Psychometric evaluation of the 5-item Medication Adherence Report Scale questionnaire in persons with multiple sclerosis.

The 5-item Medication Adherence Report Scale (MARS-5) is a reliable and valid questionnaire for evaluating adherence in patients with asthma, hypertension, and diabetes. Validity has not been determined in multiple sclerosis (MS). We aimed to establish criterion validity and reliability of the MARS-5 in persons with MS (PwMS). Our prospective study included PwMS on dimethyl fumarate (DMF). PwMS self-completed the MARS-5 on the same day before baseline and follow-up brain magnetic resonance imaging (MRI) 3 and 9 months after treatment initiation and were graded as highly and medium adherent upon the 24-cut-off score, established by receiver operator curve analysis. Health outcomes were represented by relapse occurrence from the 1st DMF dispense till follow-up brain MRI and radiological progression (new T2 MRI lesions and quantitative analysis) between baseline and follow-up MRI. Criterion validity was established by association with the Proportion of Days Covered (PDC), new T2 MRI lesions, and Beliefs in Medicines questionnaire (BMQ). The reliability evaluation included internal consistency and the test-retest method. We included 40 PwMS (age 37.6 ± 9.9 years, 75% women), 34 were treatment-naive. No relapses were seen during the follow-up period but quantitative MRI analysis showed new T2 lesions in 6 PwMS. The mean (SD) MARS-5 score was 23.1 (2.5), with 24 PwMS graded as highly adherent. The higher MARS-5 score was associated with higher PDC (b = 0.027, P<0.001, 95% CI: (0.0134-0.0403)) and lower medication concerns (b = -1.25, P<0.001, 95% CI: (-1.93-(-0,579)). Lower adherence was associated with increased number (P = 0.00148) and total volume of new T2 MRI lesions (P = 0.00149). The questionnaire showed acceptable internal consistency (Cronbach α = 0.72) and moderate test-retest reliability (r = 0.62, P < 0.0001, 95% CI: 0.33-0.79). The MARS-5 was found to be valid and reliable for estimating medication adherence and predicting medication concerns in persons with MS.

Effects of Multidisciplinary Biopsychosocial Rehabilitation on Short-Term Pain and Disability in Chronic Low Back Pain: A Systematic Review with Network Meta-Analysis.

Chronic low back pain (CLBP) is a significant public health issue, with prevalence intensifying due to an ageing global population, amassing approximately 619 million cases in 2020 and projected to escalate to 843 million by 2050. In this study, we analyzed the effects of multidisciplinary biopsychosocial rehabilitation (MBR) on pain and disability. To address this question, we conducted a PRISMA-guided systematic review and random-effect network meta-analysis on studies collected from six electronic databases. The network comprised diverse MBR modalities (behavioral, educational, and work conditioning) alongside exercise therapy (ET), minimal intervention, and usual care, with pain and disability as outcomes. Ninety-three studies were included, encompassing a total of 8059 participants. The NMA substantiated that both ET and MBR modalities were effective in alleviating CLBP, with education-oriented MBR emerging as the most efficacious for pain mitigation (MD = 18.29; 95% CI = 13.70; 22.89) and behavior-focused MBR being the most efficacious for disability reduction (SMD = 0.88; 95% CI = 0.46; 1.30). Nevertheless, the discerned differences amongst the treatments were minimal and uncertain, highlighting that no modality was definitively superior to the others. Given the intricate nature of CLBP, embodying various facets, our findings advocate for a combined therapeutic approach to optimize treatment efficacy.

Medication persistence among people with multiple sclerosis in Slovenia treated with dimethyl fumarate.

Objective: Multiple sclerosis is a chronic, demyelinating inflammatory disease of the central nervous system. Medication persistence is defined as an interval between the initiation and last dose of the applied medication and presents a useful surrogate marker of a stable disease course. This observational study aimed to evaluate medication persistence and discontinuation reasons in Slovenian people with multiple sclerosis treated with dimethyl fumarate.Methods: Our retrospective cohort study evaluated people with relapsing-remitting multiple sclerosis treated with dimethyl fumarate as an initial monotherapy or switched from injectable disease-modifying therapy medication between 2014 and 2021. Medication dispenses were extracted from the Slovenian National Institute of Public Health Outpatient Medication Database. The medication persistence criterion was based on the treatment gap. Patients exceeding a 60-day gap were considered nonpersistent. The median time to discontinuation was assessed using survival analyses. Considering discontinuation reasons, patients were further divided into safety and inefficacy groups. Due to the high probability of adverse effects, patients exceeding a 60-day gap were included in the safety group, but definite discontinuation reason remains unknown. The impact of covariates was evaluated by Cox regression.Results: A total of 269 patients were included (183 women, mean age 37 years). During the 7-year follow-up period, 123 (45.7%) patients discontinued treatment. The median time to discontinuation was 5.6 years. After 1, 2, and 5 years of treatment, 84%, 77%, and 57% of patients were found to be persistent, respectively. All patients older than 30 years (p = 0.0013) and among them, those in the inefficacy group (p = 0.037) were more likely to be persistent.Conclusions: The results of our study proved a high persistence rate among our patients. The most frequent discontinuation reason was gastrointestinal adverse effects. Medication persistence requires interventions in younger patients with an unstable disease course.

Medication adherence and health outcomes in persons with multiple sclerosis treated with dimethyl fumarate.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that particularly affects people in their 30s. Oral disease-modifying therapy (DMT) offers a simple dosage form, good efficacy and safety. Dimethyl fumarate (DMF) is a frequently prescribed oral DMT medication worldwide. The aim of this study was to evaluate the impact of medication adherence on health outcomes in Slovenian persons with MS treated with DMF. METHODS: Our retrospective cohort study included persons with relapsing-remitting MS on DMF treatment. The medication adherence was evaluated by AdhereR software package using the proportion of days covered (PDC) measure. The threshold was set at 90%. Health outcomes after treatment initiation were represented by relapse occurrence, disability progression and occurrence of active (new T2 and T1/Gadolinium (Gd) enhancing) lesions between first two outpatient visits and first two brain magnetic resonance imaging (MRI), respectively. For each health outcome a separate multivariable regression model was built. RESULTS: The study included 164 patients. Their mean age (SD) was 36.7 (8.8) years, and the majority of patients were women (114 or 70%). Eighty-one patients were treatment naive. The mean (SD) PDC value was 0.942 (0.08) and 82% of patients were considered adherent above the 90% threshold. Older age (OR 1.06 per one year, P = 0.017, 95% CI (1.01-1.11)) and treatment naivety (OR 3.93, P = 0.004, 95% CI (1.64-10.4)) were related to higher adherence. In the 6-year follow-up period after DMF treatment initiation, 33 patients experienced a relapse. Among those, 19 required an emergency visit. Sixteen patients had a 1-point disability progression on the Expanded Disability Status Scale (EDSS) score between two consecutive outpatient visits. Thirty-seven patients were found to have active lesions between first and second brain MRI. Medication adherence showed no impact on relapse occurrence or disability progression. Lower medication adherence (10% lower PDC) was associated with higher occurrence of active lesions (OR 1.25, P=0.038, 95% CI: 1.01-1.56). Higher disability prior to DMF initiation was related to a higher risk for relapse occurrence and EDSS progression. CONCLUSION: Our study showed high medication adherence among Slovenian persons with relapse-remitting MS on DMF treatment. Higher adherence was associated with lower incidence of the radiological progression of MS. Interventions for improving medication adherence should be intended for younger patients with higher disability prior treatment with DMF and those switching from alternative DMTs.

Epidemiology and risk factors of self-reported systemic allergic reactions to a Hymenoptera venom in beekeepers worldwide: a protocol for a systematic review of observational studies.

INTRODUCTION: Systemic allergic reaction (SAR) to a Hymenoptera venom is a potentially life-threatening disorder. The rate of SAR between beekeepers in comparison with a healthy individual is different. The risk for an SAR is particularly high in beekeepers due to their persistent or seasonal exposure to the stinging Hymenoptera. We aim to provide a critical appraisal and a synthesis of evidence-based data from epidemiological observational studies, focusing on SARs to a Hymenoptera venom and the associated risk factors for SARs in beekeepers worldwide. METHODS AND ANALYSIS: Searching will include seven electronic databases for published studies without language restrictions, from inception up to 3 August 2021, and it will be rerun for all electronic databases prior publication. Only epidemiological observational studies in beekeepers will be included. The risk of bias in the included studies will be appraised by using the Joanna Briggs Institute Critical Appraisal Checklist for Analytical Cross-Sectional Studies and the Newcastle-Ottawa Scale, adapted for cross-sectional studies. For the certainty of evidence, the Grading of Recommendations Assessment, Development and Evaluation approach will be used. Qualitative synthesis will be presented in a tabulated format with the selected characteristics across primary studies and the main outcome of interest. A meta-analysis is planned to be performed if there will be a sufficient number of homogeneous studies with complete data. The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 statement will guide the reporting of this systematic literature review. ETHICS AND DISSEMINATION: No ethics approval is needed to conduct the systematic literature review since it will be solely based on the published literature. Findings will be disseminated through the relevant conferences, peer-review and open-access journals.PROSPERO registration numberCRD42021260922.

General antidepressants prescribing trends 2009-2018 in Slovenia: a cross-sectional retrospective database study.

BACKGROUND: Antidepressants are one of the most frequently prescribed groups of medications. The aim of the study was to evaluate the prevalence and patterns of antidepressants prescribed between 2009 and 2018 in Slovenia in different patient-age groups. METHODS: This retrospective cross-sectional study performed a nationwide database analysis of all outpatient antidepressant prescriptions based on Slovenian health claims data. Prevalence was defined as number of recipients prescribed at least one antidepressant per 1000 inhabitants. Antidepressant consumption was presented as total dispensed defined daily doses per year. RESULTS: In 2018, 147,300 patients were prescribed at least one antidepressant. The prevalence had increased by 16% in ten years and by 7.6% in age standardised data. The largest increase in prevalence was seen in the oldest patients (>80 years, 25% increase); of these, antidepressants are now prescribed to 1 in 4. Use of antidepressants had increased by 38%, suggesting longer treatment duration, increase in dose prescribed or both. SSRIs (selective serotonin reuptake inhibitors) were the most prescribed antidepressants (70% share), with escitalopram and sertraline the most commonly prescribed antidepressants. CONCLUSION: The prevalence of antidepressant prescribing and antidepressant consumption is increasing, mainly due to the population ageing and the increasing prescribing in elderly patients.Key PointsThe prevalence of antidepressant prescribing as well as antidepressants' consumption is increasing, reflecting both population ageing and rising prescribing rates.The increase in prevalence and consumption is most dramatic in the oldest patients (over 80 years of age).SSRIs continue to be the most commonly prescribed antidepressants, whilst prescribing of SNRIs is increasing.Future research should focus on evaluating appropriate prescribing of antidepressants (treatment selection, dosage and duration), especially in the elderly.

Genetic markers for non-syndromic orofacial clefts in populations of European ancestry: a meta-analysis.

To date, the involvement of various genetic markers in the aetiopathogenesis of non-syndromic orofacial cleft (nsOFC) has been extensively studied. In the present study, we focused on studies performed on populations of European ancestry to systematically review the available literature to define relevant genetic risk factors for nsOFC. Eligible studies were obtained by searching Ovid Medline and Ovid Embase. We gathered the genetic markers from population-based case-control studies on nsOFC, and conducted meta-analysis on the repeatedly reported markers. Whenever possible, we performed stratified analysis based on different nsOFC phenotypes, using allelic, dominant, recessive and overdominant genetic models. Effect sizes were expressed as pooled odds ratios (ORs) with 95% confidence intervals (CIs), and p ≤ 0.05 were considered statistically significant. A total of 84 studies were eligible for this systematic review, with > 700 markers included. Of these, 43 studies were included in the meta-analysis. We analysed 47 genetic variants in 30 genes/loci, which resulted in 226 forest plots. There were statistically significant associations between at least one of the nsOFC phenotypes and 19 genetic variants in 13 genes/loci. These data suggest that IRF6, GRHL3, 8q24, VAX1, TGFA, FOXE1, ABCA4, NOG, GREM1, AXIN2, DVL2, WNT3A and WNT5A have high potential as biomarkers of nsOFC in populations of European descent. Although other meta-analyses that included European samples have been performed on a limited number of genetic variants, this study represents the first meta-analysis of all genetic markers that have been studied in connection with nsOFC in populations of European ancestry.

Risk of lower extremity amputations in patients with type 2 diabetes using sodium-glucose co-transporter 2 inhibitors.

AIMS: To compare the influence of sodium-glucose co-transporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP-4i) on the risk of lower extremity amputations in patients with type 2 diabetes in Slovenia. METHODS: This retrospective cohort study included patients aged 40 years or more who were administered a newly introduced SGLT2i or DPP-4i between June 2014 and June 2018. Patients treated with insulin at baseline and patients with a history of amputation were excluded. Patients were matched in a 1:1 ratio using propensity score matching. Survival analysis was performed; hazard ratio (HR) and ratios of cumulative hazards at 1, 2, 3, and 4 years were estimated. On-treatment and intention-to-treat approaches were used. RESULTS: The study cohort (mean age: 64 years) consisted of 2,939 new users of SGLT2i (empagliflozin, 59%; dapagliflozin, 41%) matched to 2,939 new users of DPP-4i. In the on-treatment analysis (median follow-up of 2 years), the incidence of amputations was higher in SGLT2i than in DPP-4i users (4.2 vs. 2.7 per 1,000 patient years), resulting in a HR of 1.58 (95% CI 0.85-2.92; p = 0.145). An intention-to-treat analysis yielded to similar HR of 1.86 (95% CI: 1.10-3.14; p = 0.020). There was no difference in amputation rates in the first two years, but SGLT2i users had a 2.81-fold higher (95% CI: 1.63-4.84; p = 0.007) cumulative hazard of amputation at 4 years than did DPP-4i users. CONCLUSIONS: Compared with DPP-4i use, SGLT2i use did not result in a statistically significant higher overall risk of lower extremity amputations. However, the results suggest that SGLT2i may increase the risk of amputation with long-term use.

Initiation of insulin therapy in patients with type 2 diabetes: An observational study.

The aim of the study was to assess the initiation of insulin therapy in patients with type 2 diabetes using health claims data on prescription medicines. The study evaluated time to insulin initiation and prescribing patterns of other anti-diabetic medicines before and after insulin initiation. Five years after starting non-insulin antidiabetic therapy, 6.4 % of patients were prescribed insulin, which is substantially lower compared to other similar studies. Among all patients who initiated insulin therapy in 2013, 30 % did not continue any other antidiabetic therapy. However, this proportion was lowered to 20 % in 2018. Before insulin initiation in 2018, metformin was prescribed in only 67 % of patients and sulfonylureas in 78 % of patients. Moreover, metformin and sulfonylureas were discontinued after insulin initiation in 26 and 37 % of patients, resp. More attention should be paid to the continuation of oral anti-diabetics, particularly metformin, after insulin initiation.

Cardiovascular morbidity and mortality in patients with type 2 diabetes using novel antidiabetic medicines as add-on therapy: an observational real-world study.

OBJECTIVE: To evaluate the effect of sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA), compared with dipeptidyl peptidase-4 inhibitors (DPP-4i) as add-on therapy on cardiovascular (CV) morbidity and mortality in patients with type 2 diabetes (T2D). DESIGN AND SETTING: A nationwide cohort study using three linked healthcare databases from Slovenia (outpatient prescription claims data, hospitalisation claims data and death registry data). PARTICIPANTS: Patients with T2D with newly introduced DPP-4i (n=3817), GLP-1RA (n=855) or SGLT2i (n=2851) add-on therapy between June 2014 and June 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was a major adverse CV event (MACE), while the secondary outcomes were CV death and heart failure (HF). The effects of the antidiabetic medicine group on the risk of each outcome were estimated with Cox proportional hazards regression. Intention-to-treat and on-treatment approaches were used. RESULTS: In the intention-to-treat analysis, SGLT2i as add-on therapy, when compared with DPP-4i, was associated with lower risk of MACE (HR=0.66; 95% CI 0.50 to 0.85; p=0.002) and CV death (HR=0.46; 95% CI 0.30 to 0.73; p=0.001). On-treatment analysis revealed lower HF risk in patients initiating SGLT2i (HR=0.54; 95% CI 0.30 to 0.99; p=0.047). In the intention-to-treat analysis, GLP-1RA add-on therapy was associated with a lower MACE risk when compared with DPP-4i (HR=0.64; 95% CI 0.43 to 0.97; p=0.034), but it had a non-significant effect on CV death (HR=0.62; 95% CI 0.34 to 1.14; p=0.128) and HF (HR=1.39; 95% CI 0.88 to 2.21; p=0.157). The results of on-treatment analyses were in agreement with the results of intention-to-treat analyses. CONCLUSIONS: SGLT2i and GLP-1RA improved CV morbidity and mortality in patients with T2D when compared with DPP-4i as an add-on therapy. The results of this study may serve as a basis for the selection of an optimal add-on antidiabetic medicine to reduce CV morbidity and mortality in patients with T2D in clinical practice. TRIAL REGISTRATION NUMBER: EUPAS32558.

Prevalence and Incidence of Frailty Among Community-dwelling Older Adults in Slovenia.

INTRODUCTION: Frailty is recognized as one of the most important global health challenges as the population is aging. The aim of this study was to evaluate prevalence and incidence of frailty, and associated factors, among the population of older adults in Slovenia compared to other European countries. METHODS: The prevalence and 4-year incidence of frailty among older adults (≥65 years) were evaluated using data from the Survey of Health, Ageing and Retirement in Europe (SHARE). Frailty was defined by the SHARE operationalization of Frailty phenotype. Multiple logistic regression model was used to explore factors associated with frailty. RESULTS: Age-standardized prevalence (95% CI) of frailty and pre-frailty in Slovenia were 14.9% (13.3-16.5) and 42.5% (39.8-45.2), respectively. Factors (OR, 95% CI) associated with increased frailty in Slovenia included age (7584 years: 5.03 (3.08-8.22); ≥85 years 21.7 (10.6-44.7) vs. 65-74 years), self-rated health (fair: 4.58 (2.75-7.61), poor: 54.6 (28.1-105.9) vs. excellent/very good/good), number of chronic diseases (1.20 (1.03-1.40)), and polypharmacy (yes: 3.25 (1.93-5.48) vs. no). Female gender and lower education were significantly associated with pre-frailty, but not frailty, in the adjusted model. Independently of these characteristics, age-standardized prevalence of frailty varied among geographical regions. Age-standardized 4-year incidence of frailty and pre-frailty in Slovenia were 6.6% (3.0-10.1) and 40.2% (32.7-47.6), respectively. CONCLUSION: Among the Slovenian population of older adults aged 65 years and older, the age-standardized prevalence of frailty is 15% and 4-year incidence of frailty is 7%. Regional differences in Slovenia show the lowest prevalence in central Slovenian regions and the highest in northeastern Slovenian regions.

Uptake of new antidiabetic medicines in 11 European countries.

BACKGROUND: Several new antidiabetic medicines (GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors) have been approved by the European Medicines Agency since 2006. The aim of this study was to evaluate the uptake of new antidiabetic medicines in European countries over a 10-year period. METHODS: The study used IQVIA quarterly value and volume sales data January 2006-December 2016. The market uptake of new antidiabetic medicines together with intensity of prescribing policy for all antidiabetic medicines were estimated for Austria, Croatia, France, Germany, Hungary, Italy, Poland, Slovenia, Spain, Sweden, and the United Kingdom. The following measures were determined: number of available new active substances, median time to first continuous use, volume market share, and annual therapy cost. RESULTS: All countries had at least one new antidiabetic medicine in continuous use and an increase in intensity of prescribing policy for all antidiabetic medicines was observed. A tenfold difference in median time to first continuous use (3-30 months) was found. The annual therapy cost in 2016 of new antidiabetic medicines ranged from EUR 363 to EUR 769. Among new antidiabetic medicines, the market share of DPP-4 inhibitors was the highest. Countries with a higher volume market share of incretin-based medicines (Spain, France, Austria, and Germany) in 2011 had a lower increase in intensity of prescribing policy. This kind of correlation was not found in the case of SGLT-2 inhibitors. CONCLUSIONS: This study found important differences and variability in the uptake of new antidiabetic medicines in the included countries.

Improved adherence with Medicines Use Review service in Slovenia: a randomized controlled trial.

BACKGROUND: Based on several existing patient-oriented activities, Medicines Use Review (MUR) service was standardized and officially adopted in Slovenia in 2015. Service aims to provide adherence support and ensure safe and effective medicines use. Therefore, the aim of the study was to evaluate the benefits of MUR in Slovenia, primarily the impact on medication adherence. METHODS: A randomised controlled trial was performed in community pharmacies to compare MUR with standard care. Patients were randomised into either the test (patients received MUR by a certified MUR provider at visit 1), or control group. The study primary outcome was self-reported adherence to multiple medications, assessed by electronic ©Morisky Widget MMAS-8 Software at the first visit (V1) and after 12 weeks (V2). A sub-analysis of intentional and unintentional non-adherence was performed. MUR impact was defined as the relative difference in ©MMAS-8 score after 12 weeks between the test and control group. A multiple linear regression model was used to predict MUR impact based on baseline adherence (low versus medium and high). Several secondary outcomes (e.g. evaluation of drug-related problems (DRPs)) were also assessed. RESULTS: Data from 153 (V1) and 140 (V2) patients were analysed. Baseline adherence was low, moderate and high in 17.6, 48.4 and 34.0% patients, respectively. In the low adherence subpopulation, test group patients showed a 1.20 point (95% CI = 0.16-2.25) increase in total ©MMAS-8 score (p = 0.025) compared to control group patients. A 0.84 point (95% CI = 0.05-1.63) increase was due to intentional non-adherence (p = 0.038), and a 0.36 point (95% CI = - 0.23-0.95) was due to unintentional non-adherence (p = 0.226). Additionally, statistically significant decrease in the proportion of patients with manifested DRPs (p < 0.001) and concerns regarding chronic medicines use (p = 0.029) were revealed. CONCLUSION: MUR service in Slovenia improves low medication adherence and is effective in addressing DRPs and concerns regarding chronic medicines use. TRIAL REGISTRATION: ClinicalTrials.gov - NCT04417400 ; 4th June 2020; retrospectively registered.

The association between medication or alcohol use and the incidence of frailty: a retrospective cohort study.

BACKGROUND: Understanding potentially modifiable factors that influence the risk of frailty is a key concern for the management of this urgent contemporary public health challenge. This study evaluates the association between the use of various medications or alcohol and the incidence of frailty among older adults. METHODS: This study was a retrospective cohort study on older adults (≥ 65 years) using data from the longitudinal Survey of Health, Ageing and Retirement in Europe (SHARE survey, 28 countries). Medication use was measured as taking several different groups of medications. Alcohol use was assessed with SHARE questions corresponding to AUDIT-C. The outcome measure was the incidence of frailty after two years, defined by frailty index (FI) and frailty phenotype (FP). A multiple logistic regression model was used to evaluate the association with adjustment for several potential confounding factors. RESULTS: Of the 14,665 FI-population participants, 1800 (12.3%) developed frailty within two years. Of the 8133 FP-population participants, 2798 (34.4%) developed pre-frailty and 247 (3.0%) developed frailty within two years of baseline. After adjustment for potential confounding variables, non-hazardous alcohol use (adjusted OR; 95% CI for the FI-population: 0.68; 0.60-0.77) and hazardous alcohol use (0.80; 0.68-0.93) are associated with lower incidence of frailty compared to no alcohol use. The odds of frailty are increased when taking medications; the largest effect size was observed in older adults taking medication for chronic bronchitis (adjusted OR; 95% CI for the FI-population: 2.45; 1.87-3.22), joint pain and other pain medication (2.26; 2.00-2.54), medication for coronary and other heart disease (1.72; 1.52-1.96), medication for diabetes (1.69; 1.46-1.96), and medication for anxiety, depression and sleep problems (1.56; 1.33-1.84). Additionally, the risk of frailty was increased with stroke, Parkinson's disease and dementia. CONCLUSIONS: Taking certain groups of medication was associated with increased incidence of frailty and pre-frailty, which might be due to either medication use or the underlying disease. Alcohol use was associated with a lower risk of pre-frailty and frailty compared to no alcohol use, which might be due to reverse causality or residual confounding. There was no significant interaction effect between medication groups and alcohol use on frailty incidence.

Comparative Bioavailability of Different Coenzyme Q10 Formulations in Healthy Elderly Individuals.

Coenzyme Q10 (CoQ10) plays a central role in mitochondrial oxidative phosphorylation. Several studies have shown the beneficial effects of dietary CoQ10 supplementation, particularly in relation to cardiovascular health. CoQ10 biosynthesis decreases in the elderly, and consequently, the beneficial effects of dietary supplementation in this population are of greater significance. However, most pharmacokinetic studies have been conducted on younger populations. The aim of this study was to investigate the single-dose bioavailability of different formulations of CoQ10 in a healthy geriatric population. A randomized, three-period, crossover bioavailability study was conducted on 21 healthy older adults (aged 65-74). The treatment was a single dose with a one-week washout period. Three different formulations containing the equivalent of 100 mg of CoQ10 were used: Q10Vital® water-soluble CoQ10 syrup (the investigational product-IP); ubiquinol capsules (the comparative product-CP); and ubiquinone capsules (the standard product-SP). Ubiquinone/ubiquinol was followed in the plasma for 48 h. An analysis of the ratio of the area under the baseline-corrected concentration curve (ΔAUC48) for total CoQ10 and a comparison to SP yielded the following: The bioavailability of CoQ10 in the IP was 2.4-fold higher (95% CI: 1.3-4.5; p = 0.002), while the bioavailability of ubiquinol (CP) was not significantly increased (1.7-fold; 95% CI: 0.9-3.1, p = 0.129). No differences in the redox status of the absorbed coenzyme Q10 were observed between formulations, showing that CoQ10 appeared in the blood mostly as ubiquinol, even if consumed as ubiquinone.

Inhalation technique and asthma outcomes with different corticosteroid-containing inhaler devices.

Objective: Inhaler devices must be used correctly to ensure the effectiveness of the asthma treatment. This study evaluated inhalation technique across different types of corticosteroid-containing inhaler devices as well as health outcomes in patients with asthma. Methods: In a cross-sectional study, we evaluated inhaler technique by observing patients' handling of the inhaler devices and using checklists for four inhaler types, namely Diskus (n = 52), pressure metered dose inhalers (pMDIs; n = 41), Turbuhaler (n = 36) and Twisthaler (n = 16). We also collected data on patients' characteristics, asthma therapy, exacerbations, medication adherence (8-item Morisky Medication Adherence Scale), asthma control (Asthma Control Test) and quality of life (Saint George Respiratory Questionnaire). Results: In total, we included 145 patients. The mean (SD) age of the patients was 54.5 (18.9) years and 57% were female. The majority of the patients (70%) made at least one error in their inhalation technique. Patients using Turbuhaler performed the highest number of elements correctly, followed by pMDIs, Twisthaler and Diskus. Patients with Diskus or Twisthaler had better adherence compared with patients using pMDIs or Turbuhaler. Patients using Twisthaler had better asthma outcomes than patients using the other device types. Conclusions: Most patients with asthma made mistakes when handling their inhaler devices, especially those using Diskus. However, in addition to the device type being used, patients' characteristics, asthma therapy and medication adherence also played an important role in achieving good health outcomes.

Comparative effectiveness of pulmonary arterial hypertension drugs in treatment-naive patients: a network meta-analysis.

Aim: No network meta-analysis has been conducted to study efficacy of drug therapies specific for treatment of pulmonary arterial hypertension in treatment-naive patients only. Methods: Randomized controlled trials on pulmonary arterial hypertension-specific drug therapies were searched and a Bayesian network meta-analysis was performed. The 6-min walking distance (6MWD) and all-cause mortality were efficacy outcomes, whereas discontinuation due to adverse events was a safety-related outcome. Results: Analysis included 3.713 patients from 21 trials. Combination of ambrisentan and tadalafil showed the greatest impact on 6MWD, followed by epoprostenol and intravenous treprostinil (high dose). The latter two demonstrated marked effect size on mortality, although not statistically significant. Conclusion: According to 6MWD, ambrisentan/tadalafil combination was considered as most effective among all comparisons. Prospero ID: CRD42019110832.

A Bayesian Network Meta-analysis of Add-on Drug Therapies Specific for Pulmonary Arterial Hypertension.

Background: Recently published meta-analyses did not discriminate between drug agents used for initial and sequential combination therapy. Objective: To assess the comparative efficacy of drugs specific for the treatment of pulmonary arterial hypertension (PAH) as add-on therapies based on 6-minute walk distance (6MWD), all-cause mortality, and discontinuation due to adverse events (AEs). Methods: EMBASE, PubMed, Cochrane Library, and ClinicalTrials.gov were searched until December 9, 2018, for the randomized, placebo-controlled clinical trials (RCTs) conducted on primarily adult patients diagnosed with PAH. Data extracted from applicable RCTs were as follows: for 6MWD mean change from baseline, the total number of patients, and the number of patients with events, per treatment. Network meta-analysis (NMA) was conducted in a Bayesian framework. Results: A total of 16 RCTs were eligible for analysis, with 4112 patients. Add-on therapy with tadalafil or inhaled treprostinil performed better than endothelin receptor antagonists alone [27 m; 95% credible interval (CrI): (11, 43); and 19 m; 95% CrI: (10, 27); respectively]. Add-on therapy with macitentan or bosentan performed better than phosphodiesterase type 5 inhibitors alone [26 m; 95% CrI: (6.4, 45); and 22 m; 95% CrI: (5.1, 38); respectively]. Differences in all-cause mortality and discontinuation due to AEs were nonsignificant. Conclusion and Relevance: Our NMA evaluated efficacy and safety of add-on therapies in patients with PAH. None of the previous meta-analyses evaluated RCTs focusing solely on patients pretreated with another PAH-specific drug therapy. Our results support guideline recommendations on combination therapy in PAH patients and add the quantitative perspective on which sequential therapy demonstrated the greatest effect size.

Impact of drugs on venous thromboembolism risk in surgical patients.

PURPOSE: This review focuses on the most common drugs administered to surgical patients during the perioperative period that affect the risk of venous thromboembolism (VTE). RESULTS: Among analgesics, the risk of VTE is increased in patients treated with diclofenac, ibuprofen, and rofecoxib, but not naproxen, while metamizole can confer a protective effect. The relationship between sedatives and VTE has not been sufficiently studied. Tricyclic antidepressants, low-potency serotonin reuptake inhibitors, and antipsychotics have been associated with increased risk of VTE. The use of diuretics in the perioperative period is poorly researched; however, hyponatremia is considered a risk factor. Other factors that may influence the risk of VTE include bridging anticoagulation, allogeneic transfusion, and hemostatic management before surgery. Pharmacotherapy for HIV or cancer may also increase VTE risk. CONCLUSION: Increased monitoring for VTE is therefore advisable in surgical patients and those receiving antipsychotics, antidepressants, diuretics, or analgesics.

Efficacy, Acceptability, and Tolerability of Lisdexamfetamine, Mixed Amphetamine Salts, Methylphenidate, and Modafinil in the Treatment of Attention-Deficit Hyperactivity Disorder in Adults: A Systematic Review and Meta-analysis.

OBJECTIVE: Psychostimulants are the first-line treatment in adults with attention-deficit hyperactivity disorder (ADHD). This meta-analysis aimed to evaluate the efficacy, acceptability, and tolerability of lisdexamfetamine (LDX), mixed amphetamine salts (MASs), modafinil (MDF), and methylphenidate (MPH) in comparison with placebo. DATA SOURCES: We systematically searched PubMed/MEDLINE and Clinicaltrials.gov in May 2016, along with CENTRAL and EU Clinical Trials Register in February 2016, for the randomized, double-blind, placebo-controlled, parallel-group clinical trials conducted on adults diagnosed with ADHD. STUDY SELECTION AND DATA EXTRACTION: Substantial comorbidity, substance abuse or dependence, and nonpharmacological interventions represented grounds for exclusion. Published reports were the sole source for data extraction. Improvement in ADHD symptoms was the primary outcome. Random-effects model meta-analysis was applied to calculate the standardized mean difference (SMD) with 95% CIs. DATA SYNTHESIS: The search retrieved 701 records, of which 20 studies were eligible for analysis. High effect size (expressed as SMD) in reducing ADHD symptoms was observed for LDX (-0.89; 95% CI = -1.09, -0.70), whereas MASs (-0.64; 95% CI = -0.83, -0.45) and MPH (-0.50; 95% CI = -0.58, -0.41) reduced symptoms moderately compared with placebo. No efficacy was shown for MDF (0.08; 95% CI; -0.18, 0.34). Relevance to Patient Care and Clinical Practice: In this meta-analysis, the efficacy, tolerability, and acceptability of psychostimulants were compared with that for placebo. Five of the included trials have not been evaluated in any of the previously published meta-analyses. CONCLUSIONS: The results suggest that LDX has the largest effect size and has a promising potential for treating adults with ADHD.