Incidence of postoperative opioid-induced respiratory depression episodes in patients on room air or supplemental oxygen: a post-hoc analysis of the PRODIGY trial.

BACKGROUND: Supplemental oxygen (SO) potentiates opioid-induced respiratory depression (OIRD) in experiments on healthy volunteers. Our objective was to examine the relationship between SO and OIRD in patients on surgical units. METHODS: This post-hoc analysis utilized a portion of the observational PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) trial dataset (202 patients, two trial sites), which involved blinded continuous pulse oximetry and capnography monitoring of postsurgical patients on surgical units. OIRD incidence was determined for patients receiving room air (RA), intermittent SO, or continuous SO. Generalized estimating equation (GEE) models, with a Poisson distribution, a log-link function and time of exposure as offset, were used to compare the incidence of OIRD when patients were receiving SO vs RA. RESULTS: Within the analysis cohort, 74 patients were always on RA, 88 on intermittent and 40 on continuous SO. Compared with when on RA, when receiving SO patients had a higher risk for all OIRD episodes (incidence rate ratio [IRR] 2.7, 95% confidence interval [CI] 1.4-5.1), apnea episodes (IRR 2.8, 95% CI 1.5-5.2), and bradypnea episodes (IRR 3.0, 95% CI 1.2-7.9). Patients with high or intermediate PRODIGY scores had higher IRRs of OIRD episodes when receiving SO, compared with RA (IRR 4.5, 95% CI 2.2-9.6 and IRR 2.3, 95% CI 1.1-4.9, for high and intermediate scores, respectively). CONCLUSIONS: Despite oxygen desaturation events not differing between SO and RA, SO may clinically promote OIRD. Clinicians should be aware that postoperative patients receiving SO therapy remain at increased risk for apnea and bradypnea. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02811302, registered June 23, 2016.

Meta-Analysis of Rates and Risk Factors for Local Recurrence in Surgically Resected Patients With NSCLC and Differences Between Asian and Non-Asian Populations.

Introduction: Postoperative radiotherapy (PORT) reduces local failure in patients with NSCLC, without a clear overall survival benefit. It is unknown whether the subsets of patients benefit. Two recent large randomized controlled trials, PORT-C (People's Republic of China) and Lung ART (Europe), reported widely different locoregional recurrence (LR) rates in the control arms, at 18.3% and 28.1% (46% of which were mediastinal recurrences), respectively. We performed a meta-analysis of patients with pathologic (p) N0 to N2 disease to evaluate the risk factors for LR and to explore possible differences in recurrence risk between Asian population (AP) and non-Asian population (NAP). Methods: We identified all original studies of curative NSCLC surgical resection which reported risk of LR between January 1, 2000, and January 10, 2021, excluding studies with less than 10 LR, patients with metastatic disease, or any neoadjuvant therapy. A total of 87 studies were identified with pN0 to N2 disease; of these, 56 were of high quality (HQ) on the basis of the Newcastle-Ottawa Scale. For each risk factor, we derived pooled relative risk (RR) and 5-year rate estimates using random-effects models. Results: Overall, the three significant highest pooled RRs (95% confidence intervals) for LR were pN2 versus pN0 (3.01, 1.39-6.55), lymphovascular invasion (1.92, 1.58-2.33), and advanced pT3-4 stage versus pT1 (1.86, 1.53-2.25). For HQ studies, the highest RRs for LR were lymphovascular invasion (1.94, 1.57-2.40), sublobar versus lobar resection (1.86, 1.46-2.36), and pN1 versus pN0 (1.84, 1.37-2.47), but pN2 versus pN0 was no longer significant (3.0, 0.57-15.61), on the basis of only two eligible studies. The RRs for LR were consistent for most factors in AP and NAP, although the RR for male versus female sex was higher in AP (1.44, 1.21-1.72) than in NAP (1.09, 0.99-1.19). Where reported, the pooled rate of LR at 5 years was lower in AP (12.0%) than in NAP (22.7%), despite similar overall 5-year recurrence rates (both LR and distal) in both populations: 38.0% in AP and 37.3% in NAP. Nevertheless, a lower 5-year mortality rate was noted in AP (24.3%) than in NAP (45.9%). Conclusions: There is little high-quality evidence to support the hypothesis that pN2 disease is a risk factor for LR, but LR seems to be lower in Asians. Prospective evaluation of LR factors and rates may be necessary before further prospective evaluation of PORT, because it may not depend on nodal status alone. Recurrence rates may differ in Asians. The impact of mutational status and modern treatment including targeted therapies and immune checkpoint inhibitors is inadequately studied.

Vertebral augmentation reduces the 12-month mortality and morbidity in patients with osteoporotic vertebral compression fractures.

OBJECTIVES: To investigate the 12-month all-cause mortality and morbidity in patients with osteoporotic vertebral compression fractures (OVCFs) undergoing vertebroplasty/balloon kyphoplasty (VP/BKP) versus non-surgical management (NSM). METHODS: Following a Medline and EMBASE search for English language articles published from 2010 to 2019, 19 studies reporting on mortality and morbidity after VP/BKP in patients with OVCFs were selected. The 12-month timeline was set due to the largest amount of data availability at such time interval. Estimates for each study were reported as odds ratios (OR) along with 95% confidence intervals (CI) and p values. Fixed or random-effects meta-analyses were performed. All tests were based on a two-sided significance level of 0.05. RESULTS: Pooled OR across 5 studies favored VP/BKP over NSM in terms of 12-month all-cause mortality (OR: 0.81 [95% CI: 0.46-1.42]; p = .46). Pooled OR across 11 studies favored VP/BKP over NSM in terms of 12-month all-cause morbidity (OR: 0.64 [95% CI: 0.31-1.30]; p = .25). Sub-analysis of data dealing with 12-month infective morbidity from any origin confirmed the benefit of VP/BKP over NSM (OR: 0.23 [95% CI, 0.02-2.54]; p = .23). CONCLUSION: Compared to NSM, VP/BKP reduces the 12-month risk of all-cause mortality and morbidity by 19% and 36%, respectively. Moreover, VP/BKP reduces by 77% the 12-month risk of infection from any origin. KEY POINTS: • Compared to non-surgical management, vertebral augmentation reduces the 12-month risk of all-cause mortality by 19% and all-cause morbidity by 36%. • Vertebral augmentation reduces the 12-month risk of infection morbidity from any origin by 77%.

Non-albuminuric renal impairment is a strong predictor of mortality in individuals with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicentre study.

AIMS/HYPOTHESIS: Non-albuminuric renal impairment has become the prevailing diabetic kidney disease (DKD) phenotype in individuals with type 2 diabetes and an estimated GFR (eGFR) <60 ml min-1 1.73 m-2. In the present study, we compared the rate and determinants of all-cause death in individuals with this phenotype with those in individuals with albuminuric phenotypes. METHODS: This observational prospective cohort study enrolled 15,773 individuals with type 2 diabetes in 2006-2008. Based on baseline albuminuria and eGFR, individuals were classified as having: no DKD (Alb-/eGFR-), albuminuria alone (Alb+/eGFR-), reduced eGFR alone (Alb-/eGFR+), or both albuminuria and reduced eGFR (Alb+/eGFR+). Vital status on 31 October 2015 was retrieved for 15,656 individuals (99.26%). RESULTS: Mortality risk adjusted for confounders was lowest for Alb-/eGFR- (reference category) and highest for Alb+/eGFR+ (HR 2.08 [95% CI 1.88, 2.30]), with similar values for Alb+/eGFR- (1.45 [1.33, 1.58]) and Alb-/eGFR+ (1.58 [1.43, 1.75]). Similar results were obtained when individuals were stratified by sex, age (except in the lowest age category) and prior cardiovascular disease. In normoalbuminuric individuals with eGFR <45 ml min-1 1.73 m-2, especially with low albuminuria (10-29 mg/day), risk was higher than in microalbuminuric and similar to macroalbuminuric individuals with preserved eGFR. Using recursive partitioning and amalgamation analysis, prevalent cardiovascular disease and lower HDL-cholesterol were the most relevant correlates of mortality in all phenotypes. Higher albuminuria within the normoalbuminuric range was associated with death in non-albuminuric DKD, whereas the classic 'microvascular signatures', such as glycaemic exposure and retinopathy, were correlates of mortality only in individuals with albuminuric phenotypes. CONCLUSIONS/INTERPRETATION: Non-albuminuric renal impairment is a strong predictor of mortality, thus supporting a major prognostic impact of renal dysfunction irrespective of albuminuria. Correlates of death partly differ from the albuminuric forms, indicating that non-albuminuric DKD is a distinct phenotype. TRIAL REGISTRATION: ClinicalTrials.gov NCT00715481.

Efficacy, safety and acceptability of the new pen needle 34G × 3.5 mm: a crossover randomized non-inferiority trial; AGO 02 study.

OBJECTIVE: 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. METHODS: 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%. RESULTS: 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/m2 (±5.6), HbA1c 8% (±1.1) and baseline fructosamine level 350 µmol/l (±84). Mean fructosamine levels increased by 0.56 µmol/l with the 34G needle, while a reduction of 7.29 µmol/l was documented with the 32G needle. The difference between the two groups (7.84 µmol/l) was not statistically significant (p = .27). The % |ΔFru| between the two groups was 7.55% (95% CI 5.67-9.44), meeting the non-inferiority criterion. Glycemic variability, expressed as standard deviation of fasting blood glucose and post-prandial glucose, was not different between the two treatment groups (p = .63 and p = .77, respectively). CONCLUSIONS: The 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. CLINICAL TRIAL REGISTRATION: NCT02690467.

Insulin pump breakdown and infusion set failure in Italian children with type 1 diabetes: A 1-year prospective observational study with suggestions to minimize clinical impact.

AIM: To evaluate the incidence of insulin pump and infusion set failures in a cohort of children and adolescents with type 1 diabetes during a 1-year follow-up. MATERIALS AND METHODS: Insulin pump breakdown and infusion set failures were prospectively registered in a cohort of 1046 children and adolescents from 25 tertiary pediatric diabetes centres (50% male, mean age 12.2 ± 4.1 years), with type 1 diabetes from the age of 6.7 ± 3.6 years, and using an insulin pump from the age of 3.3 ± 2.2 years. RESULTS: An average rate of 4.5 failures/person-year was registered; the incidences (events per person-year) for each failure were 8.4 for hyperglycaemia episodes solved with infusion set change, 7 for bubbles, 2.8 for kinking, 2.4 for bleeding, 2 for set dislodge, 2 for pump blockage, 1.9 for tunnelling, 1.8 for lipohypertrophy, and 0.3 for infection. At multivariate analysis significant association between HbA1c and lipohypertrophy (P < 0.0028) was shown. Analysis by age group (<6, 6-11, >11 years) showed a higher frequency of bubbles, hyperglycaemia episodes and lipohypertrophy in preschoolers; tunnelling and pump blockage were more frequent in adolescents. Aspart was associated with a lower risk of bubbles and hyperglycaemia whereas glulisine was associated with a higher risk of lipohypertrophy and pump blockage. The usage of oblique cannula was associated with a low risk of all failures except infections. CONCLUSIONS: This prospective 1-year study on a large cohort of Italian children and adolescents with type 1 diabetes using insulin pump therapy showed a low total failure rate, highlighting the importance of continuous education to reduce failures. Lipohypertrophy was the only issue associated with a worsening of metabolic control.

Impact of Insulin Degludec in Hospitalized Patients With and Without Type 2 Diabetes Requiring Parenteral/Enteral Nutrition: An Observational Study.

INTRODUCTION: Hyperglycemia in inpatients is a major problem, especially when nutritional support is required. This study aims to assess the impact of treatment with insulin degludec (IDeg) on mean blood glucose (BG) and glycemic variability in noncritical hospitalized patients with and without type 2 diabetes (T2DM) receiving enteral and/or parenteral nutrition (EN, PN). METHODS: Mean BG and glycemic variability from admission up to 7 days of hospitalization were evaluated in consecutive cases with and without T2DM. Percentage of coefficient of variation (CV) for glucose was used to express glycemic variability. RESULTS: Overall, 26 patients (13 with and 13 without T2DM) were admitted to the hospital for any cause. Subjects were 65.4% men and they were mainly elderly (mean age 66.3 ± 13.4 years). PN was administered in 88.5% of patients and EN in 19.2%. At admission, mean HbA1c level was 5.9 ± 0.7% in patients without diabetes and 9.1 ± 2.5% in patients with T2DM. During hospitalization, mean daily BG levels changed from 151 ± 47.3 mg/dl (day 1) to 157 ± 66.7 mg/dl (day 7) in patients without diabetes and from 210 ± 66.5 mg/dl to 192 ± 48.6 mg/dl in patients with T2DM. CV decreased from 14% (day 1) to 11% (day 7) in patients without diabetes and from 20% (day 1) to 9% (day 7) in patients with T2DM. No symptomatic or severe hypoglycemia occurred. CONCLUSIONS: Despite the small sample size and the lack of control group, this study represents the first proof-of-concept that IDeg in hospitalized patients with or without T2DM who require nutritional support has the potential to maintain stable levels of BG and reduce glycemic variability. FUNDING: Novo Nordisk S.p.A. grant.

Autosomal Recessive Hypercholesterolemia: Long-Term Cardiovascular Outcomes.

BACKGROUND: Autosomal recessive hypercholesterolemia (ARH) is a rare lipid disorder characterized by premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data for clinical management and cardiovascular outcomes in ARH. OBJECTIVES: Evaluation of changes in lipid management, achievement of low-density lipoprotein cholesterol (LDL-C) goals and cardiovascular outcomes in ARH. METHODS: Published ARH cases were identified by electronic search. All corresponding authors and physicians known to treat these patients were asked to provide follow-up information, using a standardized protocol. RESULTS: We collected data for 52 patients (28 females, 24 males; 31.1 ± 17.1 years of age; baseline LDL-C: 571.9 ± 171.7 mg/dl). During a mean follow-up of 14.1 ± 7.3 years, there was a significant increase in the use of high-intensity statin and ezetimibe in combination with lipoprotein apheresis; in 6 patients, lomitapide was also added. Mean LDL-C achieved at nadir was 164.0 ± 85.1 mg/dl (-69.6% from baseline), with a better response in patients taking lomitapide (-88.3%). Overall, 23.1% of ARH patients reached LDL-C of <100 mg/dl. During follow-up, 26.9% of patients had incident ASCVD, and 11.5% had a new diagnosis of aortic valve stenosis (absolute risk per year of 1.9% and 0.8%, respectively). No incident stroke was observed. Age (≥30 years) and the presence of coronary artery disease at diagnosis were the major predictors of incident ASCVD. CONCLUSIONS: Despite intensive treatment, LDL-C in ARH patients remains far from targets, and this translates into a poor long-term cardiovascular prognosis. Our data highlight the importance of an early diagnosis and treatment and confirm the fact that an effective treatment protocol for ARH is still lacking.

Portrait of women with type 1 or type 2 diabetes of childbearing age attending diabetes clinics in Italy: the AMD-Annals initiative.

AIM: To describe characteristics relevant in case of an unplanned pregnancy for T1D or T2D women of childbearing age. METHODS: We analyzed the 2011 AMD-Annals dataset, compiling information from 300 clinics (28,840 T1D patients and 532,651 T2D patients). A risk score of unfavorable conditions for pregnancy included HbA1c > 8.0%; BMI ≥ 35; systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg; microalbuminuria/proteinuria; use of statins, ACE inhibitors, ARB; use of diabetes drugs other than metformin/insulin. RESULTS: The proportion of T2D cases increased from 30.8% (95% CI 29.9-32.4) at age 18-30 years to 67.5% (66.6-68.5) at age 36-45 years. The proportion of women with HbA1c < 7.0% was 20.4% (20.0-20.8) in T1D and 43.4% (42.8-43.9) in T2D women. Furthermore, 47.6% (47.0-48.3) of T1D women and 34.5% (33.9-35.0) of T2D women had HbA1c ≥ 8.0%. The prevalence of obesity (BMI ≥ 30) was sevenfold higher among T2D than T1D women [49.9% (49.4-50.5) and 7.4% (7.2-7.5), respectively]. T2D women were more likely to have hypertension or microalbuminuria than T1D women. Almost half of the T2D women were taking drugs not approved during pregnancy. At least one unfavorable condition for starting a pregnancy was present in 51% of T1D women of childbearing age and in 66.7% of T2D women. CONCLUSIONS: Women with either T1D or T2D of childbearing age in Italy were far from the ideal medical condition for conception. Our data strongly support the need for counseling all women with diabetes about pregnancy planning.

The prevalence and correlates of low sexual functioning in women on hemodialysis: A multinational, cross-sectional study.

Sexual dysfunction may affect 80% of women in hemodialysis. However the specific patterns and clinical correlates of sexual functioning remain poorly described. The aim of this study was to assess prevalence and correlates of the individual domains of sexual functioning in women treated with hemodialysis. We recruited, into this multinational cross-sectional study, women treated with long-term hemodialysis (Collaborative Working Group on Depression and Sexual dysfunction in Hemodialysis study). Self-reported domains of sexual functioning were assessed by the Female Sexual Function Index, which is routinely administered within the network of dialysis patients followed by the working group. Lower scores represented lower sexual functioning. Socio-demographic and clinical correlates of each domain of sexual functioning were identified by stepwise multivariable linear regression. Sensitivity analyses were restricted to women who reported being sexually active. We found that of 1309 enrolled women, 659 (50.3%) provided complete responses to FSFI survey questions and 232 (35%) reported being sexually active. Overall, most respondents reported either no sexual activity or low sexual functioning in all measured domains (orgasm 75.1%; arousal 64.0%; lubrication 63.3%; pain 60.7%; satisfaction 60.1%; sexual desire 58.0%). Respondents who were waitlisted for a kidney transplant reported scores with higher sexual functioning, while older respondents reported scores with lower functioning. The presence of depression was associated with worse lubrication and pain scores [mean difference for depressed versus non-depressed women (95% CI) -0.42 (-0.73 to -0.11), -0.53 (-0.89 to -0.16), respectively] while women who had experienced a previous cardiovascular event reported higher pain scores [-0.77 (-1.40- to -0.13)]. In conclusion, women in hemodialysis reported scores consistent with marked low sexual functioning across a range of domains; the low functioning appeared to be associated with comorbidity.

Efficacy and Safety of Insulin Degludec for Hyperglycemia Management in Noncritical Hospitalized Patients with Diabetes: An Observational Study.

INTRODUCTION: To assess the efficacy and safety of insulin degludec administered in a basal-bolus regimen according to the GesTIO protocol in noncritical hospitalized patients with T1DM and T2DM. METHODS: Mean blood glucose levels (BG) and their standard deviations (SD) at admission vs. discharge were compared in 52 subjects (48.1% ≥75 years) managed through a basal-bolus scheme including degludec. The percentages of patients with BG at target (140-180 mg/dl) or below at discharge and the incidence rate (and the 95% confidence interval for it) of hypoglycemia were assessed. RESULTS: From admission to discharge, fasting BG decreased from 237 to 153 mg/dl (p < 0.0001) and SD dropped from 125 to 38 mg/dl (p < 0.0001); average BG decreased from 189 to 145 mg/dl (SD dropped from 57 to 32 mg/dl). At discharge, 28.9% had BG at target, while 50.0% had lower levels (average 119.0 ± 14.4 mg/dl). The incidence rate of hypoglycemia was 0.07 (0.05; 0.11) episodes per person-day; 1 out of 27 episodes occurred during the night. CONCLUSIONS: Degludec in hospitalized, mainly elderly patients is effective and minimizes glucose variability and nocturnal hypoglycemia.

Depression and all-cause and cardiovascular mortality in patients on haemodialysis: a multinational cohort study.

Background: Depression and early death are both common in adults with Stage 5 chronic kidney disease. Studies have shown an association between depression and total mortality, but the association between depression and cardiovascular death is less certain. Methods: We conducted a prospective multinational cohort study involving adults who were treated with long-term haemodialysis within a single dialysis network between April and November 2010. Depression was considered present when patients reported a Beck Depression Inventory (BDI) II score ≥14 at baseline. Sensitivity analyses considered a BDI II score ≥20 to identify moderate depression. Multivariable Cox proportional hazards regression was used to assess adjusted hazards for all-cause and cardiovascular mortality at 12 months. Results: Three thousand and eighty-six participants in the network received the BDI II questionnaire, and 2278 (73%) provided complete responses to the survey questions. Among these, 1047 (46%) reported depression. During a mean follow-up of 11 (standard deviation: 2.5) months (2096 person-years), we recorded 175 deaths, of which 66 were attributable to cardiovascular causes. Depression (BDI score ≥14) was not associated with all-cause mortality [adjusted hazard ratio: 1.26 (95% confidence interval: 0.93­1.71)] or cardiovascular mortality [0.82 (0.50­1.34)]. When a higher BDI score (BDI score ≥20) was used to identify moderate depression, depression was associated with total mortality [1.40 (1.02­1.93)] but not cardiovascular mortality [1.05 (0.63­1.77)]. Conclusions: The association between depression and cardiovascular mortality in adults with kidney failure treated with haemodialysis is uncertain. Depression is a heterogeneous disorder and may only be a risk factor for premature death when at least of moderate severity.

The complex interplay between clinical and person-centered diabetes outcomes in the two genders.

BACKGROUND: New approaches to cope with clinical and psychosocial aspects of type 2 diabetes (T2DM) are needed; gender influences the complex interplay between clinical and non-clinical factors. We used data from the BENCH-D study to assess gender-differences in terms of clinical and person-centered measures in T2DM. METHODS: Clinical quality of care indicators relative to control of HbA1c, lipid profile, blood pressure, and BMI were derived from electronic medical records. Ten self-administered validated questionnaires (SF-12 Health Survey; WHO-5 well-being index; Problem Areas in Diabetes (PAID) 5, Health Care Climate Questionnaire, Patients Assessment of Chronic Illness Care, Diabetes Empowerment Scale, Diabetes Self-care Activities, Global Satisfaction for Diabetes Treatment, Barriers to Taking Medications, Perceived Social Support) were adopted as person-centered outcomes indicators. RESULTS: Overall, 26 diabetes clinics enrolled 2,335 people (men: 59.7%; women: 40.3%). Lower percentages of women reached HbA1c levels < =7.0% (23.2% vs. 27.8%; p = 0.03), LDL-cholesterol < 100 mg/dl (48.3 vs. 57.8%; p = 0.0005), and BMI <27 Kg/m2 (27.2 vs. 31.6%; p = 0.04) than men. Women had statistically significant poorer scores for physical functioning, psychological well-being, self-care activities dedicated to physical activities, empowerment, diabetes-related distress, satisfaction with treatment, barriers to medication taking, satisfaction with access to chronic care and healthcare communication, and perceived social support than men; 24.8% of women and 8.8% of men had WHO-5 < =28 (likely depression) (p < 0.0001); 67.7% of women and 55.1% of men had PAID-5 > 40 (high levels of diabetes-related distress) (p < 0.0001). At multivariate analysis, factors associated with an increased likelihood of having elevated HbA1c levels (≥8.0%) were different in men and women, e.g. having PAID-5 levels >40 was associated with a higher likelihood of HbA1c ≥8.0% in women (OR = 1.15; 95%CI 1.05-1.25) but not in men (OR = 1.00; 95%CI 0.93-1.08). CONCLUSIONS: In T2DM, women show poorer clinical and person-centered outcomes indicators than men. Diabetes-related distress plays a role as a correlate of metabolic control in women but not in men. The study provides new information about the interplay between clinical and person-centered indicators in men and women which may guide further improvements in diabetes education and support programs.

Young patients with type 1 diabetes poorly controlled and poorly compliant with self-monitoring of blood glucose: can technology help? Results of the i-NewTrend randomized clinical trial.

AIMS: To compare iBGStar™ + DMApp (experimental meter + telemedicine system) (iBGStar) with a traditional glucose meter (Control) in type 1 diabetes adolescents/young adults. METHODS: i-NewTrend was a multicenter, open-label, randomized trial involving subjects aged 14-24 years, on basal-bolus insulin, HbA1c ≥ 8.0%, and poorly compliant with SMBG (i.e., <30% of the recommended frequency). Primary end points were change in HbA1c and achievement of compliance with SMBG (≥30% of the recommended frequency) after 6 months. Quality of life was also evaluated. A post-trial observational phase was conducted, where both groups used the experimental device. RESULTS: Of 182 randomized patients (51.1% male; age 17.7 ± 3.0 years; diabetes duration 8.8 ± 4.7 years; HbA1c levels 10.0% ± 1.4), 92 were allocated to iBGStar and 90 to Control; 6.5% in iBGStar and 8.9% in Control dropped-out. After 6 months, HbA1c changes (±SE) were -0.44% ± 0.13 in iBGStar and -0.32% ± 0.13 in Control (p = 0.51). In the post-trial phase, HbA1c changes from 6 months (±SE) were -0.07% ± 0.14 in iBGStar and -0.31% ± 0.14 in Control (p = 0.24). Compliance end point was reached by 53.6% in iBGStar and 55.0% in Control (p = 0.86). Mean daily SMBG measurements increased from 1.1 to 2.3 in both groups without worsening quality of life. Compliant subjects showed a greater reduction in HbA1c levels (-0.60% ± 0.23 in iBGStar; -0.41% ± 0.21 in Control; p = 0.31). Within iBGStar group, telemedicine users (38.0%) reduced HbA1c by -0.58 ± 0.18. CONCLUSIONS: iBGStar was not superior to the traditional meter. Irrespective of the strategy, increasing from 1 to 2 SMBG tests/day was associated with HbA1c reduction in both groups, without pharmacologic interventions. Identifying new technologies effective and acceptable to patients is an option to improve adherence to diabetes care. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov (registration number NCT02073188).

Use of Liraglutide in the Real World and Impact at 36 Months on Metabolic Control, Weight, Lipid Profile, Blood Pressure, Heart Rate, and Renal Function.

PURPOSE: An observational retrospective study was conducted by 2 diabetes clinics in Italy to assess patterns of use and long-term effectiveness of liraglutide on established and emerging parameters. METHODS: Data from 261 patients with type 2 diabetes who started treatment with liraglutide between 2010 and 2014 were collected. Hierarchical linear regression models were applied to assess trends over time of clinical parameters. Factors associated with higher likelihood of dropout were identified through multivariate logistic analysis. FINDINGS: Liraglutide was initiated as a switch in 42.5% of patients and as an add-on in 49.8%; in 7.7% of the patients initiation of liraglutide was associated with a reduction in the number of pharmacologic agents. A statistically significant reduction after 36 months was found for the following parameters (mean change [95% CIs]): glycosylated hemoglobin (HbA1c; -1.01% [1.34% to -0.68%]), fasting blood glucose (-27.5 [-40.6 to -14.4] mg/dL), weight (-2.9 [-4.5 to -1.3] kg), body mass index (-1.13 [-1.76 to -0.50] kg/m2), waist circumference (-1.74 [-3.85 to -0.37] cm), and LDL-C (-24.7 [-36.67 to -12.8] mg/dL). Improvements in systolic (-3.5 mm Hg) and diastolic (-2.3 mm Hg) blood pressures were observed at 24 months. Albuminuria was reduced by -16.6 mg/L during 36 months, although statistical significance was not reached. Glomerular filtration rate and heart rate were unchanged. Reductions in HbA1c between -0.6% and -1.3% were obtained in specific subgroups. Treatment was effective also in patients with >20 years of diabetes duration, although the likelihood of dropout was 6% higher for each additional year of disease duration (RR = 1.06; 95% CI, 1.01-1.12). The likelihood of dropout was almost four times higher for subjects treated with insulin (RR = 3.82; 95% CI, 1.22-11.96) and more than twice for those treated with sulfonylureas (RR = 2.39; 95% CI, 1.16-4.94) compared with patients not treated with these agents. IMPLICATIONS: Liraglutide used in routine clinical conditions maintains its effectiveness on metabolic control and weight after 3 years. Improvements in terms of metabolic control were found when liraglutide was used as both switch and add-on treatment. In addition, improvements were sustained when liraglutide replaced sulfonylureas or insulin. Diabetes duration had no impact on drug efficacy. Long-term benefits relative to blood pressure and LDL-C were also found, which could not be entirely explained by antihypertensive/lipid-lowering treatment intensification. No major effect on renal parameters was documented. Diabetes duration and some concomitant treatments were associated with a higher likelihood of liraglutide discontinuation. These data can contribute to improve appropriateness and cost-effectiveness profile of liraglutide.

Effectiveness and safety of liraglutide after three years of treatment.

BACKGROUND: The aim of this study was to evaluate long-term effectiveness and safety of liraglutide in real world. METHODS: A diabetes clinic in Italy systematically collected data of all patients treated with liraglutide. Generalized hierarchical linear regression models for repeated measures were applied to assess trends over time of HbA1c, fasting plasma glucose (FPG), body weight, blood pressure and lipid profile. RESULTS: Overall, 255 patients (mean age: 63.5±9.7 years, men: 56.9%, mean diabetes duration: 12.0±8.1 years) were treated with liraglutide during 36 months. Mean HbA1c levels decreased by -1.0±0.1% (P<0.0001), FPG by -46±6 mg/dL (P<0.0001), and body weight by -3.9±0.8 Kg (P<0.0001). HbA1c reduction was inversely related to diabetes duration, while body weight reduction was directly related to baseline BMI. Significant improvements in HDL-cholesterol and triglycerides levels were also documented. Trends of improvement in systolic blood pressure (SBP) levels were also found, with significant reduction in patients with baseline SBP≥140 mmHg. Treatment was well-tolerated by the vast majority of the patients. Neither severe hypoglycemia nor pancreatitis occurred. Drop-out rate was of 28.2%. Main causes of drop-out were gastrointestinal side effects and lack of efficacy. CONCLUSION: Our analysis documents a prolonged effectiveness and safety of liraglutide, even after three years of treatment. In addition to significant improvement in glycemic control and body weight, liraglutide also provides additional benefits on cardiovascular risk profile, while minimizing the risk of hypoglycemia. However, magnitude of benefits reflects specific patient characteristics that deserve further investigation.

Clobetasol and Halcinonide Act as Smoothened Agonists to Promote Myelin Gene Expression and RxRγ Receptor Activation.

One of the causes of permanent disability in chronic multiple sclerosis patients is the inability of oligodendrocyte progenitor cells (OPCs) to terminate their maturation program at lesions. To identify key regulators of myelin gene expression acting at the last stages of OPC maturation we developed a drug repositioning strategy based on the mouse immortalized oligodendrocyte (OL) cell line Oli-neu brought to the premyelination stage by stably expressing a key factor regulating the last stages of OL maturation. The Prestwick Chemical Library of 1,200 FDA-approved compound(s) was repositioned at three dosages based on the induction of Myelin Basic Protein (MBP) expression. Drug hits were further validated using dosage-dependent reproducibility tests and biochemical assays. The glucocorticoid class of compounds was the most highly represented and we found that they can be divided in three groups according to their efficacy on MBP up-regulation. Since target identification is crucial before bringing compounds to the clinic, we searched for common targets of the primary screen hits based on their known chemical-target interactomes, and the pathways predicted by top ranking compounds were validated using specific inhibitors. Two of the top ranking compounds, Halcinonide and Clobetasol, act as Smoothened (Smo) agonists to up-regulate myelin gene expression in the Oli-neuM cell line. Further, RxRγ activation is required for MBP expression upon Halcinonide and Clobetasol treatment. These data indicate Clobetasol and Halcinonide as potential promyelinating drugs and also provide a mechanistic understanding of their mode of action in the pathway leading to myelination in OPCs. Furthermore, our classification of glucocorticoids with respect to MBP expression provides important novel insights into their effects in the CNS and a rational criteria for their choice in combinatorial therapies in de-myelinating diseases.

Interplay among patient empowerment and clinical and person-centered outcomes in type 2 diabetes. The BENCH-D study.

OBJECTIVE: We evaluated empowerment in T2DM and identified its correlates. METHODS: A sample of individuals self-administered the Diabetes Empowerment Scale-Short Form (DES-SF) and other 9 validated instruments (person-centered outcomes). Correlates of DES-SF were identified through univariate and multivariate analyses. For person-centered outcomes, ORs express the likelihood of being in upper quartile of DES-SF (Q4) by 5 units of the scale. RESULTS: Overall, 2390 individuals were involved. Individuals in Q4 were younger, more often males, had higher levels of school education, lower HbA1c levels and prevalence of complications as compared to individuals in the other quartiles. The likelihood of being in Q4 was directly associated with higher selfreported self-monitoring of blood glucose (SDSCA6-SMBG) (OR=1.09; 95% CI: 1.03-1.15), higher satisfaction with diabetes treatment (GSDT) (OR=1.15; 95% CI: 1.07-1.25), perceived quality of chronic illness care and patient support (PACIC-SF) (OR=1.23; 95% CI: 1.16-1.31), and better person-centered communication (HCC-SF) (OR=1.10; 95% CI: 1.01-1.19) and inversely associated with diabetes-related distress (PAID-5) (OR=0.95; 95% CI: 0.92-0.98). Adjusted DES-SF mean scores ranged between centers from 69.8 to 93.6 (intra-class correlation=0.10; p<0.0001). CONCLUSIONS: Empowerment was associated with better glycemic control, psychosocial functioning and perceived access to person-centered chronic illness care. Practice of diabetes center plays a specific role. PRACTICE IMPLICATIONS: DES-SF represents a process and outcome indicator in the practice of diabetes centers.

The long-term effects of stillbirth on women with and without gestational diabetes: a population-based cohort study.

AIMS/HYPOTHESIS: The aim of this study was to estimate the incidence of type 2 diabetes (primary objective) and hospitalisation for cardiovascular events (secondary objective) in women with previous gestational diabetes mellitus (GDM) and in those with normal glucose tolerance (NGT) in pregnancy, and to evaluate the role of stillbirth in differentiating the risks. METHODS: This was a population-based cohort study using administrative data and involving 12 local health authorities. Women with GDM (n = 3,851) during the index period from 2002 to 2010 were propensity matched with women with NGT (n = 11,553). Information was collected on type 2 diabetes development and hospitalisation for cardiovascular events. RESULTS: During a median follow-up of 5.4 years, the incidence rate per 1,000 person-years of type 2 diabetes was 2.1 (95% CI 1.8, 2.5) in women without GDM and 54.0 (95% CI 50.2, 58.0) among women with GDM and pregnancy at term (incidence rate ratio [IRR] 26.9; 95% CI 22.1, 32.7 compared with NGT and pregnancy at term). A history of stillbirth increased the risk of type 2 diabetes development by about twofold, irrespective of GDM status. No significant interaction between stillbirth and GDM on type 2 diabetes risk was found. GDM was associated with a significantly higher risk of cardiovascular events compared with NGT (IRR 2.4; 95% CI 1.5, 3.8). CONCLUSIONS/INTERPRETATION: Pregnancy complicated by GDM and ending in stillbirth represents an important contributory factor in determining type 2 diabetes development. Women with GDM are at a high risk of future cardiovascular events. Women with pregnancy complicated by GDM and stillbirth deserve careful follow-up.