CD40-CD154: A perspective from type 2 immunity.

The interaction between CD40 and CD154 (CD40 ligand) is central in immunology, participating in CD4+ T cell priming by dendritic cells (DC), CD4+ T cell help to B cells and classical macrophage activation by CD4+ T cells. However, its role in the Th2 side of immunology including helminth infection remains incompletely understood. Contrary to viral and bacterial stimuli, helminth products usually do not cause CD40 up-regulation in DC, and exogenous CD40 ligation drives Th2-biased systems towards Th1. On the other hand, CD40 and CD154 are necessary for induction of most Th2 responses. We attempt to reconcile these observations, mainly by proposing that (i) CD40 up-regulation in DC in Th2 systems is mostly induced by alarmins, (ii) the Th2 to Th1 shift induced by exogenous CD40 ligation is related to the capacity of such ligation to enhance IL-12 production by myeloid cells, and (iii) signals elicited by endogenous CD154 available in Th2 contexts and by exogenous CD40 ligation are probably different. We stress that CD40-CD154 is important beyond cognate cellular interactions. In such a context, we argue that the proliferation response of B-cells to IL-4 plus CD154 reflects a Th2-specific mechanism for polyclonal B-cell amplification and IgE production at infection sites. Finally, we argue that CD154 is a general immune activation signal across immune polarization including Th2, and propose that competition for CD154 at tissue sites may provide negative feedback on response induction at each site.

Psychosocial experiences of involuntary definitive childless women: a comparative study based on reproductive status.

STUDY QUESTION: Do involuntary definitive childless women have lower psychosocial adjustment levels than women with infertility diagnoses actively trying to conceive and presumably fertile women? SUMMARY ANSWER: Involuntary definitive childless women have lower levels of sexual functioning than infertile women actively trying to conceive and presumably fertile women, and higher levels of depression than presumably fertile women. WHAT IS KNOWN ALREADY: Involuntary definitive childless defines those who wanted to become parents but were unable to do so. Studies have provided evidence about infertility and its psychosocial consequences, but there is a lack of knowledge about the impact of involuntary definitive childlessness, namely on sexual function, social support, marital satisfaction, and psychological adjustment. STUDY DESIGN, SIZE, DURATION: This associative study was conducted between July 2021 and January 2022 for involuntary definitive childless women and between July 2016 and February 2018 for women with an infertility diagnosis actively trying to conceive as well as presumably fertile women. An online questionnaire announced in social media and gynaecology and fertility clinics was used. The inclusion criteria for all participants were being childless, in a heterosexual relationship and cohabiting for at least 2 years. Specific inclusion criteria for involuntary definitive childless women were: trying to conceive for at least 2 years; not achieving pregnancy because of biological and medical constraints; and not undergoing fertility treatment or being a candidate for adopting a child at time of the study. For women with an infertility diagnosis the inclusion criteria were: actively trying to conceive (naturally or through fertility treatments); having a primary fertility diagnosis; and aged between 22 and 42 years old. For presumably fertile women, the inclusion criteria were: having a parenthood wish in the future; and not knowing of any condition that could prevent them from conceiving. PARTICIPANTS/MATERIALS, SETTING, METHODS: Out of 360 women completing the survey, only 203 were eligible for this study (60 involuntary definitive childless women, 78 women with an infertility diagnosis actively trying to conceive, and 65 presumably fertile women). All participants completed a questionnaire including sociodemographic and clinical data, the Female Sexual Function Index, the 2-Way Social Support Scale, the Relationship Assessment Scale, and Hospital Anxiety and Depression Scale. Binary logistic regression was performed to assess the relation between sexual function, social support, marital satisfaction, anxiety, depression, and reproductive status, adjusting for age, and cohabitation length. Presumably fertile women were used as a reference group. MAIN RESULTS AND THE ROLE OF CHANCE: Women were 34.31 years old (SD = 5.89) and cohabited with their partners for 6.55 years (SD = 4.57). The odds ratio (OR) showed that involuntary definitive childless women had significantly lower sexual function than infertile women actively trying to conceive (OR = 0.88, 95% CI = 0.79-0.99) and presumably fertile women (OR = 34.89, 95% CI = 1.98-614.03), and higher depression levels than presumably fertile women (OR = 99.89, 95% CI = 3.29-3037.87). Women with an infertility diagnosis actively trying to conceive did not differ from presumably fertile women in sexual function, social support, marital satisfaction, anxiety, and depression. LIMITATIONS, REASONS FOR CAUTION: The majority of childless women underwent fertility treatments, and childlessness for circumstantial reasons owing to lack of a partner was not included, therefore these results may not reflect the experiences of all women with an involuntary childless lifestyle. There was a time gap in the recruitment process, and only the definitive childlessness group filled out the questionnaire after the coronavirus disease 2019 pandemic. We did not ask participants if they self-identified themselves with the groups' terminology they were assigned to. WIDER IMPLICATIONS OF THE FINDINGS: Our results emphasize the importance of future research to provide a more comprehensive understanding of the adjustment experiences of childless women and an awareness of the poor adjustment they might experience, highlighting the need to keep following women after unsuccessful treatments. Clinical practitioners must attend to these dimensions when consulting involuntary definitive childless women who might not have gone through treatments but also experience these adverse outcomes. STUDY FUNDING/COMPETING INTEREST(S): This study was partially supported by the Portuguese Foundation for Science and Technology. The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Fertility education: recommendations for developing and implementing tools to improve fertility literacy†.

Many recent societal trends have led to the need for fertility education, including the age at which individuals become parents, the development of new reproductive technologies, and family diversity. Fertility awareness has emerged as a concept very recently and is increasingly gaining recognition. However, fertility education is often neglected as there is no consensus on the appropriate content, target populations, or on who should provide it. This article attempts to provide an overview of the use of interventions to improve fertility education. We emphasize the importance of delivering evidence-based information on fertility and reproductive health through various methods while providing guidelines for their standardization and systematization. Recommendations are provided to aid the development and implementation of fertility education tools, including: the establishment of a comprehensive understanding of the target populations; the incorporation of theories of behavioural change; the inclusion of the users' perspectives and the use of participatory research; and the use of specific guidelines for increasing engagement. By following these recommendations, it is expected that fertility education resources can contribute to improving fertility literacy, empowering individuals and couples to make informed reproductive decisions, and ultimately reducing the incidence of infertility and need for fertility treatment.

Extracellular vesicles as modulators of monocyte and macrophage function in tumors.

The tumor microenvironment (TME) harbors several cell types, such as tumor cells, immune cells, and non-immune cells. These cells communicate through several mechanisms, such as cell-cell contact, cytokines, chemokines, and extracellular vesicles (EVs). Tumor-derived vesicles are known to have the ability to modulate the immune response. Monocytes are a subset of circulating innate immune cells and play a crucial role in immune surveillance, being recruited to tissues where they differentiate into macrophages. In the context of tumors, it has been observed that tumor cells can attract monocytes to the TME and induce their differentiation into tumor-associated macrophages with a pro-tumor phenotype. Tumor-derived EVs have emerged as essential structures mediating this process. Through the transfer of specific molecules and signaling factors, tumor-derived EVs can shape the phenotype and function of monocytes, inducing the expression of cytokines and molecules by these cells, thus modulating the TME towards an immunosuppressive environment.

Blood group is a long-term cardiovascular risk factor after carotid endarterectomy.

BACKGROUND: ABO blood group system has been clinically related to an increased incidence of cardiovascular diseases. Preliminary data relating Rhesus (Rh) factor and these outcomes also have been published. Our aim was to analyse the impact of blood group on the short and long-term outcomes after carotid endarterectomy (CEA). MATERIALS AND METHODS: From 2012 to 2019, patients from a referral centre who underwent CEA for atherosclerotic carotid stenosis were prospectively followed. Our primary outcomes were long-term major adverse cardiovascular events (MACEs) and all-cause mortality. Secondary outcomes were perioperative complications and myocardial injury after non-cardiac surgery (MINS). Median follow-up was 50 months (interquartile range 21-69). Time-to-event analysis was used to determine the effect of ABO and Rh groups in long-term outcomes. RESULTS: One hundred and eighty-four patients were included, with a mean age of 70.1 ± 9.1 years. Eighteen (25.7%) patients with O type and 48 (42.1%) patients with non-O type presented coronary artery disease (odds ratio [OR]: 2.313, 5-95% confidence interval (CI) 1.245-4.297, p = .008). Patients Rh+ presented significantly more congestive heart failure, 23 (14.7%), p = .03. The incidence of MACE in the long-term was higher in non-O patients (adjusted hazard ratio: 2.034; CI: 1.032-4.010, p = .040). Rh- patients, presented a higher incidence of perioperative MINS. However, there was no statistically significant association with long-term risk of MACE. CONCLUSION: The incidence of MACE in long-term analysis was higher in non-O blood type and 30-day MINS was significantly more common amongst Rh- patients. The benefit from a more complete preoperative cardiac study in these patients should be performed.

The use of integrative tools and multiple models for aquatic environmental quality assessment: a case study of the Mirim Lagoon, Southern Brazil.

This study performed toxicity assays with microalgae, microcrustaceans, and fish as well as evaluated biochemical and behavioral biomarkers in fish and microcrustaceans to assess the quality of the surface water of Mirim Lagoon, which belongs to one of the largest hydrographic basins in the world, located in southern Brazil. Three distinct sampling periods were chosen (January, March, and June 2022) based on the rice plantation dynamics which is the main activity surrounding the lagoon. In January, the plantation is irrigated; in March, the water is drained into the Mirim Lagoon, and July is the off-season. Concerning toxicity tests, there was significant inhibition in microalgae growth when exposed to water collected in March, but no mortality was observed for Ceriodaphia dubia, Daphnia magna, and Danio rerio. Regarding biomarkers, behavioral variables contributed more to the higher values of the Integrated Biomarker Response (IBR) index for both D. magna and D. rerio, in March. The Redundancy Analysis (RDA) indicated a correlation between the biomarkers for both organisms and abiotic parameters, mainly nutrients (total phosphorus and total nitrogen), thermotolerant coliforms, total solids, and turbidity. Spatially, there was no difference during monitoring, but the most significant ecotoxicological effects were observed in March. Multivariate analysis and the IBR index proved to be useful tools for monitoring of water bodies such as Mirim Lagoon.

Mucins Shed from the Laminated Layer in Cystic Echinococcosis Are Captured by Kupffer Cells via the Lectin Receptor Clec4F.

Cystic echinococcosis is caused by the larval stages (hydatids) of cestode parasites belonging to the species cluster Echinococcus granulosus sensu lato, with E. granulosus sensu stricto being the main infecting species. Hydatids are bladderlike structures that attain large sizes within various internal organs of livestock ungulates and humans. Hydatids are protected by the massive acellular laminated layer (LL), composed mainly of mucins. Parasite growth requires LL turnover, and abundant LL-derived particles are found at infection sites in infected humans, raising the question of how LL materials are dealt with by the hosts. In this article, we show that E. granulosus sensu stricto LL mucins injected into mice are taken up by Kupffer cells, the liver macrophages exposed to the vascular space. This uptake is largely dependent on the intact mucin glycans and on Clec4F, a C-type lectin receptor which, in rodents, is selectively expressed in Kupffer cells. This uptake mechanism operates on mucins injected both in soluble form intravenously (i.v.) and in particulate form intraperitoneally (i.p.). In mice harboring intraperitoneal infections by the same species, LL mucins were found essentially only at the infection site and in the liver, where they were taken up by Kupffer cells via Clec4F. Therefore, shed LL materials circulate in the host, and Kupffer cells can act as a sink for these materials, even when the parasite grows in sites other than the liver.

Hypertension depresses but exercise training restores both Mfsd2a expression and blood-brain barrier function within PVN capillaries.

Hypertension augments while exercise training corrects the increased vesicle trafficking (transcytosis) across the blood-brain barrier (BBB) within preautonomic areas and the autonomic imbalance. There is no information on a possible mechanism(s) conditioning these effects. Knowing that Mfsd2a is the major transporter of docosahexaenoic acid (DHA) and that Mfsd2a knockout mice exhibited leaky BBB, we sought to identify its possible involvement in hypertension- and exercise-induced transcytosis across the BBB. Spontaneously hypertensive rats (SHR) and Wistar rats were submitted to treadmill training (T) or kept sedentary (S) for 4 wk. Resting hemodynamic/autonomic parameters were recorded in conscious chronically cannulated rats. BBB permeability within the hypothalamic paraventricular nucleus (PVN) was evaluated in anesthetized rats. Brains were harvested for Mfsd2a and caveolin-1 (an essential protein for vesicle formation) expression. SHR-S versus Wistar-S exhibited elevated arterial pressure (AP) and heart rate (HR), increased vasomotor sympathetic activity, reduced cardiac parasympathetic activity, greater pressure variability, reduced HR variability, and depressed baroreflex control. SHR-S also showed increased BBB permeability, reduced Mfsd2a, and increased caveolin-1 expression. SHR-T versus SHR-S exhibited increased Mfsd2a density, reduced caveolin-1 protein expression, and normalized PVN BBB permeability, which were accompanied by resting bradycardia, partial AP drop, reduced sympathetic and normalized cardiac parasympathetic activity, increased HR variability, and reduced pressure variability. No changes were observed in Wistar-T versus Wistar-S. Training is an efficient tool to rescue Mfsd2a expression, which by transporting DHA into the endothelial cell reduces caveolin-1 availability and vesicles' formation. Exercise-induced Mfsd2a normalization is an important mechanism to correct both BBB function and autonomic control in hypertensive subjects.

Did the Use of Minimum Interventions for Caries Management Change during the COVID-19 Pandemic? A Cross-Sectional Study.

The aim of this study was to evaluate changes in the frequency of use of minimum intervention (MI) techniques for caries management during the COVID-19 pandemic. A questionnaire was applied through the SurveyMonkeyTM platform to evaluate changes in the dentist's frequency of use of noninvasive, microinvasive, minimally invasive, and mixed interventions, nonaerosol or aerosol productive, to manage dental caries before and during COVID-19 pandemic. Differences in the use of MI techniques were analyzed by Wilcoxon test, and the effect size (ES) was calculated. An α = 0.05 was adopted. A total of 781 dentists answered the questionnaire; most of them were female (76.4%), with 30s (76.4%), graduated over 10-24 years ago (38%) in public dental schools (62%), graduated in southwest of Brazil (38%), that work in clinical environment (66.8%) and in private jobs (53.4%). During COVID-19, among the sample, 91 respondents were not working. In relation to the noninvasive techniques, only the use of casein phosphopeptide amorphous calcium phosphate (CPP-ACP) decreased during the COVID-19 pandemic (p < 0.01; ES = 0.11). The frequency of sealants to repair defective restorations was the only microinvasive technique that increased during the pandemic (p < 0.01; ES = 0.03). Among the minimally invasive techniques, the use of atraumatic restorative treatment increased significantly (p < 0.01; ES = 0.06), while the use of air abrasion decreased (p = 0.02; ES = 0.04) during COVID-19 pandemic. Moreover, nonrestorative cavity control (mixed intervention) increased during pandemic period (p < 0.001; ES = 0.11). Although the results demonstrated differences in the use of some procedures, a very small magnitude of the effect was perceived, demonstrating that the influence of COVID-19 pandemic was very little, if any, in the use of MI techniques for caries management. Moreover, the use of MI strategies was already well established between Brazilian dentists before the pandemic period.

Blackberries and Mulberries: Berries with Significant Health-Promoting Properties.

Blackberries and mulberries are small and perishable fruits that provide significant health benefits when consumed. In reality, both are rich in phytochemicals, such as phenolics and volatile compounds, and micronutrients, such as vitamins. All the compounds are well-known thanks to their medicinal and pharmacological properties, namely antioxidant, anti-inflammatory, anti-cancer, antiviral, and cardiovascular properties. Nevertheless, variables such as genotype, production conditions, fruit ripening stage, harvesting time, post-harvest storage, and climate conditions influence their nutritional composition and economic value. Given these facts, the current review focuses on the nutritional and chemical composition, as well as the health benefits, of two blackberry species (Rubus fruticosus L., and Rubus ulmifolius Schott) and one mulberry species (Morus nigra L.).

A Novel Genetic Variant in MBD5 Associated with Severe Epilepsy and Intellectual Disability: Potential Implications on Neural Primary Cilia.

Disruptions in the MBD5 gene have been linked with an array of clinical features such as global developmental delay, intellectual disability, autistic-like symptoms, and seizures, through unclear mechanisms. MBD5 haploinsufficiency has been associated with the disruption of primary cilium-related processes during early cortical development, and this has been reported in many neurodevelopmental disorders. In this study, we describe the clinical history of a 12-year-old child harboring a novel MBD5 rare variant and presenting psychomotor delay and seizures. To investigate the impact of MBD5 haploinsufficiency on neural primary cilia, we established a novel patient-derived cell line and used CRISPR-Cas9 technology to create an isogenic control. The patient-derived neural progenitor cells revealed a decrease in the length of primary cilia and in the total number of ciliated cells. This study paves the way to understanding the impact of MBD5 haploinsufficiency in brain development through its potential impact on neural primary cilia.

Impact of bone-anchored maxillary protraction on the quality of life of subjects with complete unilateral cleft lip and palate.

INTRODUCTION: This study aimed to evaluate the influence of bone-anchored maxillary protraction (BAMP) on the oral health-related quality of life (OHRQOL) in subjects with complete unilateral cleft lip and palate (UCLP) and moderate-to-severe maxillary deficiency. METHODS: A longitudinal observational study was conducted with a sample of 20 patients (13 males, 7 females) aged 10-14 years (mean age, 11.8 years) with Goslon 3, 4, and 5. To assess the patient's perception of their OHRQOL, the Quality of Life Questionnaire for Orthosurgical Patients was administered in 2 stages: after the installation of the protraction plates (T1) and 18 months after the protraction therapy started (T2). The questionnaire was composed of 4 domains, distributed over 22 questions: social aspects, facial esthetics, oral function, and awareness of facial deformity. RESULTS: The treatment protocol improved the OHRQOL in 75% of the patients who presented UCLP. The domain social aspects of the deformity were the only one that showed a significant difference from T1 to T2 and indicated an improvement in self-esteem. The girls had worse OHRQOL than boys at T1, which was statistically significant only for the domains of social aspects of deformity and awareness of deformity. After BAMP therapy, the effect size indicated a larger change in OHRQOL in girls than in boys. CONCLUSIONS: BAMP therapy positively impacted the OHRQOL and self-esteem of patients with UCLP during adolescence.

The copita question: Exploring alcohol consumption among Latina women.

We explored whether Dominican women underreport alcohol consumption according to questionnaire wording and examined factors associated with their alcohol use through structured interviews in Spanish. We measured consumption with the word "alcohol" and with the common colloquialisms "copita/trago/vinito." We used logistic regressions to examine associations between alcohol consumption, demographics, and alcohol-related norms. Of 419 female participants, 411 completed alcohol-related questions. Most (n=343, 83.5%) were current drinkers and 88 (21%) reported having never consumed alcohol but also that they occasionally drink a "copita/trago/vinito." This indicates alcohol use is potentially underreported among Dominican women. Alcohol-related research should incorporate culturally sensitive language to improve accuracy.

Impact of Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy in the Treatment of Gastric Cancer with Peritoneal Carcinomatosis: A Systematic Review and Meta-analysis.

BACKGROUND: Despite promising results, the effectiveness of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with gastric cancer with peritoneal carcinomatosis (GCPC) has not been systematically evaluated. The aim of this systematic review is to compare the survival, complications and risk of recurrence between CRS + HIPEC versus CRS alone in GCPC. PATIENTS AND METHODS: A systematic review was performed in MEDLINE and Web of Science according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Primary studies with patients with GCPC older than 18 years were included. Methodological Index for Non-randomized Studies (MINORS) criteria were used to assess the quality of the studies. We performed random-effects meta-analysis of risk ratios (RR). We assessed heterogeneity using the I2 statistic. RESULTS: Five studies were included in the qualitative and four in the quantitative analysis. The overall survival (OS) rate after 1 year was 3.65 times higher for CRS + HIPEC than CRS alone [RR = 3.65, 95% confidence interval (95% CI) = 1.01-13.26, I2 = 73%]. The OS rate after 5 years was more than three times higher for CRS + HIPEC than for CRS alone (RR = 3.25, 95% CI = 1.28-8.26, I2 = 8%). No significant differences between CRS + HIPEC and CRS alone related to complications were found (RR = 1.05, 95% CI = 0.83-1.33, I2 = 0%). The risk of peritoneal recurrence was significantly lower for CRS + HIPEC than for CRS alone (RR = 0.23, 95% CI = 0.11-0.48, I2 = 40%). The results may be associated with some information or indication bias. CONCLUSIONS: Results should be analysed cautiously given the detected heterogeneity and limitations of included studies. However, treatment with CRS + HIPEC seems to increase the survival of patients with GCPC, more than treatment with CRS alone, decrease the risk of peritoneal recurrence and not be associated with more complications.

Effects of trying to conceive using an every-other-day strategy versus fertile window monitoring on stress: a 12-month randomized controlled trial.

STUDY QUESTION: Can animation videos on how to optimize the chances of pregnancy influence stress, anxiety, depression and sexual functioning of individuals trying to conceive (TTC)? SUMMARY ANSWER: There were no differences between those educated to have intercourse every other day, on the fertile window and a control group (CG), and depression and sexual dysfunction significantly increased over time for all arms. WHAT IS KNOWN ALREADY: Recent findings indicate that time to pregnancy can be significantly shortened by targeting the fertile period, but some reproductive care guidelines recommend instead the practice of intercourse every other day on the basis that it is less stressful to the couple. Evidence to support guidelines on how to preserve well-being and psychosocial adjustment and optimize pregnancy chances is lacking. STUDY DESIGN, SIZE, DURATION: We conducted a prospective, double-blinded, three-arm randomized controlled trial between July 2016 and November 2019. Participants were randomized to either not having any stimulus (CG) or visualizing a short animated video explaining how to improve chances of pregnancy by having intercourse every other day (EOD group), or by monitoring the fertile window (FWM group). Assessments were made before the intervention (T0), and 6 weeks (T1), 6 months (T2) and 12 months after (T3), with follow-ups censored in case of pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were childless individuals of reproductive age actively TTC and not diagnosed or unaware of a condition that could prevent spontaneous pregnancy. Individuals were excluded from recruitment if they had previous children or had a condition preventing spontaneous pregnancy. Our primary outcome was stress and secondary outcomes included anxiety, depression, sexual functioning and pregnancy. Primary analyses were performed according to intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 450 randomized participants 127 were educated to use an every-other-day strategy, 135 to monitor the fertile window, and 134 received no intervention. Groups were similar regarding demographics and months TTC. Repeated measures analysis revealed that there were no significant interaction effects of psychological and sexual well-being between groups over time (P > 0.05). Significant time effects were revealed for stress (F(3,855) = 4.94, P < 0.01), depression (F(3,855) = 14.22, P < 0.01) and sexual functioning (time effects P values <0.001 for female sexual functioning dimensions and <0.002 for male dimensions), but not for anxiety (F(2,299) = 0.51, P > 0.05). Stress levels lowered after 6 months (P < 0.001) and returned to baseline levels at the 1-year follow-up. Depressive symptomatology significantly increased at 6 weeks (P = 0.023), and again 1 year after (P = 0.001). There were also significant decreases in all female sexual functioning dimensions (desire, satisfaction, arousal, pain, orgasm and lubrication). In men, there were significant variations in orgasm, intercourse satisfaction and erectile function, but not desire and sexual satisfaction. Revealed pregnancy rates were 16% for participants in the EOD group, 30% for the FWM group and 20% for the CG. Pregnancies were not significantly different between arms: EOD vs FWM (odds ratio (OR) 2.32; 95% CI 0.92-5.83); EOD vs CG (OR 0.74; 95% CI 0.30-1.87); and FWM vs CG (OR 1.71; 95% CI 0.70-4.18). LIMITATIONS, REASONS FOR CAUTION: Participants were recruited after transitioning to procreative sex. The study might be prone to bias as almost 30% of our sample fulfilled the chronological criterion for infertility, and other reproductive strategies could have been tried over time before recruitment. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggest that stress does not arise from feeling pressured on the fertile period and that advice on timing of intercourse might have to be personalized. The increasing levels of depression and sexual dysfunction over a year emphasize the crucial role of preconception care and fertility counseling in promoting psychological and sexual well-being. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by European Union Funds (FEDER/COMPETE-Operational Competitiveness Programme) and by national funds (FCT-Portuguese Foundation for Science and Technology) under the projects PTDC/MHC-PSC/4195/2012 and SFRH/BPD/85789/2012. TRIAL REGISTRATION NUMBER: NCT02814006. TRIAL REGISTRATION DATE: 27 June 2016. DATE OF FIRST PATIENT'S ENROLLMENT: 19 July 2016.

Influence of clinical and demographic factors on the oral health-related quality of life of patients with cleft lip and palate undergoing orthodontic treatment: a systematic review and meta-analysis.

OBJECTIVE: The purpose of this study was to evaluate the influence of orthodontic treatment on the oral health-related quality of life (OHRQoL) of patients with cleft lip and palate. SEARCH METHODS: Electronic searches were conducted in Pubmed, Scopus, Web of Science, Cochrane Library, VHL, and OpenGrey databases, completed in January 2021. SELECTION CRITERIA: Cross-sectional and longitudinal observational studies that presented an assessment of OHRQoL in cleft patients undergoing orthodontic treatment were included, according to PRISMA guidelines. Contacts via email were made with authors, to clarify inaccuracies or request additional data. DATA COLLECTION AND ANALYSIS: The entire process was accomplished by two authors, in case of disagreement, a third author mediated the discussion until there was a consensus. Risk assessment was performed by the Fowkes and Fulton qualifier, and the quality of evidence, assessed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) tool. A meta-analysis was performed considering the domains combined into three large groups (physical, psychological, and social). The questionnaires were standardized as to the scores and their direction. RESULTS: A total of 3822 studies were retrieved. After excluding duplicates, the titles and abstracts of the remaining articles were analysed. Twenty-eight articles were read in full; 13 met the eligibility criteria; 12 articles showed sufficient methodological quality and 7 were included in the quantitative assessment. The included studies were published between 2011 and 2019. The samples comprised 19 to 183 patients of both sexes. GRADE showed low evidence when compared to the control group, sexes, age, and types of cleft and very low evidence among longitudinal articles. CONCLUSIONS: The OHRQoL is lower in orthodontic patients with cleft than in those without. The OHRQoL of patients with cleft undergoing orthodontic treatment is not influenced by gender or age group, considering children and adolescents, but it is influenced by the type of cleft. The OHRQoL of patients with CLP does not undergo significant changes during orthodontic treatment. LIMITATIONS: The variety of instruments for measuring OHRQoL rendered meta-analysis difficult. REGISTRATION: PROSPERO database number CRD42017054764.

The remodel of the "central dogma": a metabolomics interaction perspective.

BACKGROUND: In 1957, Francis Crick drew a linear diagram on a blackboard. This diagram is often called the "central dogma." Subsequently, the relationships between different steps of the "central dogma" have been shown to be considerably complex, mostly because of the emerging world of small molecules. It is noteworthy that metabolites can be generated from the diet through gut microbiome metabolism, serve as substrates for epigenetic modifications, destabilize DNA quadruplexes, and follow Lamarckian inheritance. Small molecules were once considered the missing link in the "central dogma"; however, recently they have acquired a central role, and their general perception as downstream products has become reductionist. Metabolomics is a large-scale analysis of metabolites, and this emerging field has been shown to be the closest omics associated with the phenotype and concomitantly, the basis for all omics. AIM OF REVIEW: Herein, we propose a broad updated perspective for the flux of information diagram centered in metabolomics, including the influence of other factors, such as epigenomics, diet, nutrition, and the gut- microbiome. KEY SCIENTIFIC CONCEPTS OF REVIEW: Metabolites are the beginning and the end of the flux of information.

NEK1 deficiency affects mitochondrial functions and the transcriptome of key DNA repair pathways.

Previous studies have indicated important roles for NIMA-related kinase 1 (NEK1) in modulating DNA damage checkpoints and DNA repair capacity. To broadly assess the contributions of NEK1 to genotoxic stress and mitochondrial functions, we characterised several relevant phenotypes of NEK1 CRISPR knockout (KO) and wild-type (WT) HAP1 cells. Our studies revealed that NEK1 KO cells resulted in increased apoptosis and hypersensitivity to the alkylator methyl methanesulfonate, the radiomimetic bleomycin and UVC light, yet increased resistance to the crosslinker cisplatin. Mitochondrial functionalities were also altered in NEK1 KO cells, with phenotypes of reduced mitophagy, increased total mitochondria, elevated levels of reactive oxygen species, impaired complex I activity and higher amounts of mitochondrial DNA damage. RNA-seq transcriptome analysis coupled with quantitative real-time PCR studies comparing NEK1 KO cells with NEK1 overexpressing cells revealed that the expression of genes involved in DNA repair pathways, such as base excision repair, nucleotide excision repair and double-strand break repair, are altered in a way that might influence genotoxin resistance. Together, our studies underline and further support that NEK1 serves as a hub signalling kinase in response to DNA damage, modulating DNA repair capacity, mitochondrial activity and cell fate determination.

Clinical utility of the imunohistochemical co-expression of p53 and MDM2 in thyroid follicular lesions.

In order to investigate the possible correlation between p53 and MDM2 co-expression with clinicopathological features of differentiated thyroid cancer (DTC) and its use as diagnostic and/or prognostic markers, we used immunohistochemistry to evaluate 317 thyroid samples including 208 DTC and 94 benign nodules, in addition to 15 normal tissues. MDM2 and p53 expression were highly associated (r = 0.7161; p < 0.0001). The co-expression of p53-MDM2 was observed more frequently in malignant lesions (p < 0.0001) and helped characterize follicular patterned lesions distinguishing FVPTC from FA (p < 0.0001) and FVPTC from FTC (p < 0.0001). In addition, p53-MDM2 co-expression was associated with characteristics of less aggressiveness. It was more frequent in patients ≤45 years old (p = 0.0035), with unique tumors (p = 0.0095), tumors <2 cm (p < 0.0001), tumors without extrathyroid invasion (p = 0.0425), without metastasis at evolution (p = 0.0179), and in patients evolving free of disease after treatment (p = 0.0485). We suggest that p53-MDM2 co-expression profile analysis might help establishing diagnostic and determining prognostic of DTC patients.

Congenital Toxoplasmosis: Missed Opportunities for Diagnosis and Prevention.

OBJECTIVES: Identify missed opportunities for the prevention and early diagnosis of congenital toxoplasmosis (CT) in infants followed up in a reference center for pediatric infectious diseases (PID) in Rio de Janeiro between January 2007 and December 2016. METHODS: Descriptive study including infants with CT, diagnosis established based on Brazil's Ministry of Health's criteria. All data regarding the infants and their mother's prenatal care were collected from the medical records of the Instituto de Puericultura e Pediatria Martagão Gesteira (IPPMG)-a tertiary public pediatric university hospital. The study enrolled infants aged between 0 and 12 months followed up in the PID department of IPPMG and with confirmed infection by Toxoplasma gondii in the period between January 2007 and December 2016. All patients with diagnosis of CT registered in the PID database of the IPPMG and admitted in the above-mentioned period were included in the study. Patients whose records were not available, or who went to just one clinic appointment were excluded. RESULTS: The obstetric history of all 44 women, whose infants (45) were diagnosed with CT, was analyzed. Their median age was 22 years. None had undergone preconception serological testing for toxoplasmosis. Only 20 (45%) of them started antenatal care during the first trimester of gestation, a total of 24 (55%) had more than six antenatal care visits, and 16% of those did not undergo serological testing for toxoplasmosis. None were adequately informed of preventive measures. The diagnosis of acute toxoplasmosis was made in 50% of these pregnancies but 32% of the women were not treated. Only 10 children of these mothers were adequately screened and treated at birth. CONCLUSION: Despite the existence of national recommendations, several opportunities were missed to prevent CT during the antenatal period and to diagnose and treat this condition in the neonatal period.