Conditioned pain modulation (CPM) paradigm type affects its sensitivity as a biomarker of fibromyalgia.

Fibromyalgia (FM) is a widespread chronic pain syndrome, possibly associated with the presence of central dysfunction in descending pain inhibition pathways. Conditioned Pain Modulation (CPM) has been proposed as a biomarker of FM. Nonetheless, the wide variety of methods used to measure CPM has hampered robust conclusions being reached. To clarify the validity of CPM as a biomarker of FM, we tested two CPM paradigms (parallel and sequential) in a sample of 23 female patients and 23 healthy women by applying test (mechanical) stimuli and conditioning (pressure cuff) stimuli. We evaluated whether CPM indices could correctly classify patients and controls, and we also determined the correlations between the indices and clinical variables such as symptomatology, disease impact, depression, quality of life, pain intensity, pain interference, fatigue and numbness. In addition, we compared the clinical status of CPM responders (efficient pain inhibitory mechanism) and non-responders. We observed that only parallel CPM testing correctly classified about 70% of patients with FM. In addition, more than 80% of healthy participants were found to be responders, while the rate was about 50% in the FM patients. The sequential CPM test was not as sensitive, with a decrease of up to 40% in the response rate for both groups. On the other hand, we did not observe any correlation between CPM measures and clinical symptoms. In summary, our findings demonstrate the influence of the CPM paradigm used and confirm that CPM may be a useful marker to complement FM diagnosis. However, the findings also cast doubts on the sensitivity of CPM as a marker of pain severity in FM.

Total Synthesis and Microbiological Evaluation of Leopolic Acid A and Analogues.

New antimicrobial scaffolds are scarce, and there is a great need for the development of novel therapeutics. In this study, we report a convergent 9-step synthesis of leopolic acid A and a series of targeted analogues. The designed compounds allowed for incorporation of non-natural ureido dipeptide moieties and 4- and 5-position substituents around the 2,3-pyrrolidinedione of leopolic acid A. Leopolic acid A displayed modest antimicrobial activity (32 µg/mL) against MRSA, while the most active analogues displayed slightly improved activity (8-16 µg/mL). Additionally, several of the leopolic acid A analogues displayed promising antibiofilm activity, most notably having an MBEC:MIC ratio of ∼1. Overall, this work represents an initial SAR of the natural product and a framework for further optimization of these bioactive scaffolds within the context of bioactive pyrrolidinediones.

Evaluation of commercial doses of a feed additive and silymarin on broiler performance with and without CCl4-induced liver damage.

Improving productive performance is a daily challenge in the poultry industry. Developing cost-effective additives and strategies that improve performance in antibiotic-free poultry production is critical to maintaining productivity and efficiency. This study evaluates the influence of a commercially available phytogenic feed additive (CA-PFA, that comprises silymarin, betaine and curcumin extracts as main ingredients) and silymarin on commercial broilers' productive performance and liver function with and without carbon tetrachloride (CCl4)-induced liver damage. The experiment was conducted in a completely randomized design, with six treatments, eight replicates, and eight birds per replicate in 18 one-day-old male broilers (Cobb Vantress 500) each; under a 3 × 2 factorial arrangement (3 diets x 2 levels of CCl4, 0 and 1 mL/kg body weight orally). The experimental treatments included 3 diets, commercially recommended doses of CA-PFA (500 mg/kg of feed; this dose provides 70 mg/kg of silymarin, besides the other active ingredients included in the formulation), silymarin (250 mg/kg of feed, containing 28% of active ingredient; this dose provides 70 mg/kg of silymarin as active ingredient) and an additive-free basal diet as a control. A standard commercial silymarin was used as a reference due to its well-known and extensively studied hepatoprotective properties that can mitigate the negative effects of CCl4 in the liver. The data were analyzed as a 2-way ANOVA, and the means showing significant (P ≤ 0.05) differences were then compared using the Post-Hoc Tukey HSD test. No interaction was detected between factors. Exposure to CCl4 had a noticeable detrimental effect on alertness, productive performance, and liver function of broilers without a significant increase in mortality. Including CA-PFA in the diet improved productive performance compared to the basal diet from day 21 to the end of the trial, on day 42. While no influence in feed intake was detected for any treatment, CA-PFA improved body weight gain (BWG) and feed conversion ratio (FCR) significantly (P < 0.05) from day 21 to the end of the trial in healthy and CCl4-exposed birds. The results show that CA-PFA supplementation improves performance parameters in broilers with and without CCl4-induced liver damage, when compared to a basal diet and the addition of a standard commercial silymarin product.

Why do physicians go to work when they are sick? Presenteeism at different career stages.

INTRODUCTION AND OBJECTIVE: Physicians find it difficult to take on the role of the patient and they show unusual behaviors when ill. One of these behaviors is presenteeism, which is working while sick. The objective of this research is to analyze the factors that contribute to the phenomenon of presenteeism in Spanish physicians. MATERIAL AND METHODS: Mixed methodology study: one national survey through the General Council of Medical Associations website (quantitative part), 22 semistructured interviews with sick residents and practicing physicians, and three focus groups involving professionals from the occupational health services (qualitative). A bivariate analysis using parametric and non-parametric tests. The significance level was p<0.05 (95% confidence interval). Qualitative analysis using the comparative-constant method until saturation of information. RESULTS: Presenteeism is reported by 89.4% of doctors who responded to the survey, and it is more common among women. Contributing factors include fear of overburdening colleagues (the main reason and more common among women 58.14% vs 48.35%), self-perception of doing one's duty (the second reason and more common among men, 44.63% vs 33.14%) and economic impact and difficulty in accepting the role of a sick person. This behavior has an impact on patient safety, and is part of the hidden curriculum that also affects the training of medical professionals. CONCLUSIONS: Presenteeism is a widespread and accepted practice among medical professionals. Although normalized, and even appreciated as a way to avoid overburdening colleagues, presenteeism has important implications for clinical ethics and patient safety.

Expanded library of novel 2,3-pyrrolidinedione analogues exhibit anti-biofilm activity.

Herein we report a new library of 2,3-pyrrolidinedione analogues that expands on our previous report on the antimicrobial studies of this heterocyclic scaffold. The novel 2,3-pyrrolidinediones reported herein have been evaluated against S. aureus and methicillin-resistant S. aureus (MRSA) biofilms, and this work constitutes our first report on the antibiofilm properties of this class of compounds. The antibiofilm activity of these 2,3-pyrrolidinediones has been assessed through minimum biofilm eradication concentration (MBEC) and minimum biofilm inhibition concentration (MBIC) assays. The compounds displayed antibiofilm properties and represent intriguing scaffolds for further optimization and development.

The mediating role of reflective functioning in the association between childhood trauma and suicide attempt.

BACKGROUND: Childhood trauma is intimately related with suicidal behaviour. Patients who have suffered childhood trauma develop impaired Reflective Functioning (RF), which refers to the capacity to understand ourselves and others in terms of intentional mental states. An improvement in RF has been associated with a reduction in suicidal attempts, but the mediating role of RF between childhood trauma and suicidal behaviour has not been addressed so far. OBJECTIVE: We aim to examine the potential mediating effect of RF among childhood trauma and suicide attempts. METHOD: We included 748 patients who had attempted suicide at least once. They were asked to complete the Reflective Functioning Questionnaire (RFQ-8), the Columbia-Suicide Severity Rating scale (CSSRS), and the Childhood Trauma Questionnaire-Short Form (CTQ-SF). We conducted linear regressions by simple mediating model to examine the role of RF in the indirect association between childhood trauma and the number of suicide attempts. RESULTS: Our results show significant indirect effects through hypo and hypermentalizing between Emotional Abuse (EA) and Sexual Abuse (SA) in childhood and the number of suicide attempts in lifetime. These results indicate that ineffective RF significantly mediates the association between childhood trauma and suicidality. CONCLUSION: This is the first study supporting the mediational role of RF in the relationship between EA and SA, and the number of suicide attempt in lifetime. These findings have important implications for reducing suicide rates and preventing future re-attempts. Further studies analysing this mediating role and focusing efforts on increasing RF-based interventions are required.

A specific gut microbiota signature is associated with an enhanced GLP-1 and GLP-2 secretion and improved metabolic control in patients with type 2 diabetes after metabolic Roux-en-Y gastric bypass.

Objective: To determine changes in incretins, systemic inflammation, intestinal permeability and microbiome modifications 12 months after metabolic RYGB (mRYGB) in patients with type 2 diabetes (T2D) and their relationship with metabolic improvement. Materials and methods: Prospective single-center non-randomized controlled study, including patients with class II-III obesity and T2D undergoing mRYGB. At baseline and one year after surgery we performed body composition measurements, biochemical analysis, a meal tolerance test (MTT) and lipid test (LT) with determination of the area under the curve (AUC) for insulin, C-peptide, GLP-1, GLP-2, and fasting determinations of succinate, zonulin, IL-6 and study of gut microbiota. Results: Thirteen patients aged 52.6 ± 6.5 years, BMI 39.3 ± 1.4 kg/m2, HbA1c 7.62 ± 1.5% were evaluated. After mRYGB, zonulin decreased and an increase in AUC after MTT was observed for GLP-1 (pre 9371 ± 5973 vs post 15788 ± 8021 pM, P<0.05), GLP-2 (pre 732 ± 182 vs post 1190 ± 447 ng/ml, P<0.001) and C- peptide, as well as after LT. Species belonging to Streptococaceae, Akkermansiacea, Rickenellaceae, Sutterellaceae, Enterobacteriaceae, Oscillospiraceae, Veillonellaceae, Enterobacterales_uc, and Fusobacteriaceae families increased after intervention and correlated positively with AUC of GLP-1 and GLP-2, and negatively with glucose, HbA1c, triglycerides and adiposity markers. Clostridium perfringens and Roseburia sp. 40_7 behaved similarly. In contrast, some species belonging to Lachnospiraceae, Erysipelotricaceae, and Rumnicocaceae families decreased and showed opposite correlations. Higher initial C-peptide was the only predictor for T2D remission, which was achieved in 69% of patients. Conclusions: Patients with obesity and T2D submitted to mRYGB show an enhanced incretin response, a reduced gut permeability and a metabolic improvement, associated with a specific microbiota signature.

Social Prescribing Schemes in Primary Care in Spain (EvalRA Project): a mixed-method study protocol to build an evaluation model.

BACKGROUND: Social Prescribing is a Primary Health Care service that provides people with non-clinical care alternatives that may have an impact on their health. Social Prescribing can be more or less formal and structured. Social Prescribing Schemes are formal Social Prescribing of health assets by Primary Health Care teams in coordination and follow-up of patients with providers. The emerging evidence suggests that this service can improve people's health and well-being, create value and provide sustainability for the healthcare system. However, some evaluations note that the current evidence regarding social prescribing is insufficient and needs further investigation. The EvaLRA project aims to elaborate an evaluation model of Social Prescribing Schemes in Primary Health Care based on a set of structure, process, and outcomes indicators. METHODS: In the region of Aragon, the Community Health Care Strategy aims to promote the development of social prescription schemes in Primary Health Care teams. This study is divided into two stages. Stage 1: identification of primary health care teams that implement social prescribing schemes and establish a first set of indicators to evaluate social prescribing using qualitative consensus techniques with experts. Stage 2 evaluation of the relevance, feasibility and sensitivity of selected indicators after 6 and 12 months in primary health care teams. The results will provide a set of indicators considering structure, process and outcomes for social prescribing schemes. DISCUSSION: Current evaluations of the application of social prescribing schemes use different criteria and indicators. A set of agreed indicators and its piloting in primary health care teams will provide a tool to evaluate the implementation of social prescription schemes. In addition, the scorecard created could be of interest to other health systems in order to assess the service and improve its information system, deployment and safety.

Development and Validation of the Brief Math Anxiety Scale (BMAS) in University Students.

BACKGROUND: This study developed the Brief Math Anxiety Scale (BMAS), a brief version of the Shortened Math Anxiety Rating Scale (sMARS), maintaining its original three-factor structure, by applying item response theory. METHOD: The sMARS was administered to 1,349 undergraduates, along with other questionnaires to measure their math ability, trait and test anxieties, and attitudes toward mathematics. RESULTS: Results showed that the original scale could be reduced to nine items (three for each subscale). We provided evidence of good psychometric properties: strong internal consistency, adequate 7-week test-retest reliability, and good convergent/discriminant validity. CONCLUSIONS: In conclusion, the BMAS provides valid interpretations and reliable scores for assessing math anxiety in university students, and is especially useful in situations with time constraints where the longer form is impractical.

Racial and Ethnic Demographic Reporting in Phase 2 Proton Therapy Clinical Trials: A Review.

Purpose: Equitable inclusion of racial and ethnic participation in clinical trials is crucial to improving disparities in health care, especially for historically marginalized populations. Our study aims to describe the racial and ethnic demographics of patients enrolled in published phase 2 clinical trials involving proton therapy in the United States. Materials and Methods: Published manuscripts were identified in PubMed, Embase, World of Science, and Cochrane. Phase 2 trials evaluating proton therapy for US patients were included. For each article in the study, data were collected comprising authors, title, and publication year, and clinical trial numbers were verified. Additional data included tumor site, primary institution, sample size, reported race/ethnicity, and raw number/percentile of race/ethnicity. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were used. Results: Overall, 970 titles were identified; 636 remained after duplicate screening, and 75 full-text articles were assessed. We identified 38 eligible manuscripts for inclusion comprising 2648 patients. Only 15 (39%) of the publications reported race/ethnicity. Of these, 8 (21%) and 10 (26%) documented Hispanic or Black trial participants, respectively; however, only 6 (16%) documented trial participation for both Hispanic and Black patients. Of the 1409 patients with a documented race/ethnicity, 89.0% (n = 1254) were non-Hispanic white, 5.3% (n = 75) were Black, and 2.2% (n = 31) were Hispanic. Other and unknown race/ethnicity comprised the remaining patients (3.5%; n = 49). Conclusion: We identified underreporting of demographic data in published phase 2 proton therapy trials, which unfortunately mirrored underreporting for cancer drug clinical trials. We also noted dramatic Black and Hispanic patient underrepresentation across the trials in which race and ethnicity are reported. Findings highlight the urgent need to identify and address barriers to proton therapy trials for Black and Hispanic patients ensuring clinical trials in radiation oncology are representative of the patients seen in clinical practice.

Increased STAT3 Activation in Periodontitis Drives Inflammatory Bone Loss.

Periodontitis is one of the most prevalent human inflammatory diseases. It is characterized by periodontal tissue destruction, progressively driven by the host response. In this regard, cytokines associated with tissue destruction, such as interleukin (IL)-6 and IL-23, use a common signaling pathway mediated by STAT3. This transcription factor is also needed for IL-17A production, a key mediator in periodontitis pathogenesis. Although several studies have reported increased activation of STAT3 in experimental periodontitis, a detailed characterization of STAT3 activation in human gingival tissues and its involvement in alveolar bone loss has yet to be explored. Using a cross-sectional study design, we detected increased proportions of pSTAT3-positive cells during periodontitis compared with health, particularly in epithelial cells and T cells. Other cell types of hematopoietic and nonhematopoietic origin also display STAT3 activation in gingival tissues. We detected increased STAT3 phosphorylation and expression of STAT3-related genes during experimental periodontitis. Next, we evaluated the role of STAT3 in alveolar bone destruction using a mouse model of STAT3 loss of function (mut-Stat3 mice). Compared with controls, mut-Stat3 mice had reduced alveolar bone loss following ligature-induced periodontitis. We also evaluated pharmacologic inhibition of STAT3 in ligature-induced periodontitis. Like mut-Stat3 mice, mice treated with STAT3 small-molecule inhibitor had reduced bone loss compared with controls. Our results demonstrate that STAT3 activation is increased in epithelial and T cells during periodontitis and indicate a pathogenic role of STAT3 in inflammatory alveolar bone loss.

Elevated complement C3 and increased CD8 and type 1 helper lymphocyte T populations in patients with post-COVID-19 condition.

BACKGROUND: Biological markers associated to post-COVID-19 condition (PCC) have not been clearly identified. METHODS: Eighty-two patients attending our post-COVID-19 outpatient clinic were recruited and classified as fully recovered (40.2%) or presenting with PCC (59.8%). Clinical and radiological data, laboratory markers, cytokines, and lymphocyte populations were analyzed. RESULTS: Median number of days after hospitalization was 78.5 [p25-p75: 60-93] days. PCC was significantly more frequent in women, in patients with a previously critical COVID-19, and in those with two or more comorbidities. No differences were found in lymphocyte counts, ferritin, C-reactive protein, D-dimer or sCD25, IL-1ß, IL-1Ra, IL-6, CXCL8, IL-17A, IL-18, IL-22, IFN-γ, TNF-α, and IL-10 cytokines levels. PCC patients showed significantly higher levels of complement factor C3 than fully recovered patients: median C3 128 mg/dL [p25-p75:107-135] vs 111 mg/dL [p25-p75: 100-125] (p =.005), respectively. In the flow cytometry assessment of peripheral blood lymphocyte subpopulations, PCC patients showed significantly increased CD8 populations compared to fully recovered patients: median CD8: 529 [p25-p75: 384-683] vs 370/mm3 [p25-p75:280-523], p =.007. When type 1, 2, 17/22, and 17.1 helper and follicular T lymphocyte subpopulations were analyzed, the frequency of Th1 was significantly higher in PCC patients compared to fully recovered patients (30% vs 38.5%, p =.028). CONCLUSION: Patients with a post-COVID-19 condition showed significantly increased immunological parameters of inflammation (complement factor C3 and CD8 and Th1 T lymphocyte populations) compared to fully recovered patients. These parameters could be used as biological markers of this condition.

Prevalence of ocular findings and their association with glycemia in dogs with diabetes mellitus: A 10-year clinical study (2009-2019).

Background: Although ocular findings in diabetic patients are well described, prevalence data for those is unknown. Aim: To describe the prevalence of ocular findings and their association with glycemia in dogs with diabetes mellitus. Methods: Medical records from diabetic dogs assessed by the ophthalmology and the internal medicine services at the Veterinary Teaching Hospital of the Autonomous University of Barcelona were reviewed (2009-2019). Results: Seventy-five dogs (150 eyes) of both genders (51/75 females; 68% and 24/75 males; 32%) and a mean age of 9.37 ± 2.43 years, were included. The most common ocular findings were cataracts (146/150; 97.3%), vitreous degeneration (45/98; 45.9%), anterior uveitis (47/150; 31.3%), aqueous deficiency dry eye (ADDE) (33/150; 22%), diffuse corneal edema (31/150; 20.7%), non-proliferative retinopathy (13/98; 13.3%), and lipid keratopathy (9/150; 6%). The most prevalent type of cataracts observed (78/146; 53.4%) was intumescent, which was commonly accompanied by non-proliferative retinopathy (p = 0.003). Among the diabetic dogs, blood glucose levels were statistically higher in dogs with non-proliferative retinopathy or anterior uveitis (p < 0.005). Conclusions: Ocular complications of diabetes mellitus in dogs are numerous, being the most frequent intumescent cataracts, vitreous degeneration, anterior uveitis, ADDE, diffuse corneal edema, and non-proliferative retinopathy. This high prevalence warrants a more detailed ophthalmic evaluation in diabetic dogs especially for those undergoing cataract surgery. Furthermore, a predisposition for anterior segment inflammation and non-proliferative retinopathy is suggested when fasting plasma glucose is higher than 600 mg/dl..

Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD.

OBJECTIVE: Succinate and succinate receptor 1 (SUCNR1) are linked to fibrotic remodeling in models of non-alcoholic fatty liver disease (NAFLD), but whether they have roles beyond the activation of hepatic stellate cells remains unexplored. We investigated the succinate/SUCNR1 axis in the context of NAFLD specifically in hepatocytes. METHODS: We studied the phenotype of wild-type and Sucnr1-/- mice fed a choline-deficient high-fat diet to induce non-alcoholic steatohepatitis (NASH), and explored the function of SUCNR1 in murine primary hepatocytes and human HepG2 cells treated with palmitic acid. Lastly, plasma succinate and hepatic SUCNR1 expression were analyzed in four independent cohorts of patients in different NAFLD stages. RESULTS: Sucnr1 was upregulated in murine liver and primary hepatocytes in response to diet-induced NASH. Sucnr1 deficiency provoked both beneficial (reduced fibrosis and endoplasmic reticulum stress) and detrimental (exacerbated steatosis and inflammation and reduced glycogen content) effects in the liver, and disrupted glucose homeostasis. Studies in vitro revealed that hepatocyte injury increased Sucnr1 expression, which when activated improved lipid and glycogen homeostasis in damaged hepatocytes. In humans, SUCNR1 expression was a good determinant of NAFLD progression to advanced stages. In a population at risk of NAFLD, circulating succinate was elevated in patients with a fatty liver index (FLI) ≥60. Indeed, succinate had good predictive value for steatosis diagnosed by FLI, and improved the prediction of moderate/severe steatosis through biopsy when added to an FLI algorithm. CONCLUSIONS: We identify hepatocytes as target cells of extracellular succinate during NAFLD progression and uncover a hitherto unknown function for SUCNR1 as a regulator of hepatocyte glucose and lipid metabolism. Our clinical data highlight the potential of succinate and hepatic SUCNR1 expression as markers to diagnose fatty liver and NASH, respectively.

Efecto del plomo y del arsénico en condiciones de laboratorio sobre la rana africana de uñas (Xenopus laevis) y la rana leopardo (Lithobates berlandieri) / Effect of lead and arsenic under laboratory conditions on African clawed frog (Xenopus laevis) and leopard frog (Lithobates berlandieri)

Actualmente, existe una creciente preocupación ya que algunas especies de anfibios han mostrado un declive en sus poblaciones por causa de diversos factores, entre ellos los metales pesados; por esta razón, es importante realizar estudios sobre esta problemática ambiental. El objetivo de este estudio fue determinar la cantidad del plomo y arsénico que se concentra en los tejidos de la rana Africana de uñas (Xenopus laevis) en etapa juvenil y de la rana Leopardo (Lithobates berlandieri) en etapa larvaria y en el agua después de 16 semanas expuestas a placas de plomo y arseniato de sodio, con la finalidad de determinar si esta acumulación de metales provoca eventualmente anomalías morfológicas en su desarrollo. Los individuos fueron puestos en contacto con placas de plomo, arseniato de sodio, agua de la red de abastecimiento de agua de consumo público (grupos experimentales) y con agua potable (grupo control). Los organismos fueron inspeccionados de manera externa para identificar anomalías macroscópicas, además de realizarles análisis morfométricos. Los análisis espectroquímicos (espectrofotometría de absorción atómica, con la técnica de horno de grafito) mostraron que hay un proceso de bioconcentración y bioacumulación de metales cuando los organismos están en contacto con estos metales y con agua de la red de abastecimiento público, la cual está contaminada también, pues se detectaron cantidades altas de metales en los tejidos de las larvas. Respecto a la morfometría hubo diferencias significativas en algunas estructuras entre el grupo control y los grupos experimentales en X. laevis. En L. berlandieri fueron detectadas anomalías macroscópicas como curvatura de la cola, problemas de pigmentación, protuberancias en el abdomen e inadecuada posición de los intestinos en aquellos individuos que estuvieron en contacto con estos metales pesados. (AU)

Currently, there is growing concern as some amphibian species have shown a decline in their populations due to various factors, including heavy metals; for this reason, it is important to carry out studies on this environmental problem. The objective of this study was to determine the amount of lead and arsenic concentrated in the tissues of the African clawed frog (Xenopus laevis) in the juvenile stage and the Leopard frog (Lithobates berlandieri) in the larval stage and in the water after 16 weeks exposed to lead plates and sodium arsenate, in order to determine if this accumulation of metals eventually causes morphological abnormalities in their development. The individuals were placed in contact with lead plates, sodium arsenate, water from the public water supply network (experimental groups) and with drinking water (control group). The organisms were externally inspected to identify macroscopic anomalies, in addition to performing morphometric analysis. The spectrochemical analyzes (atomic absorption spectrophotometry, with the graphite furnace technique) showed that there is a process of bioconcentration and bioaccumulation of metals when the organisms are in contact with these metals and with water from the public supply network, which is also contaminated, since high amounts of metals were detected in the tissues of the larvae. Regarding morphometry, there were significant differences in some structures between the control group and the experimental groups in X. laevis. In L. berlandieri, macroscopic abnormalities such as curvature of the tail, pigmentation problems, protuberances in the abdomen and inappropriate position of the intestines were detected in those individuals that were in contact with these heavy metals. (AU)