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.
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.
Abstract 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.
Abstract
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.
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).
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.
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%).
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.
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
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).
Highlights • Measurement of empowerment and patient-centered outcomes can be standardized. • Empowerment is efficiently measured by DES-SF questionnaire. • Empowerment is associated with clinical and ...psychosocial outcomes and self-care. • DES-SF mean scores varies between centers due to difference in clinical practice. • DES-SF can be an indicator to monitor implementation of chronic care model.
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.
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.
Evaluation of changes in lipid management, achievement of low-density lipoprotein cholesterol (LDL-C) goals and cardiovascular outcomes in ARH.
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.
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.
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.
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