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Importance: Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking. Objective: To investigate the effectiveness of DMTs on the risk of becoming wheelchair dependent in a real-world population of patients with PPMS. Design, Setting, and Participants: This was a multicenter, observational, retrospective, comparative effectiveness research study. Data were extracted on November 28, 2018, from the Italian multiple sclerosis register and analyzed from June to December 2021. Mean study follow-up was 11 years. Included in the study cohort were patients with a diagnosis of PPMS and at least 3 years of Expanded Disability Status Scale (EDSS) evaluations and 3 years of follow-up. Main Outcomes and Measures: The risk of reaching an EDSS score of 7.0 was assessed through multivariable Cox regression models. Exposures: Patients who received DMT before the outcome were considered treated. DMT was assessed as a time-dependent variable and by class of DMT (moderately and highly effective). Results: From a total of 3298 patients with PPMS, 2633 were excluded because they did not meet the entry criteria for the phase 3, multicenter, randomized, parallel-group, double-blind, placebo-controlled study to evaluate the efficacy and safety of ocrelizumab in adults with PPMS (ORATORIO) trial. Among the remaining 665 patients (mean [SD] age, 43.0 [10.7] years; 366 female patients [55.0%]), 409 were further selected for propensity score matching (288 treated and 121 untreated patients). In the matched cohort, during the study follow-up, 37% of patients (152 of 409) reached an EDSS score of 7.0 after a mean (SD) follow-up of 10.6 (5.6) years. A higher EDSS score at baseline (adjusted hazard ratio [aHR], 1.32; 95% CI, 1.13-1.55; P

Background HbA1c variability has emerged as risk factor for cardiovascular diseases in diabetes. However, the impact of HbA1c variability on cardiovascular diseases in subjects within the recommended HbA1c target has been relatively unexplored. Methods Using data from a large database, we studied 101,533 people with type 2 diabetes without cardiovascular diseases. HbA1c variability was expressed as quartiles of the standard deviation of HbA1c during three years (exposure phase). The primary composite outcome included non-fatal myocardial infarction, non-fatal stroke, all-cause mortality and was assessed during five years following the first three years of exposure to HbA1c variability (longitudinal phase). An expanded composite outcome including non-fatal myocardial infarction, non-fatal stroke, coronary revascularization/reperfusion procedures, peripheral revascularization procedures, and all-cause mortality was also considered, as well as a series of specific cardiovascular complications. Cox models were adjusted for a large range of risk factors and results were expressed as adjusted hazard ratios. Results An association between HbA1c variability and all the outcomes considered was found. The correlation between HbA1c variability and cardiovascular complications development was confirmed in both the subgroups of subjects with a mean HbA1c ≤ 53 mmol/mol (recommended HbA1c target) or > 53 mmol/mol during the exposure phase. The risk related to HbA1c variability was higher in people with mean HbA1c ≤ 53 mmol/mol for the primary outcome (p for interaction 0.004), for the expanded secondary outcome (p for interaction 0.001) and for the stroke (p for interaction 0.001), even though HbA1c remained at the target during the follow-up. Conclusions These findings suggest that HbA1c variability may provide additional information for an optimized management of diabetes, particularly in people within the target of HbA1c.

Background It is unknown whether contemporary drug‐eluting stents have a similar safety profile in high bleeding risk patients treated with 1‐month dual antiplatelet therapy following percutaneous coronary interventions. Methods and Results We performed an interventional, prospective, multicenter, single‐arm trial, powered for noninferiority with respect to an objective performance criterion to evaluate the safety of percutaneous coronary interventions with Synergy bioresorbable‐polymer everolimus‐eluting stent followed by 1‐month dual antiplatelet therapy in patients with high bleeding risk. In case of need for an oral anticoagulant, patients received an oral anticoagulant in addition to a P2Y 12 inhibitor for 1 month, followed by an oral anticoagulant only. The primary end point was the composite of cardiac death, myocardial infarction, or definite or probable stent thrombosis at 1‐year follow‐up. The study was prematurely interrupted because of slow recruitment. From April 2017 to October 2019, 443 patients (age, 74.8±9.2 years; women, 29.1%) at 10 Italian centers were included. The 1‐year primary outcome occurred in 4.82% (95% CI, 3.17%–7.31%) of patients, meeting the noninferiority compared with the predefined objective performance criterion of 9.4% and the noninferiority margin of 3.85% ( P noninferiority Conclusions Among high bleeding risk patients undergoing percutaneous coronary interventions with the Synergy bioresorbable‐polymer everolimus‐eluting stent, a 1‐month dual antiplatelet therapy regimen is safe, with low rates of ischemic and bleeding events. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03112707 .

Aims Adults affected by obesity are at higher risk of premature mortality. Medications can help to lose weight and to maintain weight loss. Aim of this meta-analysis was to assess whether anti-obesity medications affect all-cause mortality, mortality due to cardiovascular events, cardiovascular risk factors and body weight. Data synthesis A Medline search was performed to identify randomized controlled trials (RCTs) of anti-obesity medications in adults with overweight or obesity reporting data on all-cause mortality, cardiovascular mortality or non-fatal cardiovascular events, with a follow-up of at least 6 months. We identified 28 RCTs with 50,106 participants. The median follow-up was 52 weeks. Evidence did not show superiority of anti-obesity medications over placebo in reducing all-cause mortality (risk ratio 1.03, 95%Confidence Interval [CI] 0.87 to 1.21) or cardiovascular mortality (risk ratio 0.92, 95%CI 0.72 to 1.18). All-cause mortality rate was positively associated with weight loss (β = 0.0007; p = 0.045); hence, for each kg of body weight lost there was a 0.07% decrease of all-cause mortality. The pharmacological treatment reduced total-cholesterol (7.15 mg/dl; 95%CI 1.46–12.85), LDL-cholesterol (5.06 mg/dl; 95%CI 1.12–9.00), and triglycerides levels (9.88 mg/dl; 95%CI 5.02–14.75), while it increased HDL-cholesterol (1.37 mg/dl; 95%CI 0.17–2.57). Systolic blood pressure decreased (0.90 mmHg; 95%CI 0.15–1.64). Conclusions Although we were unable to demonstrate a superiority of anti-obesity medications over placebo on mortality, metaregression showed that even a small weight reduction tends to reduce all-cause mortality in obesity. Our data support public health measures to reduce the obesity burden by including the use of anti-obesity medications. Registration number (PROSPERO) CRD42020210329.

Background and ObjectivesSeveral studies have assessed risk factors associated with the severity of COVID-19 outcomes in people with multiple sclerosis (PwMS). The potential role of disease-modifying therapies (DMTs) and demographic and clinical factors on the risk of acquiring SARS-CoV-2 infection has not been evaluated so far. The objective of this study was to assess risk factors of contracting SARS-CoV-2 infection in PwMS by using data collected in the Italian MS Register (IMSR).MethodsA case-control (1:2) study was set up. Cases included PwMS with a confirmed diagnosis of COVID-19, and controls included PwMS without a confirmed diagnosis of COVID-19. Both groups were propensity score–matched by the date of COVID-19 diagnosis, the date of last visit, and the region of residence. No healthy controls were included in this study. COVID-19 risk was estimated by multivariable logistic regression models including demographic and clinical covariates. The impact of DMTs was assessed in 3 independent logistic regression models including one of the following covariates: last administered DMT, previous DMT sequences, or the place where the last treatment was administered.ResultsA total of 779 PwMS with confirmed COVID-19 (cases) were matched to 1,558 PwMS without COVID-19 (controls). In all 3 models, comorbidities, female sex, and a younger age were significantly associated (p < 0.02) with a higher risk of contracting COVID-19. Patients receiving natalizumab as last DMT (OR [95% CI]: 2.38 [1.66–3.42], p < 0.0001) and those who underwent an escalation treatment strategy (1.57 [1.16–2.13], p = 0.003) were at significantly higher COVID-19 risk. Moreover, PwMS receiving their last DMT requiring hospital access (1.65 [1.34–2.04], p < 0.0001) showed a significant higher risk than those taking self-administered DMTs at home.DiscussionThis case-control study embedded in the IMSR showed that PwMS at higher COVID-19 risk are younger, more frequently female individuals, and with comorbidities. Long-lasting escalation approach and last therapies that expose patients to the hospital environment seem to significantly increase the risk of SARS-CoV2 infection in PwMS.Classification of EvidenceThis study provides Class III evidence that among patients with MS, younger age, being female individuals, having more comorbidities, receiving natalizumab, undergoing an escalating treatment strategy, or receiving treatment at a hospital were associated with being infected with COVID-19. Among patients with MS who were infected with COVID-19, a severe course was associated with increasing age and having a progressive form of MS, whereas not being on treatment or receiving an interferon beta agent was protective.

Summary Background Cardiovascular and kidney outcome trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors slow progression of chronic kidney disease in patients with type 2 diabetes with or without chronic kidney disease. The aim of this study was to assess whether these benefits extend to patients with type 2 diabetes treated in routine clinical practice. Methods CVD-REAL 3 was a multinational observational cohort study in which new users of SGLT2 inhibitors and other glucose-lowering drugs with measurements of estimated glomerular filtration rate (eGFR) before and after (within 180 days) initiation were identified via claims, medical records, and national registries in Israel, Italy, Japan, Taiwan, and the UK. Propensity scores for SGLT2 inhibitor initiation were developed in each country, with 1:1 matching with initiators of other glucose-lowering drugs. Propensity score included (in addition to other clinical and demographic variables) baseline eGFR and eGFR slope before SGLT2 inhibitor or other glucose-lowering drug initiation. The main outcome measure was rate of eGFR decline (slope) calculated with a linear mixed regression model. Differences in eGFR slope between SGLT2 inhibitors and other glucose-lowering drugs were calculated and pooled. We also assessed a composite outcome of 50% eGFR decline or end-stage kidney disease. Findings After propensity matching, there were 35 561 episodes of treatment initiation in each group, from 65 231 individual patients. Dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, and luseogliflozin accounted for 57·9%, 34·1%, 5·7%, 1·4%, 0·5%, and 0·4% of SGLT2 inhibitor initiation episodes, respectively. At baseline, 29 363 (41·3%) of 71 122 initiations were in women, mean age was 61·3 years, mean HbA1c was 72 mmol/mol (8·71%), and mean eGFR was 90·7 mL/min per 1·73 m2. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs other glucose-lowering drugs 1·53 mL/min per 1·73 m2 per year, 95% CI 1·34–1·72, p Interpretation In this large, international, real-world study of patients with type 2 diabetes, initiation of SGLT2 inhibitor therapy was associated with a slower rate of kidney function decline and lower risk of major kidney events compared with initiation of other glucose-lowering drugs. These data suggest that the benefits of SGLT2 inhibitors on kidney function identified in clinical trials seem to be largely generalisable to clinical practice. Funding AstraZeneca.

In this study, we evaluated the knowledge, attitudes, and psychosocial impacts among Brazilian pediatric dentists during the COVID-19 pandemic. A cross-sectional study with primary data collection was carried out using an online structured questionnaire. Data were submitted to descriptive analysis by using absolute and relative frequencies. A chi-square test was used for association analysis and log-linear regression models to estimate the prevalence ratio (5%). The population comprised mostly women and knowledge regarding COVID-19 was satisfactory (above 80% in most items). N95 masks and faceshields were used, albeit 64.22% reported difficulty in providing dental care to children due to the need for extra Personal Protective Equipment. Thirty eight percent provided urgency/emergency dental care, 59.78% performed invasive procedures, 59.56% used high speed handpieces, 8.44% started using cariostatics, and 6.22% introduced the use of chemomechanical caries removal agents. Fear for the future (PR = 1.21) and use of medications (for anxiety, depression, or insomnia) increased (PR = 1.16) among the ones who had wage losses. Brazilian pediatric dentists have knowledge about COVID-19, and attitudes in their clinical routines changed due the pandemic. Financial life was harmed and a negative impact of the pandemic in psychosocial aspects of workers was found.

An ever-expanding number of disease-modifying drugs for multiple sclerosis have become available in recent years, after demonstrating efficacy in clinical trials. In the real-world setting, however, disease-modifying drugs are prescribed in patient populations that differ from those included in pivotal studies, where extreme age patients are usually excluded or under-represented. In this multicentre, observational, retrospective Italian cohort study, we evaluated treatment exposure in three cohorts of patients with relapsing-remitting multiple sclerosis defined by age at onset: paediatric-onset (≤18 years), adult-onset (18–49 years) and late-onset multiple sclerosis (≥50 years). We included patients with a relapsing-remitting phenotype, ≥5 years follow-up, ≥3 Expanded Disability Status Scale (EDSS) evaluations and a first neurological evaluation within 3 years from the first demyelinating event. Multivariate Cox regression models (adjusted hazard ratio with 95% confidence intervals) were used to assess the risk of reaching a first 12-month confirmed disability worsening and the risk of reaching a sustained EDSS of 4.0. The effect of disease-modifying drugs was assessed as quartiles of time exposure. We found that disease-modifying drugs reduced the risk of 12-month confirmed disability worsening, with a progressive risk reduction in different quartiles of exposure in paediatric-onset and adult-onset patients [adjusted hazard ratios in non-exposed versus exposed >62% of the follow-up time: 8.0 (3.5–17.9) for paediatric-onset and 6.3 (4.9–8.0) for adult-onset, P

BackgroundThere is a high incidence of cardiovascular disease in diabetes. Weight variability has been reported as independent risk factor for cardiovascular disease in the general population and preliminarily also in people with type 2 diabetes.MethodsUsing data from the Swedish National Diabetes Register the possible link between visit-to-visit body weight variability and the risk of cardiovascular complications among people with type 2 diabetes and without prevalent cardiovascular diseases at baseline has been evaluated. Overall, 100,576 people with type 2 diabetes, with at least five measurements of body weight taken over three consecutive years, were included. Variability was expressed as quartiles of the standard deviation of the measures during the three years. The primary composite outcome included non-fatal myocardial infarction, non-fatal stroke, and all-cause mortality and was assessed during five years following the first 3 years of exposure to weight variability.ResultsAfter adjusting for known cardiovascular risk factors, the risk of the primary composite outcome significantly increased with increasing body weight variability [upper quartile HR = 1.45; 95% confidence interval 1.39–1.52]. Furthermore, elevated body weight variability was associated with almost all the other cardiovascular complications considered (non-fatal myocardial infarction, non-fatal stroke, all-cause mortality, peripheral arterial disease, peripheral vascular angioplasty, hospitalization for heart failure, foot ulcer, and all-cause mortality).ConclusionsHigh body weight variability predicts the development of cardiovascular complications in type 2 diabetes. These data suggest that any strategy to reduce the body weight in these subjects should be aimed at maintaining the reduction in the long-term, avoiding oscillations.

AimsTo evaluate deep corneal densitometry and visual outcomes after big-bubble (BB-DALK) and visco-bubble (VB-DALK) deep anterior lamellar keratoplasty performed in patients with keratoconus.MethodsProspective comparative study of 50 advanced keratoconic patients who underwent DALK surgery; 25 eyes (group I) were completed with BB-DALK and 25 eyes (group II) with VB-DALK after the failure of pneumatic dissection. Best spectacle-corrected visual acuity (BSCVA), corneal tomographic parameters and endothelial cell count were recorded 1, 3, 6, 12 and 24 months after surgery. Densitometric analysis of the deep corneal interface was obtained using Scheimpflug tomography at each visit; values recorded were compared between the two groups and statistically analysed.ResultsBSCVA was significantly better in the BB-DALK group than the VB-DALK group (0.39±0.29 vs 0.65±0.23 logarithm of the minimum angle of resolution, respectively) for the first 3 months; and in the same time period, densitometry was significantly higher in the VB-DALK group than those recorded in the BB-DALK group (23.97±5.34 vs 17.13±4.44 grayscale units). However, densitometric values and visual acuity did not differ significantly in the two groups at 1 year. No statistically significant difference for the other variables analysed at any time frame was found.ConclusionThe use of viscoelastic substance in the VB-DALK technique may induce modification of interface stromal reflectivity resulting in reduced visual acuity up to 3 months postoperatively. However, this initial negative effect on the interface quality does not affect the long-term visual outcome, with densitometric values and visual outcomes similar in the two groups from 6 months postoperatively.

There are conflicting data about the role of transplant nephrectomy and immunosuppression withdrawal on the development of allosensitization and the impact on re-transplantation. We divided 109 first graft recipients into two groups according to whether they underwent nephrectomy (NX+, n = 61) or their graft was left in situ (NX-, n = 48). Sera were assessed for HLA-A/B/Cw/DR/DQ antibodies at the time of NX/transplant failure and after 3, 6, 12, 24 months. The NX+ group showed a higher rate of donor specific antibody (DSA) and non-DSA human leukocyte antigen (HLA) antibody production at all the time points. Multivariable analysis showed that nephrectomy was a strong, independent risk factor for the development of DSAs after 12 and 24 months (P = 0.005 and 0.008). In the NX- group, low tacrolimus levels correlated with DSA formation (AUC 0.817, P = 0.002; best cut-off level 2.9 ng/ml). Analysis with a standardized pool of UK donors showed a more difficult grade of HLA matchability following nephrectomy compared with the NX- group. Nephrectomy is followed by the long-term production of DSA and non-DSA HLA antibodies and negatively impacts on the chances of finding a HLA-compatible kidney. Tacrolimus levels ≥3 ng/ml are protective against the development of allosensitization and could facilitate re-transplantation in the NX- group.

In the last years, due to new regulatory guidelines requiring a stringent documentation of cardiovascular (CV) safety of novel drugs for type 2 diabetes, cardiovascular outcomes safety trials (CVOTs) are requested. CVOTs increase the knowledge about the safety profile of the new drugs, but they have intrinsic limits that make difficult their transferability to clinical practice. For this reason, real world evidence is considered an important complement to experimental data. Among the glucagon-like peptide-1 receptor agonists, liraglutide in the LEADER CVOT demonstrated superiority in reducing the risk of major CV events (MACEs) vs. placebo. We conducted an observational, retrospective, longitudinal study based on 307 patients with T2DM treated with liraglutide under routine clinical practice conditions. Real world impact of liraglutide on metabolic control, CV risk factors, hypoglycemia and CV events was assessed. Improvements during 36 months were found in HbA1c (–1.0%; p Incidence of MACEs in this cohort was lower than in the LEADER study (2.59 vs. 3.4 events per 100 person-years), confirming CV safety of liraglutide even in the real world. On the other hand, a higher incidence of CV event in patients with established CV disease was documented (8.1 events per 100 person-years), in spite of the use of liraglutide. In conclusion, 36-month durability and CV safety of liraglutide were documented in a real world cohort of T2DM patients, with sustained benefits on a large array of CV risk factors.

From population studies, solid organ transplant recipients are at increased risk of mortality from RT-PCR confirmed COVID-19 infection. The risk factors associated with infection acquisition and mortality in transplant recipients using serological data have not been reported.From 1725 maintenance transplant recipients, 855 consecutive patients were screened for SARS-CoV-2 antibodies. Serological screening utilized assays to detect both the N protein and receptor binding domain antibodies. Thirty-three of 855 (3.9%) of the screened patients had prior infection confirmed with RT-PCR. Twenty-one additional patients from our 1725 maintenance cohort with RT-PCR confirmed infection were included in our analysis.Eighty-nine of 855 (10.4%) patients tested positive for SARS-CoV-2 antibodies. Fifty-nine of 89 (66.3%) cases were patients newly identified as exposed, while 30/89 (33.7%) seropositive patients had previous infection confirmed by RT-PCR. A diagnosis of SARS-CoV-2 (RT-PCR or Ab+) was associated with being from a noncaucasoid background, P = 0.015; having a diagnosis of diabetes, P = 0.028 and a history of allograft rejection, P 0.01. Compared with the RT-PCR+ cohort, patients with serological-proven infection alone were more likely to be receiving tacrolimus monotherapy, P 0.01, and less likely to have a diagnosis of diabetes, P = 0.012. Seventeen of 113 (15.0%) of all patients with infection (RT-PCR and Ab+) died. Risk factors associated with survival were older age, odds ratio (OR): 1.07 (1.00-1.13), P = 0.041; receiving prednisolone, OR: 5.98 (1.65-21.60), P 0.01 and the absence of diabetes, OR: 0.27 (0.07-0.99), P = 0.047.This study identifies risk factors and outcome for COVID-19 infection incorporating data on serologically defined infection and highlights the important contribution of immunosuppression regimen on outcomes.

Background The risk of COVID-19 infection in transplant recipients is unknown. Patients on dialysis may be exposed to greater risk of infection due to an inability to isolate. Consideration of these competing risks is important before restarting suspended transplant programs. This study compared outcomes in kidney and kidney/pancreas transplant recipients with those on the waiting list, following admission with COVID-19 in a high prevalence region. Methods Audit data from all 6 London transplant centres were amalgamated. Demographic and laboratory data were collected and outcomes included mortality, intensive care (ITU) admission and ventilation. Adult patients who had undergone a kidney or kidney/pancreas transplant, and those active on the transplant waiting list at the start of the pandemic were included. Results 121 transplant recipients (TR) and 52 waiting list patients (WL) were admitted to hospital with COVID-19. 36 TR died (30%), whilst 14 WL patients died (27% p=0.71). There was no difference in rates of admission to ITU or ventilation. 24% of TR required renal replacement therapy, and 12% lost their grafts. Lymphocyte nadir and D-dimer peak showed no difference in those who did and did not die. No other co-morbidities or demographic factors were associated with mortality, except for age (odds ratio of 4.3 [95% CI 1.8 - 10.2] for mortality if aged over 60 years) in TR. Conclusions Transplant recipients and waiting list patients have similar mortality rates after hospital admission with COVID-19. Mortality was higher in older transplant recipients. These data should inform decisions about transplantation in the COVID era.

Animal studies have shown that irisin is a myokine secreted following physical exercise, and that it induces the remodeling of white adipose tissue toward brown adipose tissue. Therefore, a protective role of irisin against obesity, diabetes, and other metabolic and cardiovascular conditions has been hypothesized. However, data in humans are contradictory and few data are available concerning the general population.We aimed to evaluate the association between serum irisin concentrations and habitual physical activity, as well as other metabolic and cardiovascular factors in a general population in a Mediterranean area.We considered 858 consecutive individuals included in the ABCD (Alimentazione, Benessere Cardiovascolare e Diabete) study (ISRCTN15840340), a longitudinal observational single-center study of a cohort representative of the general population of Palermo, Sicily. Irisin serum concentrations (Phoenix Europe, Germany), habitual physical activity (HPA) level, and other blood and clinical variables were measured.The irisin serum concentrations were not normally distributed in the cohort (Shapiro-Wilk test=0.94; P0.001). A significant association between irisin concentrations and HPA was observed (P0.001). Irisin concentrations were higher in women than in men (P0.01), and significantly correlated with serum concentrations of HDL-cholesterol (P0.05) and hs-C-reactive protein (hs-CRP; P0.05). Binary logistic regression analysis demonstrated that high (⩾ median value) irisin serum concentrations were significantly associated with female gender (OR=1.63; 95% CI=1.16-2.28), high serum hs-CRP concentrations (OR=1.61; 95% CI=1.02-2.54) and the HPA level (OR=1.42; 95% CI=1.02-1.96).Our study confirms, in a cohort of a general population, that irisin concentrations gradually increase with the usual level of habitual physical activity.

Previous studies have investigated constructs that facilitate adaptation to chronic disease and improve quality of life and constructs that lead to psychopathological complications. The purpose of this research is to investigate the impact of coping and emotional regulation on the quality of life of patients on dialysis. Three questionnaires were administered to 78 patients on dialysis: Coping Orientations to Problems Experienced, Short Form (36), and Cognitive Emotion Regulation Questionnaire. Regressions analyses indicated that age, Rumination, Positive Refocusing, Avoidance Strategies, Approach to the Problem, and Transcendent Orientation predicted Physical Health. With regard to Mental Health, the predictors were gender, Self-Blame, Acceptance, Rumination, Positive Reappraisal, Catastrophizing, Avoidance Strategies, and Transcendent Orientation. This study confirms the relationship between emotional regulation, coping, and quality of life. The results highlight the need for total care of the patients, including an assessment of both physical state and psychological functioning in order to promote total well-being.

Objective The aim of this work was to assess through a questionnaire the features of vertiginous episodes, accompanying symptoms, familial history, and migraine precursors in a sample of 252 subjects with a diagnosis of definite vestibular migraine. Background Migraine is a common neurological disorder characterized by episodic headaches with specific features. About two-thirds of cases run in families, and patients may refer symptoms occurring in infancy and childhood, defined as episodic syndromes that may be associated with migraine. Migraine is associated with episodic vertigo, called vestibular migraine, whose diagnosis mainly relies on clinical history showing a temporary association of symptoms. Methods In this cross-sectional multicentric study, 252 subjects were recruited in different centers; a senior specialist through a structured questionnaire assessed features of vestibular symptoms and accompanying symptoms. Results The age of onset of migraine was 23 years, while onset of vertigo was at 38 years. One hundred and eighty-four subjects reported internal vertigo (73%), while 63 subjects (25%) reported external vertigo. The duration of vertigo attacks was less than 5 minutes in 58 subjects (23%), between 6 and 60 minutes in 55 (21.8%), between 1 and 4 hours in 29 (11.5%), 5 and 24 hours in 44 (17.5%), up to 3 days in 14 (5.5%), and more than 3 days in seven (2.8%); 14 subjects (5.5%) referred attacks lasting from less than 5 minutes and up to 1 hour, nine (3.6%) referred attacks lasting from less than 5 minutes and up to 1 to 4 hours, six (2.4%) referred attacks lasting from less than 5 minutes and up to 5 to 24 hours, and five (2%) cases referred attacks lasting from less than 5 minutes and up to days. Among accompanying symptoms, patients referred the following usually occurring, in order of frequency: nausea (59.9%), photophobia (44.4%), phonophobia (38.9%), vomiting (17.8%), palpitations (11.5%), tinnitus (10.7%), fullness of the ear (8.7%), and hearing loss (4%). In total, 177 subjects referred a positive family history of migraine (70.2%), while 167 (66.3%) reported a positive family history of vertigo. In the sample, 69% of patients referred at least one of the pediatric precursors, in particular, 42.8% of subjects referred motion sickness. The age of onset of the first headache was lower in the subsample with a familial history of migraine than in the total sample. Among the pediatric precursors, benign paroxysmal vertigo - BPV, benign paroxysmal torticollis, and motion sickness were predictive of a lower age of onset of vertigo in adulthood; cyclic vomiting was predictive for vomiting during vertigo attacks in adults. Conclusions Our results may indicate that vestibular symptoms in pediatric patients may act as a predisposing factor to develop vestibular migraine at an earlier age in adulthood.

The increase in disease-modifying drugs (DMDs) allows individualization of treatment in relapsing multiple sclerosis (RMS); however, the long-term impact of different treatment sequences is not well established. This is particularly relevant for MS patients who may need to postpone more aggressive DMD strategies. To evaluate different therapeutic strategies and their long-term outcomes, measured as relapses and confirmed disability progression (CDP), in MS ‘real-world’ settings. Multicentre, observational, retrospectively acquired cohort study evaluating the long-term impact of different treatment strategies on disability outcomes in patients with RMS in the Italian MS Register. We evaluated 1152 RMS-naive patients after propensity-score adjustment. Patients included were receiving: interferon beta-1a (IFN-β1a) 44 µg switching to fingolimod (FTY; IFN-switchers; n = 97); FTY only (FTY-stayers; n = 157); IFN-β1a only (IFN-stayers; n = 849). CDP and relapses did not differ between FTY-stayers and IFN-switchers [HR (95% CI) 0.99 (0.48–2.04), p = 0.98 and 0.81 (0.42–1.58), p = 0.55, respectively]. However, IFN-stayers showed increased risk of relapses compared with FTY-stayers [HR (95% CI) 1.46 (1.00–2.12), p = 0.05]. The ideal treatment option for MS is becoming increasingly complex, with the need to balance benefit and risks. Our results suggest that starting with FTY affects the long-term disease outcome similarly to escalating from IFN-β1a to FTY.

Background Current guidelines suggest to consider dual antiplatelet therapy (DAPT) continuation for longer than 12 months in selected patients with myocardial infarction (MI). Hypothesis We sought to assess the criteria used by cardiologists in daily practice to select patients with a history of MI eligible for DAPT continuation beyond 1 year. Methods We analyzed data from the EYESHOT Post-MI, a prospective, observational, nationwide study aimed to evaluate the management of patients presenting to cardiologists 1 to 3 years from the last MI event. Results Out of the 1633 post-MI patients enrolled in the study between March and December 2017, 557 (34.1%) were on DAPT at the time of enrolment, and 450 (27.6%) were prescribed DAPT after cardiologist assessment. At multivariate analyses, a percutaneous coronary intervention (PCI) with multiple stents and the presence of peripheral artery disease (PAD) resulted as independent predictors of DAPT continuation, while atrial fibrillation was the only independent predictor of DAPT interruption for patients both at the second and the third year from MI at enrolment and the time of discharge/end of the visit. Conclusions Risk scores recommended by current guidelines for guiding decisions on DAPT duration are underused and misused in clinical practice. A PCI with multiple stents and a history of PAD resulted as the clinical variables more frequently associated with DAPT continuation beyond 1 year from the index MI.

Trauma-induced coagulopathy (TIC) is well documented in injured children. However, many important features of pediatric hemostasis are still in development in early childhood and may impact TIC. Certain pediatric subgroups are at a higher risk. Traumatic brain injury, which occurs with a higher rate in children, and physical child abuse are known risk factors for TIC that deserve special consideration. Resuscitation of a pediatric trauma patient follows many of the same goals as in the injured adult trauma, although some key aspects of pediatric resuscitation require ongoing investigation. Venous thromboembolism occurs with higher rates in certain high-risk groups of pediatric trauma patients, although overall it is considerably less frequent in children as compared with adults.

Background Older adults dialysis patients represent the frailest subgroup of the End Stage Renal Disease (ESRD) population and physical exercise program may mitigate the age-related decline in muscle mass and function. Methods Dialysis patients of the EXCITE trial aged > 65 years (n = 115, active arm, n = 53; control arm, n = 62) were submitted in random order to a home based, low intensity physical exercise program. At baseline and 6 months after exercise training 6-min walking distance (6MWD) and 5-time sit-to-stand test (5STS) were performed, and quality of life (QoL) was tested. Results The training program improved both the 6MWD (6-months: 327 ± 86 m versus baseline: 294 ± 74 m; P

Diagnosis of type 1 diabetes (T1D) in a child is often associated with anger, denial, fear, and depression from the parents. The aim of the study was to improve parents’ adaptation to the diagnosis of diabetes of their child. Sixty-two parents (29 mothers, 33 fathers) of 36 children with type 1 diabetes (mean age=11.3‐3.3 years; diabetes duration>1 year; HbA1c=57±11 mmol/mol) participated in a three-day educational working group pilot intervention study. Intervention was based on the reexamination of the traumatic event of diagnosis of T1D through spatial and time-line anchorage, retracing of the future, emotional awareness, and interactive discussion. Relaxing technique, diaphragmatic breathing, and guided visualization were used by 2 psychologists and 1 pediatric endocrinologist. The study was approved by EC and participants filled a consent form. At baseline and after intervention, parents filled in a questionnaire including Diabetes-Related Distress (DRD), Parent Health Locus of Control Scale (PHLOC), Parent Stress Index Short Form (PSI-SF), Hypoglycemia Fear Survey-Parents (HFS-P) and Hypoglycemia Fear Survey-Parents of Young Children (HFS-P-YC), and Health Survey Short Form-36 (SF-36). Three months after the intervention, both parents reported a reduction in the “difficult child” subscale of the PSI-SF (p<0.05) and increased scores of social functioning of the SF-36 (p<0.05). DRD score was significantly reduced in mothers (p=0.03), while the “parental distress” subscale of the PSI-SF was significantly improved in fathers (p=0.03). This weekend-based parent group intervention seems to reduce stress and improve social functioning of parents of children and adolescents with type 1 diabetes.

Insulin injection aspects, such as fear of injection and pain, directly affect glycemic control, patient adherence and quality of life. Use of thinner and shorter needles could increase acceptance of injections. The aim of the study is to evaluate the non-inferiority of the new 34G × 3.5 mm needle compared to a 32G × 4 mm in patients with diabetes treated with insulin.This is an open, randomized, two-period crossover, non-inferiority trial. Every treatment period lasted 3 weeks. Patients with type 1 or type 2 diabetes, treated with multiple daily insulin injections, were randomly assigned to receive a 34G × 3.5 mm or a 32G × 4 mm pen needle. The primary endpoint was the non-inferiority of the 34G × 3.5 mm in comparison with the 32G × 4 mm pen needle in terms of percentage absolute change of blood fructosamine (% |ΔFru|), using a non-inferiority margin of 20%.Overall 77 patients were randomized and 73 completed the study. Patients characteristics were: 52% male, 80.5% affected by type 1 diabetes, mean age 52 years (±14.6), mean BMI 24.5 kg/mThe 34G × 3.5 mm needle was non-inferior to the 32G × 4 mm needle regarding fructosamine levels and glycemic variability supporting the suitability of the 34G × 3.5 mm needle for insulin injection in patients with diabetes.NCT02690467.

The aim of this study was to evaluate the gene expression of proinflammatory cytokines, matrix metalloproteinases (MMPs), and cathepsin K in apical periodontitis (AP) and the volume of lesions in ovariectomized and sham-operated rats.Twenty 12-week-old female Wistar rats were subjected to ovariectomy (OVX) or sham surgery. After 9 weeks, access cavities were prepared in the maxillary and mandibular first molars, pulp tissue was removed, and canals were exposed to the oral environment during 21 days for the induction of AP. The groups were as follows: sham, OVX, sham+AP, and OVX+AP. Animals were euthanized, and blocks containing the maxillary first molar and the surrounding bone were removed for quantification of proinflammatory cytokines cathepsin K and MMP genes by real-time polymerase chain reaction. The hemimandibles containing the mandibular first molars were used for analysis of the AP lesion volume by micro-computed tomographic imaging.AP in OVX rats showed an increased expression of interleukin 1 beta, tumor necrosis factor alpha, interleukin 6, MMP-8, and MMP-13 (P .05). OVX alone, without AP induction, did not affect the expression of the evaluated genes. Additionally, AP induced an increase in cathepsin K expression, without significant differences between AP in the sham and OVX groups (P .05). Micro-computed tomographic imaging showed a significantly greater AP lesion mean volume in OVX compared with sham animals (P .05).AP lesions in ovariectomized rats are larger and have an increased expression of proinflammatory cytokines and MMPs, indicating that the infection combined with ovariectomy has an important role in the regulation of these signaling molecules and enzymes during the development of AP. Based on that, it may be assumed that the hypoestrogenic condition aggravates inflammation and degradation of extracellular matrix components in AP, which may provide insight into understanding the development of AP in female postmenopausal patients.

Background The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes. Methods TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50–75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2–3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15–45 mg) or a sulfonylurea (5–15 mg glibenclamide, 2–6 mg glimepiride, or 30–120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856. Findings Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74–1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p

Background The comparative effectiveness of treatment with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or their combination in people with albuminuria and cardiovascular risk factors is unclear. Methods In a multicenter, randomized, open label, blinded end point trial, we evaluated the effectiveness on cardiovascular events of ACE or ARB monotherapy or combination therapy, targeting BP,130/80 in patients with moderate or severe albuminuria and diabetes or other cardiovascular risk factors. End points included a primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for cardiovascular causes and a revised end point of all-cause mortality. Additional end points included ESRD, doubling of serum creatinine, albuminuria, eGFR, BP, and adverse events. Results Because of slow enrollment, the trial was modified and stopped 41% short of targeted enrollment of 2100 participants, corresponding to 35% power to detect a 25% reduced risk in the primary outcome. Our analysis included 1243 adults, with median follow-up of 2.7 years. Efficacy outcomes were similar between groups (ACE inhibitor versus ARB, ACE inhibitor versus combination, ARB versus combination) as were rates of serious adverse events. The rate of permanent discontinuation for ARB monotherapy (6.3%) was significantly lower than for ACE inhibitor monotherapy (15.7%) or combined therapy (18.3%). Conclusions Patients may tolerate ARB monotherapy better than ACE inhibitor monotherapy. However, data from this trial and similar trials, although as yet inconclusive, show no trend suggesting differences in mortality and renal outcomes with ACE inhibitors or ARBs as dual or monotherapy in patients with albuminuria and diabetes or other cardiovascular risk factors. Copyright © 2018 by the American Society of Nephrology Background The comparative effectiveness of treatment with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or their combination in people with albuminuria and cardiovascular risk factors is unclear. Methods In a multicenter, randomized, open label, blinded end point trial, we evaluated the effectiveness on cardiovascular events of ACE or ARB monotherapy or combination therapy, targeting BP,130/80 in patients with moderate or severe albuminuria and diabetes or other cardiovascular risk factors. End points included a primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for cardiovascular causes and a revised end point of all-cause mortality. Additional end points included ESRD, doubling of serum creatinine, albuminuria, eGFR, BP, and adverse events. Results Because of slow enrollment, the trial was modified and stopped 41% short of targeted enrollment of 2100 participants, corresponding to 35% power to detect a 25% reduced risk in the primary outcome. Our analysis included 1243 adults, with median follow-up of 2.7 years. Efficacy outcomes were similar between groups (ACE inhibitor versus ARB, ACE inhibitor versus combination, ARB versus combination) as were rates of serious adverse events. The rate of permanent discontinuation for ARB monotherapy (6.3%) was significantly lower than for ACE inhibitor monotherapy (15.7%) or combined therapy (18.3%). Conclusions Patients may tolerate ARB monotherapy better than ACE inhibitor monotherapy. However, data from this trial and similar trials, although as yet inconclusive, show no trend suggesting differences in mortality and renal outcomes with ACE inhibitors or ARBs as dual or monotherapy in patients with albuminuria and diabetes or other cardiovascular risk factors.

In 2013, the Italian Society of Nephrology joined forces with Nephrocare-Italy to create a clinical research cohort of patients on file in the data-rich clinical management system (EUCLID) of this organization for the performance of observational studies in the hemodialysis (HD) population. To see whether patients in EUCLID are representative of the HD population in Italy, we set out to compare the whole EUCLID population with patients included in the regional HD registries in Emilia-Romagna (Northern Italy) and in Calabria (Southern Italy), the sole regions in Italy which have systematically collected an enlarged clinical data set allowing comparison with the data-rich EUCLID system. An analysis of prevalent and incident patients in 2010 and 2011 showed that EUCLID patients had a lower prevalence of coronary heart disease, peripheral vascular disease, heart failure, valvular heart disease, liver disease, peptic ulcer and other comorbidities and risk factors and a higher fractional urea clearance (Kt/V) than those in the Emilia Romagna and Calabria registries. Accordingly, survival analysis showed a lower mortality risk in the EUCLID 2010 and 2011 cohorts than in the combined two regional registries in the corresponding years: for 2010, hazard ratio (HR) EUCLID vs. Regional registries: 0.80 [95% confidence interval: 0.71–0.90]; for 2011, HR: 0.76 [0.65–0.90]. However, this difference was nullified by statistical adjustment for the difference in comorbidities and risk factors, indicating that the longer survival in the EUCLID database was attributable to the lower risk profile of patients included in that database. This preliminary analysis sets the stage for future observational studies and indicates that appropriate adjustment for difference in comorbidities and risk factors is needed to generalize to the Italian HD population analyses based on the data-rich EUCLID database.

To examine whether free (3-PD-5Incorporation of 3-PD-5 into unilamellar liposomes of soya phosphatidylcholine and cholesterol was efficient (57.5 ± 7.9%) and yielded vesicles with low diameter (133.7 ± 18.4 nm), polydispersity index (0.39 ± 0.06), and zeta potential (- 1.22 ± 0.34 mV). 3-PD-5Altogether, the results reported herein indicate that 3-PD-5 is a promising modulator of the early stages of acute joint inflammation that can help to diminish not only excessive neutrophil infiltration in the synovia but also neutrophil activation and its outcomes in RA patients.

To answer the questions: (1) Does reducing estrogen levels influence the microbial composition of the oral cavity? (2) Does the presence of periapical lesion (PL) cause changes in the oral microbiota? (3) Since estrogen deficiency alters the oral microbiota, can this be one of the factors that contribute to the increase of the PL?Thirty-six rats were divided into four groups: sham (control), ovariectomy (OVX), control with PL (Sham + PL), and OVX + PL. After 9 weeks of OVX, the lower first molars were submitted to PL induction. After 21 days, the microbiological collection of the oral cavity was performed, and the animals were euthanized. The contents were evaluated by the checkerboard DNA-DNA hybridization method, to verify the prevalence of 40 bacterial species (divided into 7 microbial complexes). The blocks containing the lower first molars were submitted to histotechnical processing and staining with hematoxylin and eosin (HE), for the measurement of the periapical lesion area. The results were submitted to ANOVA and Kruskal-Wallis tests and Tukey and Dunn post-tests, with a significance level of 5%.In conditions of estrogen deficiency, there was alteration of the oral microbiota. The OVX groups had a higher amount of bacteria compared to the SHAM group in most of the microbial complexes (p0.001). The animals in the control group (with or without lesion) did not present a statistically significant difference (p0.001) in any of the microbial complexes. The PLs in OVX animals were significantly higher compared to SHAM animals (p0.001).Hypoestrogenicity conditions interfere in the oral microbiota by increasing the amount of bacteria in the saliva and influencing the progression of periapical lesions.This inedited study shows that deficiency of estrogen leads to alteration of the oral microbiota.

Whether reexposure to mismatched HLA antigens (RMM) in the setting of a negative crossmatch is associated with increased immunological risk remains an area of uncertainty. This is due to evidence derived predominantly from registry data, which lacks comprehensive information on alloantibody and rejection. In this study, we analyze the impact of low-level preformed donor-specific antibodies (DSA) against an RMM on transplant outcomes. From 1988 consecutive renal transplant recipients, we analyzed 179 patients undergoing retransplantation, of whom 55 had a RMM. All patients were crossmatch negative and preformed DSA were detected by single antigen beads alone. Multivariate analysis revealed that patients with preformed DSA against an RMM were independently at risk of antibody-mediated rejection (HR 8.70 [3.42-22.10], P < .0001) and death-censored allograft loss (HR 3.08 [1.17-8.14], P = .023). In addition, prior transplant nephrectomy (HR 2.04 [1.00-4.17], P = .0495) was also associated with allograft failure, whereas receiving a retransplant that was matched at HLA class II was associated with a favorable outcome (HR 0.37 [0.14-0.99], P = .047). In the absence of preformed DSA, an RMM was not associated with de novo DSA development, rejection, or allograft loss. In conclusion, an RMM portends increased immunological risk only in the presence of a preformed DSA in patients undergoing retransplantation.

Introduction: In relapsing Multiple Sclerosis (RMS) patients treated with disease modifying drugs (DMDs), few data are available regarding the biomarkers of treatment response. We aimed to assess the predictive value of lymphocyte count (LC) and Body Mass Index (BMI) for treatment response in a real life setting of dimethyl fumarate (DMF) treated patients. Materials and Methods: We included in our observational analysis 338 patients who were prescribed DMF in an Italian MS Center. We collected clinical and demographic data at the beginning of DMF (T0), and assessed White Blood Cells (WBC) and LC at T0 and at 3 (T3), 6 (T6), 9 (T9), and 12 (T12) months. Gadolinium enhancing (Gd+), new T2 lesions and relapses within the first year of treatment (T12) were recorded in order to evaluate clinical activity at 12 months. Analysis of correlation was performed to correlate WBC, LC and BMI with clinical and radiological responses. We evaluated whether BMI or LC can predict treatment response by using multivariate logistic regression models at each follow-up. Results: Our cohort was followed up for a mean period of 19.8 ± 6.8 months. The mean BMI at baseline was 24.19 ± 4.48. The multivariate models gave as predictive factors for Gd+ lesions at T12, LC at T3 (OR = 1.003, 95% CI = 1.00-1.07; p = 0.046) and baseline BMI (OR = 0.71, 95% CI = 0.52-0.98; p = 0.037). Predictive factors for new T2 lesions at T12 were LC at T3 (OR = 1.01 95%CI = 1.00-1.95; p = 0.005) and baseline BMI (OR = 0.99, 95% CI = 0.98-1.00; p = 0.026). Conclusions: In our real life-experience, BMI and LC may be early biomarkers to predict treatment response during DMF.

OBJECTIVE An association between variability in clinical parameters (HbA1c, blood pressure, cholesterol, and uric acid) and risk of complications in type 2 diabetes has been reported. In this analysis, we investigated to what extent such variability is associated with overall quality of care. RESEARCH DESIGN AND METHODS The quality of care summary score (Q-score) represents a validated, overall quality of care indicator ranging between 0 and 40; the higher the score, the better the quality of care provided by the diabetes center. We identified patients with five or more measurements of clinical parameters after the assessment of the Q-score. Multiple linear regression analyses assessed the role of the Q-score in predicting the variability of the different parameters. RESULTS Overall, 273,888 patients were analyzed. The variability of all the parameters systematically increased with decreasing Q-score values. At multivariate linear regression analysis, compared with a Q-score >25, a score CONCLUSIONS The variability of risk factors for diabetic complications is associated with quality of care. Quality of care improvement initiatives should be targeted to increase the achievement of the recommended target while reducing such variability.

Background Cerebral palsy (CP) describes a group of permanent disorders in the development of movement and posture due to non-progressive disturbances during foetal or infant brain development that can result in activity limitations, including engagement in pretend play. Methods Twenty children aged four to seven years with spastic CP participated in this descriptive qualitative study. The Child-Initiated Pretend Play Assessment (ChIPPA) clinical observations were analysed from five categories: Time, Interaction with the examiner, Imitation, Theme and Story. Results Seventy per cent (70%) of the children completed the assessment (Time), and 90% of children interacted socially with the examiner during the play (Interaction with the examiner). All children initiated their pretend play without requiring examiner demonstration (Imitation). Sixty per cent (60%) of the children were appropriate to their stage of development for Theme. Finally, 60% of the children set up a scenario, but did not develop a narrative (Story). Conclusion Qualitative aspects of the children's pretend play performance were satisfactory, showing typical play indicators in all the categories, except for 'Story'. 'Story' represents more complexity in a child's pretend play ability. Therefore, a play intervention is suggested to stimulate and expand the pretend play ability of preschool children with CP.

Here we report the effects of exogenous and endogenous galectin-1 (Gal-1) in modulating the functional responses of human and murine neutrophils at different stages of activation, i.e. naive, primed, and activated. Exposure to Gal-1 did not induce ROS production in either naive or N-formyl-methionyl-leucyl-phenylalanine-primed (fMLP; 10-9 M) neutrophils. However, Gal-1 elicited a concentration-dependent ROS production in neutrophils activated with fMLP at concentrations ranging from 10-8 M to 10-6 M. Additional fMLP (10-7 M) stimulation of fMLP-activated neutrophils increased ROS production, whose intensity was inversely related to the fMLP concentration used in the first activation step (10-8 M to 10-6 M), and was not influenced by the presence of Gal-1. Naive neutrophils treated with Gal-1 and then exposed to fMLP (10-6 M) or phorbol-12-myristate-13-acetate (10-7 M) produced less ROS, as compared to naive neutrophils not treated with Gal-1. Interestingly, these in vitro Gal-1 effects were associated with Gal-1 carbohydrate-binding activity and the ability to decrease FPR-1 (formyl peptide receptor 1) expression in naive human neutrophils. Conversely, positive ROS modulation by Gal-1 in activated neutrophils was not associated with FPR-1 expression but it was related to its carbohydrate recognition. In vitro, fMLP stimulation of Gal-1-/- mouse neutrophils produced more ROS than fMLP stimulation of Gal-1+/+ neutrophils and this effect may be associated with increased FPR-1 expression. Exogenous Gal-1 induced ROS production in Gal-1-/- mouse neutrophils more effectively than in Gal-1+/+ mouse neutrophils. Compared to Gal-1+/+ mice, Gal-1-/- mice exhibited lower bacterial load in the peritoneal fluid and peripheral blood, thus indicating a greater bactericidal activity in vivo. These findings demonstrate that endogenous Gal-1 restricts ROS generation that correlates with bacterial killing capacity in inflammatory neutrophils. Thus, endogenous and exogenous Gal-1 may either positively or negatively modulate the effector functions of neutrophils according to the cell activation stage.

Background and Aims Parathyroid hormone (PTH) measurements in hemodialysis (HD) patients are routinely performed every 3 to 6 months of therapy, which are adjusted in accordance with PTH. However, recent evidences show very high PTH biological variability. The aim of our study was to evaluate the role of serum β-crosslap (CTX), a validated marker of bone resorption, as indicator of PTH maintenance at different time intervals. Methods Forty-six HD patients fulfilled the inclusion criteria (HD age of more than 21 months and 7 PTH measurements for the last 21 months) for this retrospective cohort study and were enrolled. Data of the backward quarter PTH values for the last 21 months were collected from clinical records, and a single CTX was measured. To evaluate the relationship between CTX value and the maintenance of PTH in the short-term and long-term, 7 time intervals (3, 6, 9, 12, 15, 18, and 21 months) were stated and the mean value of PTH was measured within each interval and calculated for every patient. Results We found the following: (1) positive correlation between mean PTH in each time interval and β-crosslaps with a progressive increase of the correlation coefficient (highest value for the 12- and 21-month intervals); (2) significant differences between tertiles of β-crosslaps at 6-, 9-, 12-, 15-, 18-, and 21-month intervals, with a progressively growing value of the test coefficient; and (3) after the computation of receiver operating characteristic curves, β-crosslaps showed to significantly estimate threshold PTH values with the highest areas under the curves (AUCs; AUC, 0.763; 95% confidence interval, 0.625–0.901 for 300 pg/mL of PTH) and best value of both sensitivity and specificity at the 12-month time interval (82% and 72% for 300 pg/mL of PTH). Conclusions In HD patients, β-crosslaps have a potential ability to best estimate backward PTH into 12 months of interval.

Quality of care monitoring is a key strategy for health policy. In Italy, the AMD Annals continuous monitoring and quality improvement initiative has been in place since 2006. Results after 8 years are now available.Quality of diabetes care indicators during the years 2004-2011 were extracted from electronic medical records of 300 diabetes clinics. From 200,000 to 500,000 patients with type 2 diabetes were analyzed per year. Six process indicators, eight intermediate outcome indicators, seven indicators of treatment intensity/appropriateness, and a quality of care summary score (Q score) were evaluated. Previous studies documented that the risk of developing a new cardiovascular event was 80 % higher in patients with a Q score15 and 20 % higher in those with a score between 15 and 25, as compared to those with a score25.The proportion of patients with HbA1c ≤7 %, LDL cholesterol100 mg/dl, and blood pressure ≥140/90 mmHg increased by 4.8, 21.9, and 10.0 %, respectively. Process and treatment intensity/appropriateness indicators consistently improved. The proportion of patients with a Q score15 decreased from 13.5 to 6.5 %, while those with a Q score25 increased from 22.9 to 38.5 %.AMD Annals document the progress in quality of diabetes care. Longitudinal improvements in Q score can translate into less cardiovascular events, with evident clinical and economic implications. AMD Annals represent a physician-led effort not requiring allocation of extra-economic resources, which is easy to implement and deeply rooted in routine clinical practice. They are a potential case model for other healthcare systems.

To assess prognostic factors for a second clinical attack and a first disability worsening event in pediatric clinically isolated syndrome (pCIS) suggestive of Multiple Sclerosis (MS) patients. Objective: To assess prognostic factors for a second clinical attack and a first disability-worsening event in pediatric clinically isolated syndrome (pCIS) suggestive of multiple sclerosis (MS) patients. Methods: A cohort of 770 pCIS patients was followed up for at least 10 years. Cox proportional hazard models and Recursive Partitioning and Amalgamation (RECPAM) tree-regression were used to analyze data. Results: In pCIS, female sex and a multifocal onset were risk factors for a second clinical attack (hazard ratio [HR], 95% confidence interval [CI] = 1.28, 1.06–1.55; 1.42, 1.10–1.84, respectively), whereas disease-modifying drug (DMD) exposure reduced this risk (HR, 95% CI = 0.75, 0.60–0.95). After pediatric onset MS (POMS) diagnosis, age at onset younger than 15 years and DMD exposure decreased the risk of a first Expanded Disability Status Scale (EDSS)-worsening event (HR, 95% CI = 0.59, 0.42–0.83; 0.75, 0.71–0.80, respectively), whereas the occurrence of relapse increased this risk (HR, 95% CI = 5.08, 3.46–7.46). An exploratory RECPAM analysis highlighted a significantly higher incidence of a first EDSS-worsening event in patients with multifocal or isolated spinal cord or optic neuritis involvement at onset in comparison to those with an isolated supratentorial or brainstem syndrome. A Cox regression model including RECPAM classes confirmed DMD exposure as the most protective factor against EDSS-worsening events and relapses as the most important risk factor for attaining EDSS worsening. Interpretation: This work represents a step forward in identifying predictors of unfavorable course in pCIS and POMS and supports a protective effect of early DMD treatment in preventing MS development and disability accumulation in this population. Ann Neurol 2017;81:729–739.

The goal of evidence-based practice guidelines is to optimize the management of emerging diseases, such as differentiated thyroid cancer (DTC). The aim of this study was to assess therapeutic approaches for DTC in Italy and to see how closely these practices conformed to those recommended in the 2009 American Thyroid Association (ATA) guidelines.The Italian Thyroid Cancer Observatory was established to collect data prospectively on thyroid cancers consecutively diagnosed in participating centers (uniformly distributed across the nation). Data on the initial treatment of all pathologically confirmed DTC cases present in the database from January 1, 2013 (database creation) to January 31, 2016, were analyzed.A total of 1748 patients (77.2% females; median age 48.1 years [range 10-85 years]) were enrolled in the study. Most (n = 1640; 93.8%) were papillary carcinomas (including 84 poorly differentiated/aggressive variants); 6.2% (n = 108) were follicular and Hürthle cell carcinomas. The median tumor diameter was 11 mm (range 1-93 mm). Tumors were multifocal in 613 (35%) and presented extrathyroidal extension in 492 (28%) cases. Initial treatments included total thyroidectomy (involving one or two procedures; n = 726; 98.8%) and lobectomy (n = 22; 1.2%). A quarter of the patients who underwent total thyroidectomy had unifocal, intrathyroidal tumors ≤1 cm (n = 408; 23.6%). Neck dissection was performed in 40.4% of the patients (29.5% had central compartment dissection). Radioiodine remnant ablation (RRA) was performed in 1057 (61.2%) of the 1726 patients who underwent total thyroidectomy: 460 (41.2%) of the 983 classified by 2009 ATA guideline criteria as low-risk, 570 (87.1%) of the 655 as intermediate-risk, and 82 (93.1%) of the 88 as high-risk patients (p 0.001). RRA was performed in 44% of the cases involving multifocal DTCs measuring ≤1 cm.The treatment approaches for DTCs used in Italy display areas of inconsistency with those recommended by the 2009 ATA guidelines. Italian practices were characterized by underuse of thyroid lobectomy in intrathyroidal, unifocal DTCs ≤1 cm. The use of RRA was generally consistent with risk-stratified recommendations. However, its frequent use in small DTCs (≤1 cm) that are multifocal persists, despite the lack of evidence of benefit. These data provide a baseline for future assessments of the impact of international guidelines on DTC management in Italy. These findings also illustrate that the dissemination and implementation of guideline recommendations, and the change in practice patterns, require ongoing education and time.

Previous studies have suggested the benefits of physical exercise for patients on dialysis. We conducted the Exercise Introduction to Enhance Performance in Dialysis trial, a 6-month randomized, multicenter trial to test whether a simple, personalized walking exercise program at home, managed by dialysis staff, improves functional status in adult patients on dialysis. The main study outcomes included change in physical performance at 6 months, assessed by the 6-minute walking test and the five times sit-to-stand test, and in quality of life, assessed by the Kidney Disease Quality of Life Short Form (KDQOL-SF) questionnaire. We randomized 296 patients to normal physical activity (control; n=145) or walking exercise (n=151); 227 patients (exercise n=104; control n=123) repeated the 6-month evaluations. The distance covered during the 6-minute walking test improved in the exercise group (mean distance +/- SD: baseline, 328 +/- 96 m; 6 months, 367 +/- 113 m) but not in the control group (baseline, 321 +/- 107 m; 6 months, 324 +/- 116 m; P

AIMS To assess country- and individual-level correlates of psychological outcomes, and differences among countries in the associations of individual characteristics with psychological outcomes among adults with diabetes. METHODS The second Diabetes Attitudes, Wishes and Needs (DAWN2(™) ) study assessed self-reported characteristics of people with diabetes in 17 countries, including 1368 adults with Type 1 diabetes and 7228 with Type 2 diabetes. In each country, a sample of 500 adults, stratified by diabetes type and treatment, completed a questionnaire incorporating the validated WHO-5 wellbeing index, the WHOQOL-BREF, and the five-item Problem Areas in Diabetes Scale, as well as the newly developed Diabetes Impact on Life Dimensions that assessed impact ranging from very positive to very negative, with no impact as the midpoint. Multilevel regression analyses identified significant (P < 0.05) independent correlates of psychological outcomes. RESULTS There were significant variations in all outcomes across countries before adjustment for individual-level factors; adjustment reduced between-country disparities. Worse psychological outcomes were associated with more complications, incidence of hypoglycaemia, hypoglycaemic medication, perceived burden of diabetes, family conflict and experience of discrimination. Better psychological outcomes were associated with higher self-rated health, greater access to diabetes education and healthcare, and more psychosocial support from others. The associations of many factors with the outcomes were mediated by modifiable factors. The association of all factors with the outcomes varied across (interacted with) countries, highlighting the need for country-specific analyses. CONCLUSIONS Improvements in modifiable risk factors (reductions in burden and increases in support) may lead to better psychological outcomes in adults with diabetes.

Background: Gram-negative Multi-Drug-Resistant Organisms (GNMDROs) cause an increasing burden of disease in Intensive Care Units (ICUs). We deployed a multifaceted intervention to control selection and transmission of GNMDROs and to estimate at which rate GNMDROs would decline with our interventional bundle. Methods: Interventions implemented in 2015: in-ward Antimicrobial-Stewardship-Program for appropriate management of antimicrobial prescription; infection monitoring with nasal/rectal swabs and repeated procalcitonin assays; 24 h microbiological support (since 2016); prevention of catheter-related infections, VAPs and in-ward GNMDROs transmission; education of ICU personnel. In May 2017, epidemiological, clinical and microbiological data were collected and retrospectively analyzed. Rates of resistance in Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii, as well as percentages of resistance among all Gram-negative bacteria were compared during the study period. Results: Of 668 patients, at least one isolate was obtained from 399 patients. The proportions of patients with infection and with Gram-negative isolates were even across the 5 semesters (p = 0.8). For Klebsiella pneumoniae, the number of strains resistant to carbapenems fell from 94% to 6% (p

Myo-inositol supplementation prevents gestational diabetes (GDM) in women at risk and reduces insulin resistance in women with GDM. No data are available about its effect on glucose variability. The aim of this study was to evaluate the effects of a supplementation of myo-inositol on glucose variability in women with GDM.Myo-inositol effect on glucose variability was studied in a pilot case-control study involving 12 consecutive pregnant women (median age 34 years, 25.0% insulin-treated) with GDM. Six women received myo-inositol 2 g plus 200 mg folic acid twice a day, the others received only folic acid. Information on side effects was collected. A continuous glucose monitoring system was wore before and at the beginning of the supplementation. Mean amplitude of glucose excursion (MAGE), standard deviation (SD) and variability coefficient were the indexes of glucose variability.Myo-inositol lowered glucose levels in the first days after the treatment was started. However, pre-post supplementation overall mean glucose difference was similar between groups (-4.8 vs. 5.0 mg/dL for controls and treated, respectively; p = 0.79). Pre-post differences in SD (13.7 vs. 6.0; p0.001), MAGE (3.5 vs.-1.5; p0.001) and variability coefficient (0.14 vs. 0.02; p0.001) were improved in myo-inositol group. No side effects were recorded.Myo-inositol is effective in reducing glucose variability in women with GDM. It could be a useful strategy for treating GDM.

none 34 no studio multicentrico The comparative effectiveness of fingolimod versus interferon beta/glatiramer acetate was assessed in a multicentre, observational, prospectively acquired cohort study including 613 patients with relapsing multiple sclerosis discontinuing natalizumab in the Italian iMedWeb registry. First, after natalizumab suspension, the relapse risk during the untreated wash-out period and during the course of switch therapies was estimated through Poisson regression analyses in separated models. During the wash-out period an increased risk of relapses was found in patients with a higher number of relapses before natalizumab treatment (incidence rate ratio = 1.31, P = 0.0014) and in patients discontinuing natalizumab due to lack of efficacy (incidence rate ratio = 2.33, P = 0.0288), patient's choice (incidence rate ratio = 2.18, P = 0.0064) and adverse events (incidence rate ratio = 2.09, P = 0.0084). The strongest independent factors influencing the relapse risk after the start of switch therapies were a wash-out duration longer than 3 months (incidence rate ratio = 1.78, P < 0.0001), the number of relapses experienced during and before natalizumab treatment (incidence rate ratio = 1.61, P < 0.0001; incidence rate ratio = 1.13, P = 0.0118, respectively) and the presence of comorbidities (incidence rate ratio = 1.4, P = 0.0097). Switching to fingolimod was associated with a 64% reduction of the adjusted-risk for relapse in comparison with switching to interferon beta/glatiramer acetate (incidence rate ratio = 0.36, P < 0.0001). Secondly, patients who switched to fingolimod or to interferon beta/glatiramer acetate were propensity score-matched on a 1-to-1 basis at the switching date. In the propensity score-matched sample a Poisson model showed a significant lower incidence of relapses in patients treated with fingolimod in comparison with those treated with interferon beta/glatiramer acetate (incidence rate ratio = 0.52, P = 0.0003) during a 12-month follow-up. The cumulative probability of a first relapse after the treatment switch was significantly lower in patients receiving fingolimod than in those receiving interferon beta/glatiramer acetate (P = 0.028). The robustness of this result was also confirmed by sensitivity analyses in subgroups with different wash-out durations (less or more than 3 months). Time to 3-month confirmed disability progression was not significantly different between the two groups (Hazard ratio = 0.58; P = 0.1931). Our results indicate a superiority of fingolimod in comparison to interferon beta/glatiramer acetate in controlling disease reactivation after natalizumab discontinuation in the real life setting. none Iaffaldano, Pietro; Lucisano, Giuseppe; Pozzilli, Carlo; Brescia Morra, Vincenzo; Ghezzi, Angelo; Millefiorini, Enrico; Patti, Francesco; Lugaresi, Alessandra; Zimatore, Giovanni Bosco; Marrosu, Maria Giovanna; Amato, Maria Pia; Bertolotto, Antonio; Bergamaschi, Roberto; Granella, Franco; Coniglio, Gabriella; Tedeschi, Gioacchino; Sola, Patrizia; Lus, Giacomo; Ferrò, Maria Teresa; Iuliano, Gerardo; Corea, Francesco; Protti, Alessandra; Cavalla, Paola; Guareschi, Angelica; Rodegher, Mariaemma; Paolicelli, Damiano; Tortorella, Carla; Lepore, Vito; Prosperini, Luca; Saccà, Francesco; Baroncini, Damiano; Comi, Giancarlo; Trojano, Maria; Italian iMed-Web database Iaffaldano, Pietro; Lucisano, Giuseppe; Pozzilli, Carlo; Brescia Morra, Vincenzo; Ghezzi, Angelo; Millefiorini, Enrico; Patti, Francesco; Lugaresi, Alessandra; Zimatore, Giovanni Bosco; Marrosu, Maria Giovanna; Amato, Maria Pia; Bertolotto, Antonio; Bergamaschi, Roberto; Granella, Franco; Coniglio, Gabriella; Tedeschi, Gioacchino; Sola, Patrizia; Lus, Giacomo; Ferrò, Maria Teresa; Iuliano, Gerardo; Corea, Francesco; Protti, Alessandra; Cavalla, Paola; Guareschi, Angelica; Rodegher, Mariaemma; Paolicelli, Damiano; Tortorella, Carla; Lepore, Vito; Prosperini, Luca; Saccà, Francesco; Baroncini, Damiano; Comi, Giancarlo; Trojano, Maria; Italian iMed-Web database

To assess use of self-monitoring of blood glucose (SMBG) in type 2 diabetes (T2DM) in the context of a continuous quality improvement initiative (AMD Annals).14 quality-of-care indicators were developed, including frequency of SMBG, fasting blood glucose (FBG), and post-prandial glucose (PPG) levels, and hypoglycemia and hyperglycemia episodes. Clinical data and SMBG values downloaded from any glucose meter were obtained from electronic medical records. The most frequently used glucose-lowering treatment regimens were identified and the indicators were assessed separately by regimen.Overall, 21 Italian centers and 13,331 patients (accounting for 35,657 HbA1c tests and 8.44 million SMBG values collected during 2014 and 2015) were included in the analysis; 11 therapeutic regimens were selected. Patients in regimens not including insulin performed 15-23 measurements per patient-month, those treated with basal insulin 32.1 tests/patient-month, and those treated with basal and short-acting insulin 53-58 tests/patient-month. In all treatment regimens, PPG measurements represented a minority of all tests; pre-breakfast measurements accounted for about 50% of all FBG values. Mean FBG levels exceeded 130 mg/dl in 49.3-88.3% of the cases in the different treatment regimens, while PPG levels were over 140 mg/dl in 46.7-81.0%. From 5.7 to 32.7%, patients in the different regimens had at least one episode of hypoglycemia ( 70 mg/dl), while from 3.7 to 47.7% had at least one episode of hyperglycemia ( 300 mg/dl).SMBG is underutilized in patients with T2DM treated or not with insulin. In all treatment groups, PPG is seldom investigated. Poor metabolic control and rates of hyper- and hypoglycemia deserve consideration in all treatment groups.

Scope Nutrition is a major contributing factor for immunocompetence. The aim was to assess the immune status of older people after consuming milk produced by lactating cows fed with one of the following diets: control diet (C), C + vitamin E + selenium (C + A), C + sunflower oil (C + O), and C + sunflower oil + vitamin E + selenium (A + O). Methods and results Sixty elderly people received one of these biofortified milks for 12 weeks. Immune response was assessed by measurement of the expression of COX-1, COX-2, MCP-1, PPAR (δ, α, and β/δ) genes, neutrophil production of oxygen reactive species induced by immune complexes, neutrophil phagocytosis and lytic activity of the alternative pathway of the complement system, and cytokine levels. Variables were assessed before and after treatment. Our findings showed stability of some inflammatory mediators (complement activity and neutrophils burst) in treatment groups, except complement activity in C + A, and an increase of these markers in C, especially reactive oxygen species production and phagocytic activity. TNF-α was significantly increased in all groups. In C + A, IL-4 and IL-2 increased after treatment, and in the group that received the milk produced by cows fed with "O" diet, CCL20 and IL-27 increased. Conclusion Overall, as compared to C, milk biofortification was associated with stabilization of the activity of alternative complement pathway and the neutrophils burst, and modulated different cytokines levels.

To assess the risk of adverse neonatal outcomes in women with gestational diabetes (GDM) by identifying subgroups of women at higher risk to recognize the characteristics most associated with an excess of risk. Observational, retrospective, multicenter study involving consecutive women with GDM. To identify distinct and homogeneous subgroups of women at a higher risk, the RECursive Partitioning and AMalgamation (RECPAM) method was used. Overall, 2736 pregnancies complicated by GDM were analyzed. The main outcome measure was the occurrence of adverse neonatal outcomes in pregnancies complicated by GDM. Among study participants (median age 36.8 years, pre-gestational BMI 24.8 kg/m2), six miscarriages, one neonatal death, but no maternal death was recorded. The occurrence of the cumulative adverse outcome (OR 2.48, 95% CI 1.59–3.87), large for gestational age (OR 3.99, 95% CI 2.40–6.63), fetal malformation (OR 2.66, 95% CI 1.00–7.18), and respiratory distress (OR 4.33, 95% CI 1.33–14.12) was associated with previous macrosomia. Large for gestational age was also associated with obesity (OR 1.46, 95% CI 1.00–2.15). Small for gestational age was associated with first trimester glucose levels (OR 1.96, 95% CI 1.04–3.69). Neonatal hypoglycemia was associated with overweight (OR 1.52, 95% CI 1.02–2.27) and obesity (OR 1.62, 95% CI 1.04–2.51). The RECPAM analysis identified high-risk subgroups mainly characterized by high pre-pregnancy BMI (OR 1.68, 95% CI 1.21–2.33 for obese; OR 1.38 95% CI 1.03–1.87 for overweight). A deep investigation on the factors associated with adverse neonatal outcomes requires a risk stratification. In particular, great attention must be paid to the prevention and treatment of obesity.

Objective Selective unilateral vestibular neurectomy (VN) is considered a reliable surgical treatment in case of recurrent vertigo in Meniere’s disease (MD) because of hearing preservation and a minimally invasive posterior fossa retrosigmoid approach. The present study aimed to assess the quality of life and the long-term vestibular function in patients submitted to yearly follow-up after VN because of intractable MD. Methods Retrospective series of 15 MD patients undergoing retrosigmoid VN for recurrent vertigo. Outcome measures included cVEMPs and oVEMPs (cervical and ocular vestibular evoked myogenic potentials), VHIT (Video Head Impulse Test) and caloric test, besides to DHI (Dizziness Handicap Inventory) and PTA (Pure Tone Audiometry). Results Mean DHI score resulted within normal values in 74% of patients, significantly correlated to the duration of the follow-up. In the operated side, cVEMPs and oVEMPs have not been elicited respectively in 11 patients (73%) and 13 patients (87%), whereas it was not possible to evoke any response at bithermal caloric test in 4 cases. The gain of VOR from VHIT resulted always below normal values after VN except in one patient, who has also undergone an episode of posterior BBPV. The difference between average PTA threshold before and after VN resulted not significant. Conclusion The vestibular outcomes prove VN to be an effective and safe surgery in MD; furthermore, the unexpected occurrence of BPPV after VN can justify the presence of neural anastomosis between the inferior vestibular nerve and the cochlear nerve, allowing to still perceive vestibular symptomatology despite of a proper neurectomy.

We examined the functional activity of peripheral blood neutrophils and the complement system activation status in patients with rheumatoid arthritis (RA) undergoing infliximab/methotrexate combined therapy. We studied female RA patients under treatment with infliximab (3–5 mg/kg) and methotrexate (15–25 mg/week) who presented inactive (i-RA; n = 34, DAS-28 ≤ 2.6) or at least moderately active disease (a-RA; n = 29, DAS-28 > 3.2), and age-matched healthy women (n = 38). We measured the levels of reactive oxygen species (ROS) generation (chemiluminescence assay) and membrane expression of FcγRIIa/CD32, FcγRIIIb/CD16, CR1/CD35, and CR3/CD11b receptors (ELISA assay) in neutrophils. We also determined the hemolytic activity of the alternative and classical pathways of the complement system (spectrophotometry), serum levels of C5a and Bb (ELISA assay), and serum chemotactic activity (Boyden chamber). Compared with the control group, i-RA and a-RA patients exhibited: (1) increased neutrophil ROS production and membrane expression of FcγRIIa/CD32, FcγRIIIb/CD16, and CR1/CD35, indicating neutrophil activation; and (2) increased serum chemotactic activity and decreased activity of the alternative complement pathway, indicating systemic complement system activation. The levels of C-reactive protein in a-RA patients were augmented, compared with i-RA patients. Although infliximab/methotrexate combined therapy induced disease remission according to the DAS-28 criteria, both i-RA and a-RA patients still exhibited significant levels of systemic activation of neutrophils and the complement system.

Background Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage ≥3 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage ≥3 CKD in a large cohort of patients affected by T1DM. Methods A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage ≥3 CKD (eGFR 30% from baseline was evaluated. Results The mean estimated GFR was 98 ± 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions Albuminuria and eGFR reduction represent independent risk factors for incident stage ≥3 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening. Electronic supplementary material The online version of this article (10.1186/s12882-018-1136-6) contains supplementary material, which is available to authorized users.