l’ensemble des effets génétiques et environnementaux, susceptibles d’intervenir sur le déterminisme des caractères reproductifs. Mots clés: chèvre local, amélioration, évaluation, modèle uni-varié, modèle Bi-varié, reproduction

Abstract A State of the Art lecture titled “Proteomics in Thrombosis Research” was presented at the ISTH Congress in 2021. In clinical practice, there is a need for improved plasma biomarker‐based tools for diagnosis and risk prediction of venous thromboembolism (VTE). Analysis of blood, to identify plasma proteins with potential utility for such tools, could enable an individualized approach to treatment and prevention. Technological advances to study the plasma proteome on a large scale allows broad screening for the identification of novel plasma biomarkers, both by targeted and nontargeted proteomics methods. However, assay limitations need to be considered when interpreting results, with orthogonal validation required before conclusions are drawn. Here, we review and provide perspectives on the application of affinity‐ and mass spectrometry‐based methods for the identification and analysis of plasma protein biomarkers, with potential application in the field of VTE. We also provide a future perspective on discovery strategies and emerging technologies for targeted proteomics in thrombosis research. Finally, we summarize relevant new data on this topic, presented during the 2021 ISTH Congress.

Abstract Background Navafenterol (AZD8871) is an inhaled long-acting dual-pharmacology muscarinic antagonist/β2-adrenoceptor agonist (MABA) in development for the treatment of obstructive airways diseases. The safety, tolerability, pharmacodynamics, and pharmacokinetics of navafenterol were investigated in patients with mild asthma. Methods This was a randomised, single-blind, placebo-controlled, single-ascending-dose study. Patients were randomly assigned to one of two cohorts which evaluated escalating doses of navafenterol (50–2100 μg) in an alternating manner over three treatment periods. The primary pharmacodynamic endpoint was the change from pre-dose baseline in trough forced expiratory volume in 1 s (FEV1) for each treatment period. Results Sixteen patients were randomised; 15 completed treatment. Data from all 16 patients were analysed. The maximum tolerated dose was not identified, and all doses of navafenterol were well tolerated. The most frequently reported treatment-emergent adverse events (TEAEs) were headache (n = 10, 62.5%) and nasopharyngitis (n = 7, 43.8%). No TEAEs were serious, fatal, or led to discontinuation, and no dose dependency was identified. Navafenterol demonstrated a dose-ordered bronchodilatory response with a rapid onset of action (within 5 min post-dose). Doses ≥200 μg resulted in improvements in trough FEV1 (mean change from baseline range 0.186–0.463 L) with sustained bronchodilation for 24–36 h. Plasma concentrations increased in a dose-proportional manner, peaking ~ 1 h post-dose, with a derived terminal elimination half-life of 15.96–23.10 h. Conclusions In this study navafenterol was generally well tolerated with a rapid onset of action which was sustained over 36 h. Trial registration ClinicalTrials.gov; No.: NCT02573155

This article is part of a doctoral research that has as its object of study the field of Teacher Education in Brazil, in particular the training offered by the Federal Institutes, created in 2008. The number of Teaching courses in this new locus has increased dramatically in recent years, becoming a fruitful environment for research, given its peculiar historical, political and social characteristics. The researches developed regarding the mathematics teacher training courses in this locus already point us in the direction of the training offered, establishing a state of knowledge. There is a formation not far from what has been offered for decades at Federal Universities, which puts into (re) discussion the real motivations for the insertion of Teaching courses in Federal Institutes.

Abstract Background Studies of individuals with autism spectrum disorder (ASD) have revealed a strong multigenic basis with the identification of hundreds of ASD susceptibility genes. ASD is characterized by social deficits and a range of other phenotypes, implicating complex genetics and involvement of a variety of brain regions. However, how mutations and mis-expression of select gene sets are associated with the behavioral components of ASD remains unknown. We reasoned that for genes to be associated with ASD core behaviors they must be: (1) expressed in brain regions relevant to ASD social behaviors and (2) expressed during the ASD susceptible window of brain development. Methods Focusing on the amygdala, a brain region whose dysfunction has been highly implicated in the social component of ASD, we mined publicly available gene expression databases to identify ASD-susceptibility genes expressed during human and mouse amygdala development. We found that a large cohort of known ASD susceptibility genes is expressed in the developing human and mouse amygdala. We further performed analysis of single-nucleus RNA-seq (snRNA-seq) data from microdissected amygdala tissue from five ASD and five control human postmortem brains ranging in age from 4 to 20 years to elucidate cell type specificity of amygdala-expressed genes and their dysregulation in ASD. Results Our analyses revealed that of the high-ranking ASD susceptibility genes, 80 are expressed in both human and mouse amygdala during fetal to early postnatal stages of development. Our human snRNA-seq analyses revealed cohorts of genes with altered expression in the ASD amygdala postnatally, especially within excitatory neurons, with dysregulated expression of seven genes predicted from our datamining pipeline. Limitations We were limited by the ages for which we were able to obtain human tissue; therefore, the results from our datamining pipeline approach will require validation, to the extent possible, in human tissue from earlier developmental stages. Conclusions Our pipeline narrows down the number of amygdala-expressed genes possibly involved in the social pathophysiology of ASD. Our human single-nucleus gene expression analyses revealed that ASD is characterized by changes in gene expression in specific cell types in the early postnatal amygdala.

Abstract Background Health-related quality of life (HRQoL) is defined as the patient’s perception of their health status. HRQoL can be modified by illnesses, treatments or social and health policies. Chronic musculoskeletal pain is a modifying factor of HRQoL that leads to lower quality of life, elevated suffering and disability. Knowing HRQoL in subjects reporting chronic musculoskeletal symptoms (cMSS), like pain, discomfort or swollenness lasting more than 3 months, will provide information to health teams and organizations engaged in the Chilean health system. This study aim was to determine the relationship between HRQoL and musculoskeletal symptoms measured in three different Chilean groups: [1] without symptoms; [2] with acute symptoms; and [3] with cMSS. Methods A secondary analysis of the 2009–10 Chilean National Health Survey (NHS) was executed to determine the relationship between HRQoL (measured with SF-12) in three MSS groups. The Chilean NHS considered a national, probabilistic, stratified and multistage sample of 5293 participants aged 15 and older; it was representative at the national, urban-rural and regional levels. A multivariate logistic regression model studied the relationship between cMSS and HRQoL, adjusted for age, sex, educational level and residence area as control variables (p

INTRODUCTION Ménière's disease is a multifactorial disorder affecting the inner ear, characterized by episodes of spontaneous and recurrent vertigo, fluctuating hearing loss and tinnitus. Intratympanic gentamicin therapy has been used to reduce the intensity and frequency of attacks in intractable Ménière's disease, but it is associated with hearing loss. There is controversy regarding its efficacy and safety. METHODS We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS We identified 13 systematic reviews that included 80 primary studies overall, of which three correspond to randomized trials. We concluded that intratympanic gentamicin may improve the control of vertigo, and result in little or no difference to tinnitus, but the certainty of the evidence is low. Furthermore, we are uncertain whether intratympanic gentamicin reduces hearing or the frequency of vertigo attacks as the certainty of the evidence has been assessed as very low.

Resumo: O objetivo deste estudo foi comparar os resultados obtidos para a coordenação do cuidado a partir do Programa Nacional de Melhoria do Acesso e da Qualidade da Atenção Básica (PMAQ-AB), com os parâmetros adotados pelo Atlas de Medidas de Coordenação do Cuidado e pelo Observatório Europeu de Políticas e Sistemas de Saúde. Foi realizado estudo transversal, com base no banco de dados do 3º ciclo do PMAQ-AB. Foram criadas três tipologias de coordenação do cuidado: PMAQ-AB, Atlas e Observatório. O teste qui-quadrado foi aplicado para comparar as proporções; os testes de Kruskal-Wallis e de Nemenyi para verificar e identificar eventuais diferenças entre as tipologias. O nível de significância foi de 5%. Foram avaliadas 35.350 equipes que realizaram alguma atividade de coordenação do cuidado. Observou-se diferença significativa (p < 0,001), entre os níveis de coordenação, com maior percentual entre o nível alto e médio nos três instrumentos, PMAQ-AB (56,07% e 38,35%), Atlas (52,63% e 40,66%) e o Observatório (44,82% e 43,98%). Na comparação dos indicadores, houve diferença significativa (p < 0,001) entre as tipologias. Para o Brasil, na tipologia PMAQ-AB, todos os estratos exibiram maior percentual entre o nível alto e médio; no Atlas, o estrato 1 destacou-se no nível médio (43,81%) e, no Observatório, predominou o nível alto. Na comparação dos indicadores por estratos, pelo menos um estrato diferiu dos demais (p < 0,001). O 6 se distinguiu dos demais (p < 0,001), e o 1 diferiu de todos (p < 0,001), exceto do 2 (p > 0,05). Os níveis de coordenação do cuidado diferenciaram-se entre os instrumentos utilizados. Altos e médios níveis foram identificados, demonstrando a necessidade de estudos adicionais.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extra-nodal non-Hodgkin lymphoma (NHL). It must be confined to the brain, eyes, spinal cord or leptomeninges without systemic involvement at the time of diagnosis. Disease confined to the cerebrospinal fluid (CSF) is a rare form of presentation and poses a particular diagnostic challenge. We present the case of an 82-year-old man admitted to hospital because of an acute confusional state, later revealed to be due to PCNSL with exclusive leptomeningeal involvement. The diagnostic process was further impaired (or, perhaps, aided?) by the onset of a COVID-19 outbreak on the ward.

Giant cell arteritis is the most common type of systemic vasculitis. An increased risk of venous thromboembolism has been described in these patients. We report the case of a 79-year-old woman with a history of polymyalgia rheumatica, who presented with left thoracic pain radiating to the neck and scapula plus temporal headache. She had no changes on physical examination, but work-up tests showed increased D-dimer levels and computed tomography pulmonary angiography revealed signs of a chronic/subacute embolism in the right inferior lobe. Anticoagulation with edoxaban was started after 5-day bridging with enoxaparin. Three weeks after the initial diagnosis the headache still persisted and she developed scalp tenderness. Giant cell arteritis was diagnosed and treated with prednisolone, with complete resolution of symptoms. Extensive diagnostic work-up was performed to identify an alternative cause of pulmonary thromboembolism; however, the investigations were negative. This case supports the hypothesis that this type of vasculitis could be related to the occurrence of pulmonary embolism.