Metformin therapy effects on the expression of sodium-glucose cotransporter 2, leptin, and sirt6 levels in pericoronary fat excised from pre-diabetic patients with acute myocardial infarction

Background and purpose: pericoronary fat over-inflammation might lead to the development and destabilization of coronary plaque in patients with pre-diabetes (PDM). Notably, pericoronary fat could over-express the sodium-glucose cotransporter 2 (SGLT2) and leptin, along with decreased sirtuin 6 (SIRT6) expression in PDM vs. normoglycemic (NG) patients undergoing coronary artery bypass grafting (CABG) for acute myocardial infarction (AMI). However, in the current study, we evaluated inflammatory markers, SGLT2, SIRT6, and leptin levels in pericoronary fat and, subsequently, 12-month prognosis comparing PDM to NG subjected to CABG for AMI. In addition, we evaluated in PDM patients the effects of metformin therapy on SIRT6 expression, leptin, and SGLT2 levels, and assessed its beneficial effect on nitrotyrosine and inflammatory cytokine levels. Methods: we studied AMI patients referred for CABG, divided into PDM and NG-patients. PDM patients were divided into never-metformin users and metformin users. Finally, we evaluated major adverse cardiac events (MACE) at a 12-month follow-up. Results: the MACE was 9.1% in all PDM and 3% in NG patients (p < 0.05). Metformin users presented a significantly lower MACE rate in PDM than never-metformin users (p < 0.05). PDM showed higher inflammatory cytokines, 3-nitrotyrosine levels, SGLT2, and leptin content, and decreased SIRT6 protein levels in pericoronary fat compared to NG-patients (p < 0.05). PDM never-metformin-users showed higher SGLT2 and leptin levels in pericoronary fat than current-metformin-users (p < 0.05). Conclusions: metformin therapy might ameliorate cardiovascular outcomes by reducing inflammatory parameters, SGLT2, and leptin levels, and finally improving SIRT6 levels in AMI-PDM patients treated with CABG

Manejo de doenças desmielinizantes do sistema nervoso central na pandemia de doença do coronavírus 2019: uma abordagem prática

Background: The novel coronavirus disease 2019 (COVID-19) pandemic poses a potential threat to patients with autoimmune disorders, including multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Such patients are usually treated with immunomodulatory or immunosuppressive agents, which may tamper with the organism’s normal response to infections. Currently, no consensus has been reached on how to manage MS and NMOSD patients during the pandemic. Objective: To discuss strategies to manage those patients. Methods: We focus on how to 1) reduce COVID-19 infection risk, such as social distancing, telemedicine, and wider interval between laboratory testing/imaging; 2) manage relapses, such as avoiding treatment of mild relapse and using oral steroids; 3) manage disease-modifying therapies, such as preference for drugs associated with lower infection risk (interferons, glatiramer, teriflunomide, and natalizumab) and extended-interval dosing of natalizumab, when safe; 4) individualize the chosen MS induction-therapy (anti-CD20 monoclonal antibodies, alemtuzumab, and cladribine); 5) manage NMOSD preventive therapies, including initial therapy selection and current treatment maintenance; 6) manage MS/NMOSD patients infected with COVID-19. Conclusions: In the future, real-world case series of MS/NMOSD patients infected with COVID-19 will help us define the best management strategies. For the time being, we rely on expert experience and guidance.Introdução: A mais recente pandemia causada pelo coronavírus SARS-CoV-2 (COVID-19, do inglês coronavirus disease 2019) representa uma ameaça potencial para pacientes com doenças autoimunes, incluindo esclerose múltipla (EM) e transtorno do espectro de neuromielite óptica (NMOSD, do inglês neuromyelitis optica spectrum disorders). Esses pacientes são geralmente tratados com medicamentos imunomoduladores ou imunossupressores que podem alterar a resposta normal do organismo a infecções. Até o momento, não há consenso sobre como o manejo dos pacientes com EM e NMOSD deve ser realizado durante a pandemia. Objetivo: Discutir estratégias para manejar esses pacientes. Métodos: Focamos em como 1) reduzir o risco de infecção por COVID-19, como distanciamento social, telemedicina e exames laboratoriais e de imagem em intervalos mais amplos; 2) manejo de surtos, incluindo evitar tratamento de surto leve e uso de corticoide oral; 3) gerenciar terapias modificadoras de doença, como a preferência por medicamentos associados a menor risco de infecção (interferons, glatirâmer, teriflunomida e natalizumabe) e infusão em intervalo estendido de natalizumabe, quando seguro; 4) individualizar a escolha da terapia de indução para EM (anticorpos monoclonais anti-CD20, alentuzumabe e cladribina); 5) manejar terapias preventivas de NMOSD, incluindo seleção inicial de terapia e manutenção do tratamento atual; 6) manejar pacientes com EM/NMOSD que foram infectados por COVID-19. Conclusão: No futuro, séries de casos de pacientes com MS/NMOSD infectados com COVID-19 nos ajudará a definir as melhores estratégias de manejo. Por enquanto, contamos com a experiência e orientação especializadas

Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts

High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control

Development and validation of combined symptom-medication scores for allergic rhinitis*

Background Validated combined symptom-medication scores (CSMSs) are needed to investigate the effects of allergic rhinitis treatments. This study aimed to use real-life data from the MASK-air(R) app to generate and validate hypothesis- and data-driven CSMSs. Methods We used MASK-air(R) data to assess the concurrent validity, test-retest reliability and responsiveness of one hypothesis-driven CSMS (modified CSMS: mCSMS), one mixed hypothesis- and data-driven score (mixed score), and several data-driven CSMSs. The latter were generated with MASK-air(R) data following cluster analysis and regression models or factor analysis. These CSMSs were compared with scales measuring (i) the impact of rhinitis on work productivity (visual analogue scale [VAS] of work of MASK-air(R), and Work Productivity and Activity Impairment: Allergy Specific [WPAI-AS]), (ii) quality-of-life (EQ-5D VAS) and (iii) control of allergic diseases (Control of Allergic Rhinitis and Asthma Test [CARAT]). Results We assessed 317,176 days of MASK-air(R) use from 17,780 users aged 16-90 years, in 25 countries. The mCSMS and the factor analyses-based CSMSs displayed poorer validity and responsiveness compared to the remaining CSMSs. The latter displayed moderate-to-strong correlations with the tested comparators, high test-retest reliability and moderate-to-large responsiveness. Among data-driven CSMSs, a better performance was observed for cluster analyses-based CSMSs. High accuracy (capacity of discriminating different levels of rhinitis control) was observed for the latter (AUC-ROC = 0.904) and for the mixed CSMS (AUC-ROC = 0.820). Conclusion The mixed CSMS and the cluster-based CSMSs presented medium-high validity, reliability and accuracy, rendering them as candidates for primary endpoints in future rhinitis trials.Peer reviewe

Behavioural patterns in allergic rhinitis medication in Europe : A study using MASK-air(R) real-world data

Background Co-medication is common among patients with allergic rhinitis (AR), but its dimension and patterns are unknown. This is particularly relevant since AR is understood differently across European countries, as reflected by rhinitis-related search patterns in Google Trends. This study aims to assess AR co-medication and its regional patterns in Europe, using real-world data. Methods We analysed 2015-2020 MASK-air(R) European data. We compared days under no medication, monotherapy and co-medication using the visual analogue scale (VAS) levels for overall allergic symptoms ('VAS Global Symptoms') and impact of AR on work. We assessed the monthly use of different medication schemes, performing separate analyses by region (defined geographically or by Google Trends patterns). We estimated the average number of different drugs reported per patient within 1 year. Results We analysed 222,024 days (13,122 users), including 63,887 days (28.8%) under monotherapy and 38,315 (17.3%) under co-medication. The median 'VAS Global Symptoms' was 7 for no medication days, 14 for monotherapy and 21 for co-medication (p < .001). Medication use peaked during the spring, with similar patterns across different European regions (defined geographically or by Google Trends). Oral H-1-antihistamines were the most common medication in single and co-medication. Each patient reported using an annual average of 2.7 drugs, with 80% reporting two or more. Conclusions Allergic rhinitis medication patterns are similar across European regions. One third of treatment days involved co-medication. These findings suggest that patients treat themselves according to their symptoms (irrespective of how they understand AR) and that co-medication use is driven by symptom severity.Peer reviewe

Development and validation of combined symptom‐medication scores for allergic rhinitis*

Background: Validated combined symptom-medication scores (CSMSs) are needed to investigate the effects of allergic rhinitis treatments. This study aimed to use real-life data from the MASK-air® app to generate and validate hypothesis- and data-driven CSMSs. Methods: We used MASK-air® data to assess the concurrent validity, test-retest reliability and responsiveness of one hypothesis-driven CSMS (modified CSMS: mCSMS), one mixed hypothesis- and data-driven score (mixed score), and several data-driven CSMSs. The latter were generated with MASK-air® data following cluster analysis and regression models or factor analysis. These CSMSs were compared with scales measuring (i) the impact of rhinitis on work productivity (visual analogue scale [VAS] of work of MASK-air® , and Work Productivity and Activity Impairment: Allergy Specific [WPAI-AS]), (ii) quality-of-life (EQ-5D VAS) and (iii) control of allergic diseases (Control of Allergic Rhinitis and Asthma Test [CARAT]). Results: We assessed 317,176 days of MASK-air® use from 17,780 users aged 16-90 years, in 25 countries. The mCSMS and the factor analyses-based CSMSs displayed poorer validity and responsiveness compared to the remaining CSMSs. The latter displayed moderate-to-strong correlations with the tested comparators, high test-retest reliability and moderate-to-large responsiveness. Among data-driven CSMSs, a better performance was observed for cluster analyses-based CSMSs. High accuracy (capacity of discriminating different levels of rhinitis control) was observed for the latter (AUC-ROC = 0.904) and for the mixed CSMS (AUC-ROC = 0.820). Conclusion: The mixed CSMS and the cluster-based CSMSs presented medium-high validity, reliability and accuracy, rendering them as candidates for primary endpoints in future rhinitis trials

Allergen immunotherapy in MASK-air users in real-life : Results of a Bayesian mixed-effects model

Background Evidence regarding the effectiveness of allergen immunotherapy (AIT) on allergic rhinitis has been provided mostly by randomised controlled trials, with little data from real-life studies. Objective To compare the reported control of allergic rhinitis symptoms in three groups of users of the MASK-air(R) app: those receiving sublingual AIT (SLIT), those receiving subcutaneous AIT (SCIT), and those receiving no AIT. Methods We assessed the MASK-air(R) data of European users with self-reported grass pollen allergy, comparing the data reported by patients receiving SLIT, SCIT and no AIT. Outcome variables included the daily impact of allergy symptoms globally and on work (measured by visual analogue scales-VASs), and a combined symptom-medication score (CSMS). We applied Bayesian mixed-effects models, with clustering by patient, country and pollen season. Results We analysed a total of 42,756 days from 1,093 grass allergy patients, including 18,479 days of users under AIT. Compared to no AIT, SCIT was associated with similar VAS levels and CSMS. Compared to no AIT, SLIT-tablet was associated with lower values of VAS global allergy symptoms (average difference = 7.5 units out of 100; 95% credible interval [95%CrI] = -12.1;-2.8), lower VAS Work (average difference = 5.0; 95%CrI = -8.5;-1.5), and a lower CSMS (average difference = 3.7; 95%CrI = -9.3;2.2). When compared to SCIT, SLIT-tablet was associated with lower VAS global allergy symptoms (average difference = 10.2; 95%CrI = -17.2;-2.8), lower VAS Work (average difference = 7.8; 95%CrI = -15.1;0.2), and a lower CSMS (average difference = 9.3; 95%CrI = -18.5;0.2). Conclusion In patients with grass pollen allergy, SLIT-tablet, when compared to no AIT and to SCIT, is associated with lower reported symptom severity. Future longitudinal studies following internationally-harmonised standards for performing and reporting real-world data in AIT are needed to better understand its 'real-world' effectiveness.Peer reviewe