The impact of the obesity onset on the inflammatory and glycemic profile of women with severe obesity.

BACKGROUND: The stage of life at the onset of obesity is an important factor in assessing inflammatory state and cardiometabolic risk. OBJECTIVES: This study aimed to evaluate the relationship between the obesity onset and the inflammatory profile in women with severe obesity. SETTING: Public hospital, Brazil. METHODS: Forty-eight women with severe obesity (20-59 yr old) were evaluated according to weight, height, neck circumference (NC), waist circumference (WC), and hip circumference, as well blood metabolic and inflammatory parameters. The participants were grouped according to obesity onset stage of life (early group: ≤19 yr; late group: >19 yr). RESULTS: The demographic means of the participants were: age of 39.7 years, weight of 122.7 kg and body mass index (BMI) of 48.4 kg/m2. The late group presented significantly higher values of leptin (lep)/adiponectin (adipo) ratio and homeostatic model assessment for insulin resistance (HOMA-IR) than the early group. The late group also had a lower adipo/lep ratio. Moreover, the late group showed correlations between the lep/adipo ratio and BMI (r = .460, P = .021), NC (r = .478, P = .016), and WC (r = .535, P = .006). Adipo was also correlated with NC (r = -.418, P = .038), WC (r = -.437, P = .029), and glycated hemoglobin (HbA1C) (r = -.485, P = .019). By contrast, in the early group, the lep/adipo ratio showed correlations with insulin (r = .647, P = .004) and HOMA-B (r = .564, P = .015). CONCLUSIONS: The inflammatory profile is correlated with anthropometric values in women with late-onset obesity. Inflammatory markers seemed to correlate with the glycemic profile in women with early-onset obesity. Furthermore, inflammation was higher in women with late-onset obesity compared to those with early-onset obesity.

The search for an antiviral lead molecule to combat the neglected emerging Oropouche virus.

Oropouche virus (OROV) is a member of the Peribunyaviridae family and the causative agent of a dengue-like febrile illness transmitted by mosquitoes. Although mild symptoms generally occur, complications such as encephalitis and meningitis may develop. A lack of proper diagnosis, makes it a potential candidate for new epidemics and outbreaks like other known arboviruses such as Dengue, Yellow Fever and Zika virus. The study of natural molecules as potential antiviral compounds is a promising alternative for antiviral therapies. Wedelolactone (WDL) has been demonstrated to inhibit some viral proteins and virus replication, making it useful to target a wide range of viruses. In this study, we report the in silico effects of WDL on the OROV N-terminal polymerase and its potential inhibitory effects on several steps of viral infection in mammalian cells in vitro, which revealed that WDL indeed acts as a potential inhibitor molecule against OROV infection.

A Mechanistic Analysis of the Neural Modulation of the Inflammatory System Through Vagus Nerve Stimulation: A Systematic Review and Meta-analysis.

OBJECTIVE: We aimed to conduct a systematic review and meta-analysis assessing the antiinflammatory effects of various VNS methods while exploring multiple antiinflammatory pathways. MATERIALS AND METHODS: We included clinical trials that used electrical stimulation of the vagus nerve and assessed inflammatory markers up to October 2022. We excluded studies lacking control groups, those with combined interventions, or abstracts without full text. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Cochrane Handbook for Systematic Reviews. For each inflammatory marker, a random-effects meta-analysis using the inverse variance method was performed. Methods used include transcutaneous auricular VNS (taVNS), transcutaneous cervical VNS (tcVNS), invasive cervical VNS (iVNS), and electroacupuncture VNS (eaVNS). Main reported outcomes included tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1ß, C-reactive protein (CRP), and IL-10. Risk of bias was evaluated using the Cochrane Collaboration Tool (RoB 2.0). RESULTS: This review included 15 studies, involving 597 patients. No statistically significant general VNS effect was observed on TNF-α, IL-6, and IL-1ß. However, CRP, IL-10, and interferon (IFN)-γ were significantly modulated by VNS across all methods. Subgroup analysis revealed specific stimulation techniques producing significant results, such as taVNS effects in IL-1ß and IL-10, and iVNS in IL-6, whereas tcVNS and eaVNS did not convey significant pooled results individually. Cumulative exposure to VNS, higher risk of bias, study design, and pulse width were identified as effect size predictors in our meta-regression models. CONCLUSIONS: Pooling all VNS techniques indicated the ability of VNS to modulate inflammatory markers such as CRP, IL-10, and IFN-γ. Individually, methods such as taVNS were effective in modulating IL-1ß and IL-10, whereas iVNS modulated IL-6. However, different VNS techniques should be separately analyzed in larger, homogeneous, and powerful studies to achieve a clearer and more consistent understanding of the effect of each VNS method on the inflammatory system.

Anti-leishmanial activity of Eleutherine plicata Herb. and predictions of isoeleutherin and its analogues.

Introduction: Leishmaniasis is caused by protozoa of the genus Leishmania, classified as tegumentary and visceral. The disease treatment is still a serious problem, due to the toxic effects of available drugs, the costly treatment and reports of parasitic resistance, making the search for therapeutic alternatives urgent. This study assessed the in vitro anti-leishmanial potential of the extract, fractions, and isoeleutherin from Eleutherine plicata, as well as the in silico interactions of isoeleutherin and its analogs with Trypanothione Reductase (TR), in addition to predicting pharmacokinetic parameters. Methods: From the ethanolic extract of E. plicata (EEEp) the dichloromethane fraction (FDEp) was obtained, and isoeleutherin isolated. All samples were tested against promastigotes, and parasite viability was evaluated. Isoeleutherin analogues were selected based on similarity in databases (ZINK and eMolecules) to verify the impact on structural change. Results and Discussion: The extract and its fractions were not active against the promastigote form (IC50 > 200 µg/mL), while isoeleutherin was active (IC50 = 25 µg/mL). All analogues have high intestinal absorption (HIA), cell permeability was moderate in Caco2 and low to moderate in MDCK. Structural changes interfered with plasma protein binding and blood-brain barrier permeability. Regarding metabolism, all molecules appear to be CYP3A4 metabolized and inhibited 2-3 CYPs. Molecular docking and molecular dynamics assessed the interactions between the most stable configurations of isoeleutherin, analogue compound 17, and quinacrine (control drug). Molecular dynamics simulations demonstrated stability and favorable interactions with TR. In summary, fractionation contributed to antileishmanial activity and isoleutherin seems to be promising. Structural alterations did not contribute to improve pharmacokinetic aspects and analogue 17 proved to be more promising than isoeleutherin, presenting better stabilization in TR.

Dental Students' and Dental School Graduates' Practical Skills: An International Survey of Perceptions of National Dental Associations in Europe.

PURPOSE: Dental students learn knowledge and practical skills to provide oral health care to the population. Practical skills must be maintained or continuously developed throughout a professional career. This cross-sectional survey aimed to evaluate the perception of practical skills of dental students and dental-school graduates by national dental associations (NDAs) in international comparison in the European Regional Organization of the FDI World Dental Federation (ERO-FDI) zone. MATERIALS AND METHODS: A questionnaire of 14 items collected information on pre-/postgraduate areas. RESULTS: A total of 25 countries participated (response rate: 69.4%), with 80.0% having minimum requirements for practical skills acquisition and 64.0% starting practical training in the 3rd year of study. In countries where clinical practical work on patients begins in the 2nd year of study, practical skills of graduates are perceived as average, starting in the 3rd year of study as mainly good, starting in the 4th as varying widely from poor to very good. In total, 76.0% of respondents feel that improvements are needed before entering dental practice. Improvements could be reached by treating more patients in dental school (32.0%), increasing the quantity of clinical training (20.0%), or having more clinical instructors (12.0%). In 56.0% of the countries, it is possible to open one's own dental practice immediately after graduation, and in 16.0%, prior vocational training is mandatory. CONCLUSIONS: All participating countries in the ERO-FDI zone reported practical training in dental school, most starting in the 3rd year of study. The perception of practical skills of dental students and dental-school graduates among NDAs is very heterogeneous. Reasons for the perceived deficiencies should be further explored.

Development of Tooth Brushing Recommendations Through Professional Consensus.

INTRODUCTION: Despite being a largely preventable disease, untreated caries of permanent teeth is estimated to affect almost 2 billion people worldwide, which is followed by severe periodontal disease. The aim of this work was to provide a professional consensus on tooth brushing methods and associated oral hygiene behaviours and develop evidence-informed recommendations. METHODS: An initial scoping search was undertaken to identify systematic reviews of relevance and key questions. This was followed by comprehensive evidence mapping of the literature focussing on systematic reviews and clinical guidelines. Electronic searches of several databases including MEDLINE (via Ovid), Embase (via Ovid), Epistemonikos, and The Cochrane Library were undertaken from 2000 to May 2022, alongside a guideline repository search. Considered Judgement Forms were developed detailing the underpinning evidence, balance between benefits and harms, potential impact on the population, and feasibility of implementation. An online survey comprising 22 draft recommendations was distributed to international members of all FDI committees, including the FDI Council. Participants were asked to indicate to what level they agreed or disagreed with for each recommendation and to provide feedback. The Considered Judgement Forms were provided for reference. RESULTS: Three hundred ten records were identified and mapped to different aspects of tooth brushing methods and associated behaviours. Research literature informed 7 Considered Judgement Forms comprising 12 questions with draft recommendations. Twenty-five participants from Asia, Europe, North and South America, Africa, and Australia provided feedback on the recommendations. More than 70% of respondents showed agreement with 21 of the 22 draft recommendations. Final recommendations were drafted with associated strength of recommendation. CONCLUSION: Using a robust methodology and an international professional consensus, a set of evidence-informed recommendations was developed. These recommendations provide clinicians with practical guidance to facilitate communications with patients that may help to reinforce individual-level preventive strategies.

Functional and Neural Correlates Associated with Conditioned Pain Modulation in Patients with Chronic Knee Osteoarthritis Pain: A Cross-Sectional Study.

Background: In this study, we aimed to assess the factors that predict a dysfunctional conditioned pain modulation (CPM) in chronic knee OA. Methods: This is a cross-sectional analysis of patients with chronic knee OA from a prospective cohort study in Brazil (n = 85). We performed linear and logistic multivariate regression models using the purposeful selection approach to test the relationship between the CPM in both knees (average) as a dependent variable and demographics, clinical, and neurophysiological as independent variables. Results: A significant negative association between WOMAC pain scores and CPM (ß: -0.13) was found. This association was modified by the subjects' race, being stronger in the non-white subjects. In our logistic regression models, pain intensity indexed with the WOMAC pain scale remained a significant association with dichotomized CPM. Furthermore, a significant CPM association with balance, indexed with the Berg Balance score, was evidenced (ß: 0.04). Neurophysiological variables showed a significant negative relationship with CPM, such as the relative power of delta oscillations in the frontal area (ß: -3.11) and central area (ß: -3.23). There was no significant relationship between CPM and the following domains: cognitive, emotion, sleep, opioid receptor polymorphisms, and intrinsic variables of OA disease. There was no association of CPM with TMS-indexed inhibitory markers. Conclusions: These results may indicate that less function of the pain descending inhibitory system in patients with OA is correlated with higher activity-related pain (WOMAC), less balance, and cortical plasticity especially with increased low-frequency (delta) brain oscillations. These associations seem modified by race.

Could retrograde reperfusion combined with washout technique broaden the applicability of marginal grafts in liver transplantation? Intra-operative and short-term outcomes of a prospective cohort.

INTRODUCTION: many revascularization techniques were designed to reduce the imbalance of ischemia-reperfusion injury. This study's objective is to evaluate retrograde reperfusion (RR) compared to sequential anterograde reperfusion (AR), with and without the washout technique (WO). METHOD: this prospective cohort study collected data from 94 deceased donor orthotopic liver transplants and divided it into three groups: RR with WO (RR+WO), AP with WO (AR+WO), and AP without WO (AR). This study did not assign the reperfusion technique to the participants. The primary outcome considered the early graft dysfunction, and secondary outcomes included post-reperfusion syndrome (PRS), post-reperfusion lactate, surgery fluid balance, and vasoactive drug dose during the surgery. RESULTS: 87 patients were submitted to the final analysis-29 in the RR+WO group, 27 in the AR+WO group, and 31 in the AR group. Marginal grafts prevalence was not significantly different between the groups (34% vs. 22% vs. 23%; p=0.49) and early graft dysfunction occurred at the same rate (24% vs. 26% vs. 19%; p=0.72). RR+WO reduced serum post-reperfusion lactate (p=0.034) and the incidence of significant PRS (17% vs. 33% vs. 55%; p=0.051), but norepinephrine dosing >0.5mcg/kg/min were not different during the surgery (20,7% vs. 29,6% vs. 35,5%, p=0.45). CONCLUSIONS: primary outcome was not significantly different between the groups; however, intraoperative hemodynamic management was safer using the RR+WO technique. We theorized that the RR+WO technique could reduce the incidence of PRS and benefit marginal graft survival following diseased donor orthotopic liver transplantation.

Understanding the Neuroplastic Effects of Auricular Vagus Nerve Stimulation in Animal Models of Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: Transauricular vagus nerve stimulation (taVNS) is being studied as a feasible intervention for stroke, but the mechanisms by which this non-invasive technique acts in the cortex are still broadly unknown. OBJECTIVES: This study aimed to systematically review the current pre-clinical evidence in the auricular vagus nerve stimulation (aVNS) neuroplastic effects in stroke. METHODS: We searched, in December of 2022, in Medline, Cochrane, Embase, and Lilacs databases. The authors executed the extraction of the data on Excel. The risk of bias was evaluated by adapted Cochrane Collaboration's tool for animal studies (SYRCLES's RoB tool). RESULTS: A total of 8 studies published between 2015 and 2022 were included in this review, including 391 animal models. In general, aVNS demonstrated a reduction in neurological deficits (SMD = -1.97, 95% CI -2.57 to -1.36, I2 = 44%), in time to perform the adhesive removal test (SMD = -2.26, 95% CI -4.45 to -0.08, I2 = 81%), and infarct size (SMD = -1.51, 95% CI -2.42 to -0.60, I2 = 58%). Regarding the neuroplasticity markers, aVNS showed to increase microcapillary density, CD31 proliferation, and BDNF protein levels and RNA expression. CONCLUSIONS: The studies analyzed show a trend of results that demonstrate a significant effect of the auricular vagal nerve stimulation in stroke animal models. Although the aggregated results show high heterogeneity and high risk of bias. More studies are needed to create solid conclusions.

Combined liver-kidney transplant in polycystic diseases: a case report.

Polycystic liver disease, a hereditary pathology, usually manifests as autosomal dominant polycystic kidney disease. The many cysts in the liver cause massive hepatomegaly, majorly affecting the patient's quality of life. In cases of refractory symptoms, liver transplantation is the only treatment choice. A 43-year-old woman was followed up as a hepatology outpatient in August 2020, with a progressive increase in abdominal volume, lower limb edema, and cachexia. The patient was diagnosed with polycystic renal and liver disease with massive hepatomegaly in March 2021, a combined kidney-liver transplant. Liver size represented 13% of the patient's corporal composition, weighing 8.6kg. The patient was discharged on the 7th postoperative day with no complications. Only 10-20% of patients with polycystic liver disease have clinical manifestations, most of which result from hepatomegaly. An increase in liver volume deteriorates liver function until the condition becomes end-stage liver disease, as kidney function is already compromised; liver-kidney transplantation remains the only treatment choice. The case described drew significant attention to the massive hepatomegaly presented in the patient, with the liver representing over 10% of the patient's body weight, approximately five to six times larger than a normal-sized liver.

Evaluation of patients treated by telemedicine in the beginning of the COVID-19 pandemic in São Paulo, Brazil: A non-randomized clinical trial preliminary study.

We performed a pilot open-label, non-randomized controlled clinical trial in a clinic in São Paulo, Brazil in the beginning of the COVID-19 pandemic. "This medical pilot project was carried out during the pandemic of a new and unknown agent. It was necessary to find a new and safe therapeutic approach for pathogens with high potential for severity and contamination. The repositioning of safe and accessible pre-existing and approved medications and the telemedicine approach improved treated covid patients' symptoms and reduced the risk of disease transmission. The emergency application of a new medical technology was the major limitation of the study. This innovative care model is a low-cost safe strategy, and we understand that applicability can be expanded to other regions in emergency situations." The 187 patients of the study (mean age of 37.6 ± 15,6 years) were divided into four groups: (1) asymptomatic, (2) mild symptoms, (3) moderate symptoms and (4) severe symptoms and were followed up for five days. A drug intervention was performed in group 3 and the patients of Group 4 were oriented to seek hospital care. Of all the patients, 23.0% were asymptomatic, 29.4% reported mild symptoms, 43.9% moderate symptoms and 3.7% severe symptoms. Three patients were hospitalized and discharged after recovery. Our results indicate that the use of telemedicine with diagnosis and drug treatment is a safe and effective strategy to reduce overload of health services and the exposure of healthcare providers and the population. The patients that initiated the treatment in the early stages of the disease presented satisfactory clinical response, reducing the need of face-to-face consultations and hospitalizations. The patients who followed the protocol treatment for COVID-19 with hydroxychloroquine and azithromycin for five days presented statistically significant improvement of clinical symptoms when compared to moderate patients who opted for not following the protocol (p < 0.05) and to all no treatment patients (p < 0.001).

S100A9 Drives the Chronification of Psoriasiform Inflammation by Inducing IL-23/Type 3 Immunity.

Psoriasis is a chronic inflammatory skin disorder driven by the IL-23/type 3 immune response. However, molecular mechanisms sustaining the chronicity of inflammation and psoriatic lesions remain elusive. Combining systematic analyses of several transcriptomic datasets, we delineated gene signatures across human psoriatic skin, identifying S100A9 as one of the most up-regulated genes, which was confirmed in lesioned skin from patients with psoriasis and preclinical psoriasiform skin inflammation models. Genetic ablation or pharmacologic inhibition of S100A9 alleviated Aldara-induced skin inflammation. By single-cell mapping of human psoriatic skin and bone marrow chimeric mice experiments, we identified keratinocytes as the major source of S100A9. Mechanistically, S100A9 induced IL-23 production by dendritic cells, driving the IL-23/type 3 immunity in psoriasiform skin inflammation. In addition, the cutaneous IL-23/IL-17 axis induced epidermal S100A9 expression in human and experimental psoriasis. Thus, we showed an autoregulatory circuit between keratinocyte-derived S100A9 and IL-23/type 3 immunity during psoriasiform inflammation, identifying a crucial function of S100A9 in the chronification of psoriasis.

Effects of physical training on functional, clinical, morphological, behavioural and psychosocial outcomes in post-COVID-19 infection: COVID-19 and REhabilitation study (CORE-study)-a study protocol for a randomised controlled clinical trial.

BACKGROUND: The COVID-19 pandemic remains ongoing, with a significant number of survivors who have experienced moderate to severe clinical conditions and who have suffered losses of great magnitude, especially in functional capacity, triggering limitations to daily autonomy and quality of life. Among the possibilities of intervention for disease rehabilitation, physical exercise training stands out, which can benefit several health outcomes and favours the adoption of healthier behaviours. Therefore, the aim of the study will be to analyse the effects of physical training on the functional, clinical, morphological, behavioural and psychosocial status in adults and the elderly following COVID-19 infection. METHODS: A randomised controlled clinical trial is to be conducted in parallel, with the experimental group undergoing an intervention involving a multicomponent physical rehabilitation programme, carried out at the Sports Center in partnership with the Academic Hospital of the Federal University of Santa Catarina, in Florianópolis, Brazil. Participants will be adults and the elderly, of both sexes, in a post-COVID-19-infection state, who were hospitalised during the infection. The intervention will have a total duration of 24 weeks and will include a multicomponent physical training programme, which will have gradual progression in frequency, duration and intensity over time. Regarding the outcomes, before, at the 12th and after 24 weeks of intervention, functional (primary outcome = functional index of aerobic capacity), clinical, morphological, behavioural and psychosocial outcomes will be assessed. DISCUSSION: This study will contribute to a greater understanding of the safety, adherence and benefits of physical training in the rehabilitation of post-COVID-19 patients. The results of this study will be disseminated through presentations at congresses, workshops, peer-reviewed publications and local and international conferences, especially with a view to proposing a post-COVID-19 rehabilitation care protocol. TRIAL REGISTRATION: ReBEC, RBR-10y6jhrs . Registered on 22 February 2022. 2015.

Association of Mu opioid receptor (A118G) and BDNF (G196A) polymorphisms with rehabilitation-induced cortical inhibition and analgesic response in chronic osteoarthritis pain

Background/objective: Chronic pain due to osteoarthritis (OA) is a prevalent cause of global disability. New biomarkers are needed to improve treatment allocation, and genetic polymorphisms are promising candidates. Method: We aimed to assess the association of OPRM1 (A118G and C17T) and brain-derived neurotrophic factor (BDNF [G196A]) polymorphisms with pain-related outcomes and motor cortex excitability metrics (measured by transcranial magnetic stimulation) in 113 knee OA patients with chronic pain. We performed adjusted multivariate regression analyses to compare carriers versus non-carriers in terms of clinical and neurophysiological characteristics at baseline, and treatment response (pain reduction and increased cortical inhibitory tonus) after rehabilitation. Results: Compared to non-carriers, participants with polymorphisms on both OPRM1 (A118G) and BDNF (G196A) genes were less likely to improve pain after rehabilitation (85 and 72% fewer odds of improvement, respectively). Likewise, both carriers of OPRM1 polymorphisms (A118G and C17T) were also less likely to improve cortical inhibition (short intracortical inhibition [SICI], and intracortical facilitation [ICF], respectively). While pain and cortical inhibition improvement did not correlate in the total sample, the presence of OPRM1 (A118G) and BDNF (G196A) polymorphisms moderated this relationship. Conclusions: These results underscore the promising role of combining genetic and neurophysiological markers to endotype the treatment response in this population. (AU)

Association of Mu opioid receptor (A118G) and BDNF (G196A) polymorphisms with rehabilitation-induced cortical inhibition and analgesic response in chronic osteoarthritis pain.

Background/objective: Chronic pain due to osteoarthritis (OA) is a prevalent cause of global disability. New biomarkers are needed to improve treatment allocation, and genetic polymorphisms are promising candidates. Method: We aimed to assess the association of OPRM1 (A118G and C17T) and brain-derived neurotrophic factor (BDNF [G196A]) polymorphisms with pain-related outcomes and motor cortex excitability metrics (measured by transcranial magnetic stimulation) in 113 knee OA patients with chronic pain. We performed adjusted multivariate regression analyses to compare carriers versus non-carriers in terms of clinical and neurophysiological characteristics at baseline, and treatment response (pain reduction and increased cortical inhibitory tonus) after rehabilitation. Results: Compared to non-carriers, participants with polymorphisms on both OPRM1 (A118G) and BDNF (G196A) genes were less likely to improve pain after rehabilitation (85 and 72% fewer odds of improvement, respectively). Likewise, both carriers of OPRM1 polymorphisms (A118G and C17T) were also less likely to improve cortical inhibition (short intracortical inhibition [SICI], and intracortical facilitation [ICF], respectively). While pain and cortical inhibition improvement did not correlate in the total sample, the presence of OPRM1 (A118G) and BDNF (G196A) polymorphisms moderated this relationship. Conclusions: These results underscore the promising role of combining genetic and neurophysiological markers to endotype the treatment response in this population.