Analysis of Female Participant Representation in Registered Oncology Clinical Trials in the United States from 2008 to 2020.

BACKGROUND: Female underrepresentation in oncology clinical trials can result in outcome disparities. We evaluated female participant representation in US oncology trials by intervention type, cancer site, and funding. MATERIALS AND METHODS: Data were extracted from the publicly available Aggregate Analysis of ClinicalTrials.gov database. Initially, 270,172 studies were identified. Following the exclusion of trials using Medical Subject Heading terms, manual review, those with incomplete status, non-US location, sex-specific organ cancers, or lacking participant sex data, 1650 trials consisting of 240,776 participants remained. The primary outcome was participation to prevalence ratio (PPR): percent females among trial participants divided by percent females in the disease population per US Surveillance, Epidemiology, and End Results Program data. PPRs of 0.8-1.2 reflect proportional female representation. RESULTS: Females represented 46.9% of participants (95% CI, 45.4-48.4); mean PPR for all trials was 0.912. Females were underrepresented in surgical (PPR 0.74) and other invasive (PPR 0.69) oncology trials. Among cancer sites, females were underrepresented in bladder (odds ratio [OR] 0.48, 95% CI 0.26-0.91, P = .02), head/neck (OR 0.44, 95% CI 0.29-0.68, P < .01), stomach (OR 0.40, 95% CI 0.23-0.70, P < .01), and esophageal (OR 0.40 95% CI 0.22-0.74, P < .01) trials. Hematologic (OR 1.78, 95% CI 1.09-1.82, P < .01) and pancreatic (OR 2.18, 95% CI 1.46-3.26, P < .01) trials had higher odds of proportional female representation. Industry-funded trials had greater odds of proportional female representation (OR 1.41, 95% CI 1.09-1.82, P = .01) than US government and academic-funded trials. CONCLUSIONS: Stakeholders should look to hematologic, pancreatic, and industry-funded cancer trials as exemplars of female participant representation and consider female representation when interpreting trial results.

The impact of a csDMARD in combination with a TNF inhibitor on drug retention and clinical remission in axial spondyloarthritis.

OBJECTIVES: Many axial spondylarthritis (axSpA) patients receive a conventional synthetic DMARD (csDMARD) in combination with a TNF inhibitor (TNFi). However, the value of this co-therapy remains unclear. The objectives were to describe the characteristics of axSpA patients initiating a first TNFi as monotherapy compared with co-therapy with csDMARD, to compare one-year TNFi retention and remission rates, and to explore the impact of peripheral arthritis. METHODS: Data was collected from 13 European registries. One-year outcomes included TNFi retention and hazard ratios (HR) for discontinuation with 95% CIs. Logistic regression was performed with adjusted odds ratios (OR) of achieving remission (Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP < 1.3 and/or BASDAI < 2) and stratified by treatment. Inter-registry heterogeneity was assessed using random-effect meta-analyses, combined results were presented when heterogeneity was not significant. Peripheral arthritis was defined as ≥1 swollen joint at baseline (=TNFi start). RESULTS: Amongst 24 171 axSpA patients, 32% received csDMARD co-therapy (range across countries: 13.5% to 71.2%). The co-therapy group had more baseline peripheral arthritis and higher CRP than the monotherapy group. One-year TNFi-retention rates (95% CI): 79% (78, 79%) for TNFi monotherapy vs 82% (81, 83%) with co-therapy (P < 0.001). Remission was obtained in 20% on monotherapy and 22% on co-therapy (P < 0.001); adjusted OR of 1.16 (1.07, 1.25). Remission rates at 12 months were similar in patients with/without peripheral arthritis. CONCLUSION: This large European study of axial SpA patients showed similar one-year treatment outcomes for TNFi monotherapy and csDMARD co-therapy, although considerable heterogeneity across countries limited the identification of certain subgroups (e.g. peripheral arthritis) that may benefit from co-therapy.

European bio-naïve spondyloarthritis patients initiating TNF inhibitor: time trends in baseline characteristics, treatment retention and response.

OBJECTIVES: To investigate time trends in baseline characteristics and retention, remission and response rates in bio-naïve axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) patients initiating TNF inhibitor (TNFi) treatment. METHODS: Prospectively collected data on bio-naïve axSpA and PsA patients from routine care in 15 European countries were pooled. Three cohorts were defined according to year of TNFi initiation: A (1999-2008), B (2009-2014) and C (2015-2018). Retention, remission and response rates were assessed at 6, 12 and 24 months. RESULTS: In total, 27 149 axSpA and 17 446 PsA patients were included. Cohort A patients had longer disease duration compared with B and C. In axSpA, cohort A had the largest proportion of male and HLA-B27 positive patients. In PsA, baseline disease activity was highest in cohort A. Retention rates in axSpA/PsA were highest in cohort A and differed only slightly between B and C. For all cohorts, disease activity decreased markedly from 0 to 6 months. In axSpA, disease activity at 24 months was highest in cohort A, where also remission and response rates were lowest. In PsA, remission rates at 6 and 12 months tended to be lowest in cohort A. Response rates were at all time points comparable across cohorts, and less between-cohort disease activity differences were seen at 24 months. CONCLUSION: Our findings indicate that over the past decades, clinicians have implemented more aggressive treatment strategies in spondyloarthritis. This was illustrated by shorter disease duration at treatment initiation, decreased retention rates and higher remission rates during recent years.

Gut Microbiome Changes in Gestational Diabetes.

Gestational diabetes mellitus (GDM), one of the most common endocrine pathologies during pregnancy, is defined as any degree of glucose intolerance with onset or first discovery in the perinatal period. Physiological changes that occur in pregnant women can lead to inflammation, which promotes insulin resistance. In the general context of worldwide increasing obesity in young females of reproductive age, GDM follows the same ascending trend. Changes in the intestinal microbiome play a decisive role in obesity and the development of insulin resistance and chronic inflammation, especially in patients with type 2 diabetes mellitus (T2D). To date, various studies have also associated intestinal dysbiosis with metabolic changes in women with GDM. Although host metabolism in women with GDM has not been fully elucidated, it is of particular importance to analyze the available data and to discuss the actual knowledge regarding microbiome changes with potential impact on the health of pregnant women and newborns. We analyzed peer-reviewed journal articles available in online databases in order to summarize the most recent findings regarding how variations in diet and metabolic status of GDM patients can contribute to alteration of the gut microbiome, in the same way that changes of the gut microbiota can lead to GDM. The most frequently observed alteration in the microbiome of patients with GDM was either an increase of the Firmicutes phylum, respectively, or a decrease of the Bacteroidetes and Actinobacteria phyla. Gut dysbiosis was still present postpartum and can impact the development of the newborn, as shown in several studies. In the evolution of GDM, probiotic supplementation and regular physical activity have the strongest evidence of proper blood glucose control, favoring fetal development and a healthy outcome for the postpartum period. The current review aims to summarize and discuss the most recent findings regarding the correlation between GDM and dysbiosis, and current and future methods for prevention and treatment (lifestyle changes, pre- and probiotics administration). To conclude, by highlighting the role of the gut microbiota, one can change perspectives about the development and progression of GDM and open up new avenues for the development of innovative therapeutic targets in this disease.

Rheumatological Adverse Events Following Immunotherapy for Cancer.

Background and Objectives: The occurrence of rheumatological side effects in a patient after receiving immunotherapy for cancer is becoming increasingly common. Oncologists often fail to diagnose and refer affected patients to rheumatologists. This paper presents the various rheumatological adverse events that occur after immunotherapy in patients as well as their treatment and evolution. Materials and Methods: A total of 36 patients were monitored between November 2018 and March 2020. The oncologist monitoring the immunotherapy-treated patients identified the occurrence of musculoskeletal side effects. The grading of toxicities was performed by both the oncologist and the rheumatologist using common terminology criteria for adverse events (CTCAE). Rheumatological treatment was administered, and for some patients, immunotherapy was discontinued. Results: The clinical presentations of the patients varied. Mild side effects (grade 1-2) were reported in a higher proportion than severe side effects (grade 3-5). Therefore, thirty-one patients had mild-to-moderate side effects, and five patients had severe side effects. Adverse reactions occurred, on average, 10 weeks after the initiation of immunotherapy; this indicated that the severity of the toxicity was dose dependent. Patients were treated with NSAIDs or prednisone, depending on the severity of the side effects, and for patients with severe manifestations, immunotherapy was discontinued. The remission of rheumatic manifestations varied depending on the grade of the manifestations. Conclusions: The clinical, biological, and ultrasound presentations of the patients with adverse events followed by cancer treatments differed from classic rheumatological manifestations. Thorough examinations of these patients by both oncologists and rheumatologists are needed in order to correctly diagnose and treat rheumatological adverse events. Multiple studies that include a larger number of participants are needed in order to better understand the pathogenesis and clinical evolution of these patients under different treatment conditions.

Effectiveness and treatment retention of TNF inhibitors when used as monotherapy versus comedication with csDMARDs in 15 332 patients with psoriatic arthritis. Data from the EuroSpA collaboration.

BACKGROUND: Comedication with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) during treatment with tumour necrosis factor inhibitors (TNFi) is extensively used in psoriatic arthritis (PsA), although the additive benefit remains unclear. We aimed to compare treatment outcomes in patients with PsA treated with TNFi and csDMARD comedication versus TNFi monotherapy. METHODS: Patients with PsA from 13 European countries who initiated a first TNFi in 2006-2017 were included. Country-specific comparisons of 1 year TNFi retention were performed by csDMARD comedication status, together with HRs for TNFi discontinuation (comedication vs monotherapy), adjusted for age, sex, calendar year, disease duration and Disease Activity Score with 28 joints (DAS28). Adjusted ORs of clinical remission (based on DAS28) at 12 months were calculated. Between-country heterogeneity was assessed using random-effect meta-analyses, combined results were presented when heterogeneity was not significant. Secondary analyses stratified according to TNFi subtype (adalimumab/infliximab/etanercept) and restricted to methotrexate as comedication were performed. RESULTS: In total, 15 332 patients were included (62% comedication, 38% monotherapy). TNFi retention varied across countries, with significant heterogeneity precluding a combined estimate. Comedication was associated with better remission rates, pooled OR 1.25 (1.12-1.41). Methotrexate comedication was associated with improved remission for adalimumab (OR 1.45 (1.23-1.72)) and infliximab (OR 1.55 (1.21-1.98)) and improved retention for infliximab. No effect of comedication was demonstrated for etanercept. CONCLUSION: This large observational study suggests that, as used in clinical practice, csDMARD and TNFi comedication are associated with improved remission rates, and specifically, comedication with methotrexate increases remission rates for both adalimumab and infliximab.

The Management of Pancreatic Trauma - A Continuous Challenge.

Background: The aim of this analysis was to assess the factors that influence the severity of pancreatic trauma cases, also underlining the importance of early and accurate diagnosis and proper management of each case. Methods: This study is a retrospective analysis of patients that were presented to the Clinical Emergency Hospital of Bucharest, Romania, in several periods of time: 1985-1990 (50 patients); 1990-1999 (102 patients); 2000-2005 (56 patients); 2012-2019 (48 patients). Results: The mean age was around 40 years old, with predominance of male incidence in all the groups and traffic accidents (blunt trauma) as the main cause of injury. Most patients (almost 50% in each group) were operated on within the first 24 hours from hospital presentation. The general mortality rate varied: 42% (1985-1990), 23.5% (1990-1999), 12.7% (2000-2005) and 33% (2012-2015). Pancreatic mortality rate was 6% (1985-1990 and 1990-1999), 3.5% (2000-2005) and 8% (2012-2019). Conclusions: During the last 35 years, the preoperative diagnosis in patients with trauma of the pancreas remained a challenge and the treatment of the pancreatic trauma suffered a very interesting evolution- from the very frequent laparotomy to the nonoperative management and the damage control. These procedures produced a significant decreasing of the negative or nontherapeutic laparotomies. For the effectiveness of treatment, methods must be correlated with the lesion score.

Impact of discordance between patient's and evaluator's global assessment on treatment outcomes in 14 868 patients with spondyloarthritis.

OBJECTIVES: To assess the impact of 'patient's minus evaluator's global assessment of disease activity' (ΔPEG) at treatment initiation on retention and remission rates of TNF inhibitors (TNFi) in psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) patients across Europe. METHODS: Real-life data from PsA and axSpA patients starting their first TNFi from 11 countries in the European Spondyloarthritis Research Collaboration Network were pooled. Retention rates were compared by Kaplan-Meier analyses with log-rank test and by Cox regression, and remission rates by χ2 test and by logistic regression across quartiles of baseline ΔPEG, separately in female and male PsA and axSpA patients. RESULTS: We included 14 868 spondyloarthritis (5855 PsA, 9013 axSpA) patients. Baseline ΔPEG was negatively associated with 6/12/24-months' TNFi retention rates in female and male PsA and axSpA patients (P <0.001), with 6/12/24-months' BASDAI < 2 (P ≤0.002) and ASDAS < 1.3 (P ≤0.005) in axSpA patients, and with DAS28CRP(4)<2.6 (P ≤0.04) and DAPSA28 ≤ 4 (P ≤0.01), but not DAS28CRP(3)<2.6 (P ≥0.13) in PsA patients, with few exceptions on remission rates. Retention and remission rates were overall lower in female than male patients. CONCLUSION: High baseline patient's compared with evaluator's global assessment was associated with lower 6/12/24-months' remission as well as retention rates of first TNFi in both PsA and axSpA patients. These results highlight the importance of discordance between patient's and evaluator's perspective on disease outcomes.

Retention and response rates in 14 261 PsA patients starting TNF inhibitor treatment-results from 12 countries in EuroSpA.

OBJECTIVE: To investigate TNF inhibitor (TNFi) retention and response rates in European biologic-naïve patients with PsA. METHODS: Prospectively collected data on PsA patients in routine care from 12 European registries were pooled. Heterogeneity in baseline characteristics between registries were explored (analysis of variance and pairwise comparison). Retention rates (Kaplan-Meier), clinical remission [28-joint count DAS (DAS28) <2.6; 28 joint Disease Activity index for Psoriatic Arthritis ⩽4] and ACR criteria for 20% improvement (ACR20)/ACR50/ACR70 were calculated, including LUNDEX adjustment. RESULTS: Overall, 14 261 patients with PsA initiated a first TNFi. Considerable heterogeneity of baseline characteristics between registries was observed. The median 12-month retention rate (95% CI) was 77% (76, 78%), ranging from 68 to 90% across registries. Overall, DAS28/28 joint Disease Activity index for Psoriatic Arthritis remission rates at 6 months were 56%/27% (LUNDEX: 45%/22%). Six-month ACR20/50/70 responses were 53%/38%/22%, respectively. In patients initiating a first TNFi after 2009 with registered fulfilment of ClASsification for Psoriatic ARthritis (CASPAR) criteria (n = 1980) or registered one or more swollen joint at baseline (n = 5803), the retention rates and response rates were similar to those found overall. CONCLUSION: Approximately half of >14 000 patients with PsA who initiated first TNFi treatment in routine care were in DAS28 remission after 6 months, and three-quarters were still on the drug after 1 year. Considerable heterogeneity in baseline characteristics and outcomes across registries was observed. The feasibility of creating a large European database of PsA patients treated in routine care was demonstrated, offering unique opportunities for research with real-world data.

Treatment response and drug retention rates in 24 195 biologic-naïve patients with axial spondyloarthritis initiating TNFi treatment: routine care data from 12 registries in the EuroSpA collaboration.

OBJECTIVE: To study drug retention and response rates in patients with axial spondyloarthritis (axSpA) initiating a first tumour necrosis factor inhibitor (TNFi). METHODS: Data from 12 European registries, prospectively collected in routine care, were pooled. TNFi retention rates (Kaplan-Meier statistics), Ankylosing Spondylitis Disease Activity Score (ASDAS) Inactive disease (<1.3), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) <40 mm and Assessment of SpondyloArthritis International Society responses (ASAS 20/40) were assessed at 6, 12 and 24 months. RESULTS: A first TNFi was initiated in 24 195 axSpA patients. Heterogeneity of baseline characteristics between registries was observed. Twelve-month retention was 80% (95% CI 79% to 80%), ranging from 71% to 94% across registries. At 6 months, ASDAS Inactive disease/BASDAI<40 rates were 33%/72% (LUNDEX-adjusted: 27%/59%), ASAS 20/40 response rates 64%/49% (LUNDEX-adjusted 52%/40%). In patients initiating first TNFi after 2009, 6097 patients was registered to fulfil ASAS criteria for axSpA, 2935 was registered to fulfil modified New York Criteria for Ankylosing Spondylitis and 1178 patients was registered as having non-radiographic axSpA. In nr-axSpA patients, we observed lower 12-month retention rates (73% (70%-76%)) and lower 6-month LUNDEX adjusted response rates (ASDAS Inactive disease/BASDAI40 20%/50%, ASAS 20/40 45%/33%). For patients initiating first TNFi after 2014, 12-month retention rate, but not 6-month response rate, was numerically higher compared with patients initiating TNFi in 2009-2014. CONCLUSION: A large European database of patients with axSpA initiating a first TNFi treatment in routine care, demonstrated that 27% of patients achieved ASDAS inactive disease after 6 months, while 59% achieved BASDAI <40. Four of five patients continued treatment after 1 year.

Efficacy and safety of original and biosimilar etanercept (SB4) in active rheumatoid arthritis - A comparison in a real-world national cohort.

OBJECTIVE: The study aims to compare the efficacy and safety of biosimilar etanercept (SB4) to original etanercept (ETN) in a real-life national cohort of rheumatoid arthritis (RA). METHODS: Data from RA patients were retrieved electronically from the Romanian Registry of Rheumatic Diseases (RRBR), which contains all patients receiving biologics in the country. RESULTS: The study included 242 patients with efficacy and safety data after 6 months of treatment: 123 (50.8%) with ETN, 119 (49.2%) with SB4. There were no significant differences after 6 months regarding composite scores of RA activity between patients on ETN and SB4 (e.g. DAS28 remission: 18.7% in ETN group and 17.6% in SB4 group, p = 0.823; Boolean remission: 11.4% in ETN group and 11.8% in SB4 group, p = 0.926). There were 11 adverse events (AE) in the ETN subgroup (including 3 severe AE: lower respiratory tract infection, enterocolitis and anaphylaxis) and 12 AE in SB4 subgroup (including 4 severe AE: lower respiratory tract infection, vasculitis, anaphylaxis and rash). CONCLUSION: Biosimilar and original etanercept showed similar efficacy and safety after the first 6 months of treatment in RA patients from a national registry, which brings further evidence for biosimilarity in unselected patients in real-world setting.

The challenge of the definition of early symptomatic knee osteoarthritis: a proposal of criteria and red flags from an international initiative promoted by the Italian Society for Rheumatology.

The aim of this study was to establish consensus for potential early symptomatic knee osteoarthritis (ESKOA) clinical definition and referral criteria from primary care to rheumatologists, based on available data from literature and a qualitative approach, in order to perform studies on patients fulfilling such criteria and to validate the obtained ESKOA definition. A complex methodological approach was followed including: (1) three focus groups (FG), including expert clinicians, researchers and patients; (2) a systematic literature review (SLR); (3) two discussion groups followed by a Delphi survey. FG and SLR were performed in parallel to inform discussion groups in order to identify relevant constructs to be included in the modified Delphi survey. ESKOA is defined in the presence of: (a) two mandatory symptoms (knee pain in the absence of any recent trauma or injury and very short joint stiffness, lasting for less than 10 min, when starting movement) even in the absence of risk factors, or (b) knee pain, and 1 or 2 risk factors or (c) three or more risk factors in the presence of at least one mandatory symptom, with symptoms lasting less than 6 months. These criteria are applicable in the absence of active inflammatory arthritis, generalized pain, Kellgren-Lawrence grade >0, any recent knee trauma or injury, and age lower than 40 years. Knee pain in the absence of any recent trauma lasting for less than 6 months was considered as the referral criterion to the rheumatologist for the suspicion of ESKOA. This consensus process has identified provisional clinical definition of ESKOA and defined potential referral criterion to rheumatologist, in order to test ESKOA obtained definition in prospective validation studies.

Digital ulcers predict a worse disease course in patients with systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is a systemic autoimmune disease with high morbidity and significant mortality. There is a great need of predictors that would allow risk stratification of patients with SSc and ultimately initiation of treatment early enough to ensure optimal clinical results. In this study, we evaluated whether a history of digital ulcers (HDU) at presentation may be a predictor of vascular outcomes and of overall clinical worsening and death in patients with SSc. METHODS: Patients from the EULAR Scleroderma Trials and Research (EUSTAR) database, satisfying at inclusion the 1980 American College of Rheumatology classification criteria for SSc, who had a follow-up of at least 3 years since baseline or who have died, were included in the analysis. HDU at presentation as a predictor of disease worsening or death was evaluated by Cox proportional hazards regression analysis. RESULTS: 3196 patients matched the inclusion criteria (male sex 13.2%, 33.4% diffuse subset). At presentation, 1092/3196 patients had an HDU (34.1%). In multivariable analysis adjusting for age, gender and all parameters considered potentially significant, HDU was predictive for the presence of active digital ulcers (DUs) at prospective visits (HR (95% CI)): 2.41 (1.91 to 3.03), p<0.001, for an elevated systolic pulmonary arterial pressure on heart ultrasound (US-PAPs):1.36 (1.03 to 1.80), p=0.032, for any cardiovascular event (new DUs, elevated US-PAPs or LV failure): 3.56 (2.26 to 5.62), p<0.001, and for death (1.53 (1.16 to 2.02), p=0.003). CONCLUSIONS: In patients with SSc, HDU at presentation predicts the occurrence of DUs at follow-up and is associated with cardiovascular worsening and decreased survival.

Development of patient-centred standards of care for osteoarthritis in Europe: the eumusc.net-project.

OBJECTIVE: The eumusc.net project is an initiative founded by the European Community and the European League Against Rheumatism. One aim of the project was to facilitate equal standards for musculoskeletal health across Europe. The aim of this work-package was to develop patient-centred and consensus based standards of care (SOC) for osteoarthritis (OA), which should be available in a professional and a patient version. METHODS: A systematic review concerning guidelines dealing with OA was conducted. Furthermore, experts in musculoskeletal diseases were contacted to ensure that 'grey' literature was not excluded. Documents that fulfilled predefined inclusion/exclusion criteria were included and all interventions for OA were extracted and categorised. Based on this list of interventions, a three round Delphi exercise with an international and multidisciplinary expert panel, including patient research partners, was performed to achieve expert consensus. RESULTS: Six documents were included and used for further analysis. Out of them, 46 interventions have been extracted and 10 consensus based SOC were formulated. In addition, a patient version, written in a lay-understandable wording and in the format of checklist questions was developed. An example is SOC 5: "People with OA should achieve optimal pain control using pharmacological and non-pharmacological means." The matching patient-centred checklist question reads: "Do I know how to control pain associated with OA?" CONCLUSIONS: The SOC for OA will be available in the 23 languages of the European Union to enhance unified information to patients and professionals and to further harmonise the treatment/care of OA within Europe.

Women's health and fertility, family planning and pregnancy in immune-mediated rheumatic diseases: a report from a south-eastern European Expert Meeting.

With current advances in medical treatment, reproductive issues have become more important for women with chronic immune-mediated diseases. Most, if not all, patients report that their disease affects their personal relationships, their decision to have children, and the size of their family. These decisions are multi-factorial, influenced mainly by concerns over the effect of pregnancy on the rheumatic disease, the impact of disease activity during pregnancy on foetal health, the patient's ability to care for the child, and the possible harmful effects medication could have on the child, both pre- and post-natally during breastfeeding. Apart from that, women's health issues tend to be overlooked in favour of the management of the underlying rheumatic disease. To this end, we convened an expert panel to review the published literature on women's health and reproductive issues and provide evidence- and eminence-based points to consider for the treating physicians. We conclude that there is a need for a change in mind-set from one which 'cautions against pregnancy' to one which 'embraces pregnancy' through the practice of individualised, pre- and post-conceptual, multi-disciplinary care.

Characterizing changes in levan physicochemical properties in different pH environments using asymmetric flow field-flow fractionation.

The purpose of this study was to assess the stability of the polyfructan levan under different pH solution conditions by monitoring changes in the levan physicochemical properties, such as molar mass (M), root mean square radius (r(rms)), hydrodynamic radius (r(h)), structure factor (r(rms)/r(h)), and aggregation state with respect to solution pH and hydrolysis time. A commercial levan produced from Z. Mobilis was characterized using asymmetric flow field-flow fractionation (AF4) in combination with online multiangle light scattering (MALS) and differential refractive index (dRI) detection. Under neutral pH solution conditions the levan was found to have a M ranging from 10(5) to 5 × 10(7) g/mol, a r(rms) ranging from ~25 to 100 nm and a r(h) from ~3 to 151 nm. Two populations were observed in the sample. One population with a M less than 106 g/mol which represented ~60 % of the sample and a second population with an ultrahigh M up to 5 × 10(7) g/mol, which comprised ~40 % of the sample. The measured r(rms)/r(h) structure factor decreased from 1.8 to 0.65 across the AF4 fractogram indicating that early eluting low M levan species had a random coil configuration and late eluting high M species had more homogeneous spherical structures. The measured apparent density values decreased from 80 to 10 kg/m(3) across the elution profile and suggest that the observed second population also contains aggregates. The stability of levan in different pH conditions ranging from 1.3 to 8.5 was assessed by tracking changes in the average M and r(h), and monitoring the formation of fructose over 1 week. The onset of levan acid hydrolysis was observed to occur sooner at lower pH conditions and no hydrolysis was observed for pH 5.5 and higher.

Guideline-Optimised Treatment in Heart Failure-Do Higher Doses Reduce Systemic Inflammation More Significantly?

Background: Chronic inflammation is a constant phenomenon which accompanies the heart failure pathophysiology. In all phenotypes of heart failure, irrespective of the ejection fraction, there is a permanent low-grade activation and synthesis of proinflammatory cytokines. Many classes of anti-remodelling medication used in the treatment of chronic heart failure have been postulated to have an anti-inflammatory effect. Methods: This retrospective study enrolled 220 patients and focused on evaluating the effect of the most used active substances from these classes in reducing the level of inflammatory biomarkers (C reactive protein, erythrocyte sedimentation rate and fibrinogen) after initiation or up-titration. Our research is evaluating if this anti-inflammatory effect intensifies while raising the dose. The evaluation was performed at two visits with an interval between them of 6 months. Results: From the beta-blockers class, carvedilol showed a reduction in erythrocyte sedimentation rate (ESR), in low (6.25 mg, bi daily) and medium (12.5 mg, bi daily) doses. At the same time, sacubitril/valsartan showed a reduction in CRP levels. This effect was obtained only in the medium (49/51 mg, bi daily) and high (97/103 mg, bi daily) doses, with the maximum reduction being observed in the high dose. Conclusions: From the classes of medication evaluated, the study showed a significant reduction in ESR levels in the low and medium doses of carvedilol and a reduction in CRP values in the cases of medium and high doses of ARNI.

Drug effectiveness of 2nd and 3rd TNF inhibitors in psoriatic arthritis - relationship with the reason for withdrawal from the previous treatment.

OBJECTIVE: To investigate real-world retention and remission rates in PsA patients initiating a 2nd or 3rd TNFi and the association with reason for discontinuation from the previous TNFi-treatment. METHODS: Prospectively collected routine care data from 12 European registries were pooled. Retention rates (Kaplan-Meier estimation) and crude/LUNDEX-adjusted rates of Disease Activity Score 28 and Disease Activity index for PSoriatic Arthritis (DAS28 and DAPSA28) remission were calculated and compared with adjusted Cox regression analyses and Chi-squared test, respectively). RESULTS: We included 5233 (2nd TNFi) and 1906 (3rd TNFi) patients. Twelve-month retention rates for the 2nd and 3rd TNFi were 68% (95%CI: 67-70%) and 66% (64-68%), respectively. Patients who stopped the previous TNFi due to AE/LOE had 12-month retention rates of 66%/65% (2nd TNFi), and 65%/63% (3rd TNFi), respectively. Patients who stopped the previous TNFi due to LOE after less vs more than 24 weeks had 12-month retention rates of 54%/69% (2nd TNFi), and 58%/65% (3rd TNFi). Six-month crude/LUNDEX-adjusted DAS28 remission rates were 48%/35% and 38%/27%, and DAPSA28 remission rates were 19%/14% and 14%/10%, for the 2nd and 3rd TNFi. CONCLUSION: Two-thirds of patients remained on TNFi at 12months for both the 2nd and 3rd TNFi, while one-third and one-quarter of patients were in DAS28 remission after 6months on the 2nd and 3rd TNFi. While drug effectiveness was similar in patients who stopped the previous TNFi due to AE compared to overall LOE, drug effectiveness was better in patients who had stopped the previous TNF due to secondary LOE compared to primary LOE.

Links between Metabolic Syndrome and Hypertension: The Relationship with the Current Antidiabetic Drugs.

Hypertension poses a significant burden in the general population, being responsible for increasing cardiovascular morbidity and mortality, leading to adverse outcomes. Moreover, the association of hypertension with dyslipidaemia, obesity, and insulin resistance, also known as metabolic syndrome, further increases the overall cardiovascular risk of an individual. The complex pathophysiological overlap between the components of the metabolic syndrome may in part explain how novel antidiabetic drugs express pleiotropic effects. Taking into consideration that a significant proportion of patients do not achieve target blood pressure values or glucose levels, more efforts need to be undertaken to increase awareness among patients and physicians. Novel drugs, such as incretin-based therapies and renal glucose reuptake inhibitors, show promising results in decreasing cardiovascular events in patients with metabolic syndrome. The effects of sodium-glucose co-transporter-2 inhibitors are expressed at different levels, including renoprotection through glucosuria, natriuresis and decreased intraglomerular pressure, metabolic effects such as enhanced insulin sensitivity, cardiac protection through decreased myocardial oxidative stress and, to a lesser extent, decreased blood pressure values. These pleiotropic effects are also observed after treatment with glucagon-like peptide-1 receptor agonists, positively influencing the cardiovascular outcomes of patients with metabolic syndrome. The initial combination of the two classes may be the best choice in patients with type 2 diabetes mellitus and multiple cardiovascular risk factors because of their complementary mechanisms of action. In addition, the novel mineralocorticoid receptor antagonists show significant cardio-renal benefits, as well as anti-inflammatory and anti-fibrotic effects. Overall, the key to better control of hypertension in patients with metabolic syndrome is to consider targeting multiple pathogenic mechanisms, using a combination of the different therapeutic agents, as well as drastic lifestyle changes. This article will briefly summarize the association of hypertension with metabolic syndrome, as well as take into account the influence of antidiabetic drugs on blood pressure control.

Comparative Analysis of Hematological and Immunological Parameters in Patients with Primary Sjögren's Syndrome and Peripheral Neuropathy.

BACKGROUND: Primary Sjögren syndrome (pSS) is a multisystem disorder of autoimmune etiology, frequently involving peripheral nerves. Early detection of peripheral neuropathy (PN) manifestations might improve prognosis and disease control. The purpose of the study was to evaluate the predictive potential of hematological and immunological parameters associated with PN development in pSS patients. METHODS: This single-center retrospective study included patients with pSS who were divided into two groups, according to the occurrence of neurological manifestations throughout the follow-up period. RESULTS: From the total of 121 pSS patients included in the study, 31 (25.61%) developed neurological manifestations (PN+ group) during the follow-up period. At the moment of pSS diagnosis, 80.64% of PN+ patients exhibited increased disease activity, with ESSDAI scores above 14 (p = 0.001), and significantly higher values for VASp score (p = 0.001), with a mean value of 4.90 ± 2.45, compared to 1.27 ± 1.32 in the PN- group. The hematological assessment at the moment of pSS diagnosis revealed that neutrophils and neutrophil-to-lymphocyte ratio (NLR) were significantly higher in the PN+ group (p = 0.001), while lymphocytes, monocytes and monocyte-to-lymphocyte ratio (MLR) were significantly lower (p = 0.025, p = 0.13 and p = 0.003, respectively). Immuno-inflammatory parameters-gammaglobulins, complement fractions C3, C4, total proteins and vitamin D were significantly lower in the PN+ patients' group. In multivariate analysis, the independent predictive character for PN development in pSS patients was confirmed for NLR (95% CI 0.033 to 0.263, p = 0.012), MLR (95% CI -1.289 to -0.194, p = 0.008), gammaglobulins (95% CI -0.426 to -0.088, p < 0.003), complement fraction C4 (95% CI -0.018 to -0.001, p < 0.030) and vitamin D (95% CI -0.017 to -0.003, p < 0.009). CONCLUSIONS: Readily available and frequently used hematological and immunological markers, such as NLR, MLR, gammaglobulins, C4 and vitamin D could be helpful in predicting the neurological involvement in pSS patients. These biological parameters might become useful tools for clinicians to monitor disease progression and identify potentially severe extraglandular manifestations in pSS patients.