Metadata for Data dIscoverability aNd Study rEplicability in obseRVAtional Studies (MINERVA): Development and Pilot of a Metadata List and Catalogue in Europe.

PURPOSE: Metadata for data dIscoverability aNd study rEplicability in obseRVAtional studies (MINERVA), a European Medicines Agency-funded project (EUPAS39322), defined a set of metadata to describe real-world data sources (RWDSs) and piloted metadata collection in a prototype catalogue to assist investigators from data source discoverability through study conduct. METHODS: A list of metadata was created from a review of existing metadata catalogues and recommendations, structured interviews, a stakeholder survey, and a technical workshop. The prototype was designed to comply with the FAIR principles (findable, accessible, interoperable, reusable), using MOLGENIS software. Metadata collection was piloted by 15 data access partners (DAPs) from across Europe. RESULTS: A total of 442 metadata variables were defined in six domains: institutions (organizations connected to a data source); data banks (data collections sustained by an organization); data sources (collections of linkable data banks covering a common underlying population); studies; networks (of institutions); and common data models (CDMs). A total of 26 institutions were recorded in the prototype. Each DAP populated the metadata of one data source and its selected data banks. The number of data banks varied by data source; the most common data banks were hospital administrative records and pharmacy dispensation records (10 data sources each). Quantitative metadata were successfully extracted from three data sources conforming to different CDMs and entered into the prototype. CONCLUSIONS: A metadata list was finalized, a prototype was successfully populated, and a good practice guide was developed. Setting up and maintaining a metadata catalogue on RWDSs will require substantial effort to support discoverability of data sources and reproducibility of studies in Europe.

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.

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.

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.

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.

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.

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.

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.

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.

Patient Access to Medicines for Rare Diseases in European Countries.

BACKGROUND: The number of authorized orphan and non-orphan medicines for rare diseases has increased in Europe. Patient access to these medicines is affected by high costs, weak efficacy/safety evidence, and societal value. European health care systems must determine whether paying for expensive treatments for only a few patients is sustainable. OBJECTIVES: This study aimed to evaluate patient access to orphan and non-orphan medicines for rare diseases in 22 European countries during 2005 to 2014. METHODS: Medicines for rare diseases from the Orphanet list, authorized during 2005 to 2014, were searched for in the IMS MIDAS Quarterly Sales Data, January 2005 - December 2014 (IQVIA, Danbury, CT). The following three measures were determined for each country: number of available medicines, median time to continuous use, and medicine expenditure. A medicine was considered available if uninterrupted sales within a 1-year period were detected. RESULTS: From 2005 to 2014, 125 medicines were authorized and 112 were found in the search. Of those, between 70 (63%) and 102 (91%) were available in Germany, the United Kingdom, Italy, France, and the Scandinavian countries. These countries were also the fastest to enable continuous use (3-9 mo). Only 27% to 38% of authorized medicines were available in Greece, Ireland, Bulgaria, Romania, and Croatia, which took 1 to 2.6 years to begin continuous use. A country's expenditure on medicines for rare diseases in 2014 ranged between €0.2 and €31.9/inhabitant. CONCLUSIONS: Patient access to medicines for rare diseases varies largely across Europe. Patients in Germany, Scandinavian countries, Switzerland, France, and the United Kingdom can access larger numbers of medicines in shorter time.

Ambient air pollution and pregnancy outcomes: A comprehensive review and identification of environmental public health challenges.

There is a growing number of studies on the association between ambient air pollution and adverse pregnancy outcomes, but their results have been inconsistent. Consequently, a comprehensive review of this research area is needed. There was a wide variability in studied pregnancy outcomes, observed gestational windows of exposure, observed ambient air pollutants, applied exposure assessment methods and statistical analysis methods Gestational duration, preterm birth, (low) birth weight, and small for gestational age/intrauterine growth restriction were most commonly investigated pregnancy outcomes. Gestational windows of exposure typically included were whole pregnancy period, 1st, 2nd, 3rd trimester, first and last gestational months. Preterm birth was the outcome most extensively studied across various gestational windows, especially at the beginning and at the end of pregnancy. Particulate matter, nitrogen dioxide, ozone, and carbon monoxide were the most commonly used markers of ambient air pollution. Continuous monitoring data were frequently combined with spatially more precisely modelled estimates of exposure. Exposure to particulate matter and ozone over the entire pregnancy was significantly associated with higher risk for preterm birth: the pooled effect estimates were 1.09 (1.03-1.16) per 10 µg/m3 increase in particulate matter with an aerodynamic diameter of 10 µm or less (PM10),1.24 (1.08-1.41) per 10 µg/m3 increase in particulate matter with an aerodynamic diameter of 2.5 µm or less (PM2.5), and 1.03 (1.01-1.04) per 10 ppb increase in ozone. For pregnancy outcomes other than PTB, ranges of observed effect estimates were reported due to smaller number of studies included in each gestational window of exposure. Further research is needed to link the routine pregnancy outcome data with spatially and temporally resolved ambient air pollution data, while adjusting for commonly defined confounders. Methods for assessing exposure to mixtures of pollutants, indoor air pollution exposure, and various other environmental exposures, need to be developed.

Decision-making criteria for medicine reimbursement in Slovenia: an expert panel discussion.

BACKGROUND: Rational and transparent Health Technology Assessment and reimbursement decision-making are crucial for healthcare system sustainability. A part of the reimbursement process are decision-making criteria which should be clearly defined. METHODS: The study aimed to obtain an insight into understanding and relevance of potential criteria for the medicine reimbursement decision-making process in Slovenia. A semi-structured guided focus panel was performed in June 2017 with five Slovenian experts covering principal healthcare system sectors. First, criteria understanding and relevance for medicine reimbursement decision-making were discussed. Second, healthcare priorities and societal values affecting decision-making were debated. The analysis was carried out with NVivo 11 by two independent researchers who coded the verbatim transcript in three coding steps based on the experts' interpretations and original ideas. RESULTS: Seven decision-making criteria were derived. Among those, the impact a disease has on the lives of patient family and caregivers and the indirect medicine benefit for them were new aspects comparing to the existing criteria set in Slovenia. The experts expressed that the same decision-making criteria are relevant for evaluating any health technology, allowing for different criteria weights. They also suggested a system that would allow re-evaluation of reimbursement decisions once real-world clinical data are available. CONCLUSIONS: As proposed by the international frameworks and tools, the Slovenian healthcare experts consider including multiple aspects more ethical and comprehensive than considering a single criterion, e.g. cost-effectiveness, existing in some healthcare systems. They recognize that in the existing decision-making process, health perspectives of the public represent a largely missed aspect.

Effects of synbiotic fermented milk containing Lactobacillus acidophilus La-5 and Bifidobacterium animalis ssp. lactis BB-12 on the fecal microbiota of adults with irritable bowel syndrome: A randomized double-blind, placebo-controlled trial.

We conducted a randomized double-blind, placebo-controlled multicentric study to investigate the influence of a synbiotic fermented milk on the fecal microbiota composition of 30 adults with irritable bowel syndrome (IBS). The synbiotic product contained Lactobacillus acidophilus La-5, Bifidobacterium animalis ssp. lactis BB-12, Streptococcus thermophilus, and dietary fiber (90% inulin, 10% oligofructose), and a heat-treated fermented milk without probiotic bacteria or dietary fiber served as placebo. Stool samples were collected after a run-in period, a 4-wk consumption period, and a 1-wk follow-up period, and were subjected to real-time PCR and 16S rDNA profiling by next-generation sequencing. After 4wk of synbiotic (11 subjects) or placebo (19 subjects) consumption, a greater increase in DNA specific for L. acidophilus La-5 and Bifidobacterium animalis ssp. lactis was detected in the feces of the synbiotic group compared with the placebo group by quantitative real-time PCR. After 1wk of follow-up, the content of L. acidophilus La-5 and B. animalis ssp. lactis decreased to levels close to initial levels. No significant changes with time or differences between the groups were observed for Lactobacillus, Enterobacteriaceae, Bifidobacterium, or all bacteria. The presence of viable BB-12- and La-5-like bacteria in the feces resulting from the intake of synbiotic product was confirmed by random amplification of polymorphic DNA (RAPD)-PCR. At the end of consumption period, the feces of all subjects assigned to the synbiotic group contained viable bacteria with a BB-12-like RAPD profile, and after 1wk of follow-up, BB-12-like bacteria remained in the feces of 87.5% of these subjects. The presence of La-5-like colonies was observed less frequently (37.5 and 25% of subjects, respectively). Next-generation sequencing of 16S rDNA amplicons revealed that only the percentage of sequences assigned to Strep. thermophilus was temporarily increased in both groups, whereas the global profile of the fecal microbiota of patients was not altered by consumption of the synbiotic or placebo. In conclusion, daily consumption of a synbiotic fermented milk had a short-term effect on the amount and proportion of La-5-like strains and B. animalis ssp. lactis in the fecal microbiome of IBS patients. Furthermore, both synbiotic and placebo products caused a temporary increase in fecal Strep. thermophilus.

Prevalence and incidence of attention-deficit/hyperactivity disorder in Slovenian children and adolescents: a database study from a national perspective.

AIM: To estimate prevalence and incidence of attention deficit hyperactivity disorder (ADHD) in children and adolescents in Slovenia using different epidemiological models. METHODS: Data from the National Institute of Public Health of the Republic of Slovenia for the period 1997-2012 were analyzed. The database includes the annual number of newly diagnosed outpatients with ADHD in Slovenia. The evaluation for ADHD diagnoses was done in accordance with the Tenth Revision of the International Classification of Diseases (ICD-10) outpatient data codes. In model 1, a linear increase was proposed to fit the data in the period from 1997 to 2003 in order to extrapolate the data before 1997. In model 2 and 3, an exponential increase in the annual incidence rate was proposed. RESULTS: The incidence rate of ADHD diagnosis in 1997 was 0.032% and in 2012 it increased to 0.082%. Mean prevalence rate was 750 (95% confidence interval: 660-840) per 100 000 children and adolescents. It was estimated that the prevalence rate in 2020 would be 1% (95% confidence interval: 0.875-1.125), which is 6.3-fold higher than in 1997. CONCLUSIONS: ADHD is a common mental health disorder among Slovenian children and adolescents, but it remained underdiagnosed compared with Western countries. Our results indicated a need for improved timely interventions in Slovenia, not only in child and adolescent psychiatry but also in primary settings and adult psychiatry, where ADHD should be more efficiently recognized.

Sedative load and anticholinergic burden among older adults in Slovenia over a decade: Potential for optimization of pharmacotherapy.

This study investigates the 10-year trend in the sedative and anticholinergic burden among older adults in Slovenia, with the aim of identifying opportunities to optimize pharmacotherapy in this population. A retrospective drug utilization analysis was conducted based on a national anonymized database of dispensed prescriptions from 2009 to 2019. The study employed the sedative load model and the anticholinergic cognitive burden scale to assess the sedative and anti cholinergic burden, respectively. The findings indicate that in 2019, 45.6 % and 40.8 % of older adults (≥ 65 years) used sedative and anticholinergic medications, respectively. A high sedative load and a clinically significant anticholinergic burden were observed in a considerable proportion of older adults (13.2 % and 11.2 %, respectively, in 2019). The age-standardized prevalence of sedative load and anti-cholinergic burden significantly decreased over the 10-year study period by 5.6 % and 1.7 %, respectively (absolute difference), while the prevalence of clinically significant anticholinergic burden remained stable. Notably, the age groups 85-89 years and above 90 years had an increase in the proportion of individuals with a clinically significant anticholinergic burden over the years. These results emphasize the need for targeted interventions, particularly in the oldest age groups, to promote safe and effective medication use among older adults.

Matrixing Designs for Shelf-Life Determination of Parenteral Drug Product: A Comparative Analysis of Full and Reduced Stability Testing Design.

This article highlights the applicability of matrixing designs in stability studies for parenteral medications. The traditional approach involves extensive testing over the product's shelf-life. However, matrixing designs offer an alternative approach where only a fraction of samples is tested at each time point. The study conducted in this article focused on three parenteral medications and examined stability data under long-term condition. Degradation products were identified as critical parameter, and kinetics of degradation varied among the selected products. A systematic methodology was adopted to evaluate the data using different matrixing designs. The regression models obtained were assessed using statistical parameters S and R2. Also, each of the 28 matrixing designs were compared to the full design with statistical parameter RMSE and the shelf-life. The results confirmed that each of the evaluated matrixing designs can be applied, whether degradation product shows a linear or non-linear increase, and demonstrated that a reduction of two time points per batch is the most appropriate. In conclusion, this research contributes to the understanding of utilizing reduced matrixing designs in stability studies for parenteral medications and can be an effective strategy to reduce costs and time of stability testing while maintaining the necessary level of precision and reliability.

The Prevalence of Self-Reported Systemic Allergic Reaction to Hymenoptera Venom in Beekeepers Worldwide: A Systematic Literature Review and Meta-Analysis.

Background: Beekeepers represent a high-allergic risk population group due to their unavoidable seasonal or persistent exposure to the elicitors of Hymenoptera venom allergy, bees in particular. A systematic literature review and meta-analysis aimed to estimate the prevalence of self-reported systemic allergic reaction to Hymenoptera venom among beekeepers worldwide. Methods: We rigorously reviewed and conducted meta-analysis on observational studies retrieved from seven electronic databases (MEDLINE via PubMed, Web of Science Core Collection, Scopus, Academic Search Complete, ScienceDirect, Cumulative Index to Nursing and Allied Health Literature, Zoological Record), spanning data from inception to August 1, 2023. The Joanna Briggs Institute Prevalence Critical Appraisal Tool was employed to assess the risk of bias. A meta-analysis was conducted to synthesize evidence. Results: Out of 468 studies, eight original articles met the inclusion criteria. The estimated overall lifetime and one-year prevalence of self-reported systemic allergic reaction to bee venom were 23.7% (95% CI: 7.7-53.4) and 7.3% (95% CI: 5.8-9.2), respectively. The estimated lifetime prevalence of self-reported systemic allergic reaction to bee venom for grades III-IV (severe systemic allergic reaction) was 6.0% (95% CI: 3.0-11.7). In general, substantial heterogeneity and a high risk of bias were observed across the majority of studies. The impact of geographical location and climate differences on the estimated lifetime prevalence is suggestive for severe systemic allergic reaction. Conclusions: Future observational cross-sectional studies should employ rigorous study designs, using validated questionnaires, and thoroughly report the observed health outcomes, verified by physicians.

Prevalence of attention-deficit hyperactivity disorder (ADHD): systematic review and meta-analysis.

BACKGROUND: The estimates of attention-deficit hyperactivity disorder (ADHD) prevalence across various studies are significantly variable, contributing to uncertainty in ADHD prevalence estimation. Previous systematic reviews and meta-analyses have attributed this variability primarily to the methodological characteristics of the studies, including the diagnostic criteria, source of information, and impairment requirement for the diagnosis. METHODS: Review identified studies reporting ADHD prevalence in representative samples of children and adults in Europe and worldwide. Studies that were conducted in the general population were included. We focused on studies that report ADHD prevalence based on clinical diagnosis (clinical diagnostic criteria based on the Diagnostic and Statistical Manual of Mental Disorders and International Classification of Diseases criteria, other diagnostic tools, such as various scales or interviews based on clinical diagnostic criteria). PubMed/Medline was searched to identify relevant articles published until 2024/2/01. The study was registered in PROSPERO (CRD42020200220) and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines for systematic review and meta-analysis. RESULTS: In total, 117 studies were subjected to full evaluation. In the meta-analysis, 103 studies representing 159 independent datapoints were included. The overall prevalence of ADHD in register studies was 1.6%, 95% CI [0.9; 3.0], in survey studies 5.0%, 95% CI [2.9; 8.6], in one-stage clinical studies 4.2%, 95% CI [2.9; 6.0], and in two-stage clinical studies 4.8%, 95% CI [4.0; 5.8]. CONCLUSIONS: Exact comparisons among studies with different diagnostic criteria and types of sampling can impact prevalence estimates. When comparing data from methodologically different studies, these factors need to be considered.

Oxidative stress-related biomarkers as promising indicators of inflammatory bowel disease activity: A systematic review and meta-analysis.

Oxidative stress is believed to play an important role in the pathogenesis of inflammatory bowel disease (IBD), specifically Crohn's disease (CD) and ulcerative colitis (UC). This meta-analysis aimed to identify and quantify the oxidative stress-related biomarkers in IBD and their associations with disease activity. We systematically searched Ovid MEDLINE, Ovid Embase, and Web of Science databases, identifying 54 studies for inclusion. Comparisons included: (i) active IBD versus healthy controls; (ii) inactive IBD versus healthy controls; (iii) active CD versus inactive CD; and (iv) active UC versus inactive UC. Our analysis revealed a significant accumulation of biomarkers of oxidative damage to biomacromolecules, coupled with reductions in various antioxidants, in both patients with active and inactive IBD compared to healthy controls. Additionally, we identified biomarkers that differentiate between active and inactive CD, including malondialdehyde, Paraoxonase 1, catalase, albumin, transferrin, and total antioxidant capacity. Similarly, levels of Paraoxonase 1, erythrocyte glutathione peroxidase, catalase, albumin, transferrin, and free thiols differed between active and inactive UC. Vitamins and carotenoids also emerged as potential disease activity biomarkers for CD and UC, but their intake should be monitored to obtain meaningful results. These findings emphasize the involvement of oxidative stress in the pathogenesis of IBD and highlight the potential of oxidative stress-related biomarkers as a minimally invasive and additional tool for monitoring the activity of IBD.