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BACKGROUND: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT4 based on the risk of cardiovascular disease and mortality. METHODS: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT4, and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT4, thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576. FINDINGS: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18-106) at baseline. There was a J-shaped association of FT4 with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2-13·9]) to 40th percentiles (median 14·8 pmol/L [12·3-15·0]) conveying the lowest risk. Compared with the 20-40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT4 in the 80-100th percentiles was 1·20 (95% CI 1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for cardiovascular disease mortality, and 1·22 (1·11-1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT4 greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0-18·3]), and men with FT4 greater than the 75th percentile (16·7 pmol/L [14·0-17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68-2·25]) to 80th percentiles (2·90 mIU/L [2·41-3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60-80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0-20th percentiles was 1·07 (95% CI 1·02-1·12) for the composite outcome, 1·09 (1·05-1·14) for all-cause mortality, and 1·07 (0·99-1·16) for cardiovascular disease mortality. INTERPRETATION: There was a J-shaped association of FT4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20-40th percentiles of FT4 and the 60-80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT4 greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes. FUNDING: None.

BackgroundAntithyroid antibodies increase the likelihood of developing overt hypothyroidism, but their clinical utility remains unclear. No large randomized controlled trial (RCT) has assessed whether older adults with subclinical hypothyroidism (SHypo) caused by autoimmune thyroid disease derive more benefits from levothyroxine treatment (LT4).ObjectiveTo determine whether older adults with SHypo and positive antibodies derive more clinical benefits from LT4 than those with negative antibodies.MethodsWe pooled individual participant data from two RCTs, Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism and IEMO 80+. Participants with persistent SHypo were randomly assigned to receive LT4 or placebo. We compared the effects of LT4 versus placebo in participants with and without anti-thyroid peroxidase (TPO) at baseline. The two primary outcomes were 1-year change in Hypothyroid Symptoms and Tiredness scores on the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire.ResultsAmong 660 participants (54% women) ≥65 years, 188 (28.5%) had positive anti-TPO. LT4 versus placebo on Hypothyroid Symptoms lead to an adjusted between-group difference of -2.07 (95% confidence interval: -6.04 to 1.90) for positive antibodies versus 0.89 (-1.76 to 3.54) for negative antibodies (p for interaction = 0.31). Similarly, there was no treatment effect modification by baseline antibody status for Tiredness scores-adjusted between-group difference 1.75 (-3.60 to 7.09) for positive antibodies versus 1.14 (-1.90 to 4.19) for negative antibodies (p for interaction = 0.98). Positive anti-TPO were not associated with better quality of life, improvement in handgrip strength, or fewer cardiovascular outcomes with levothyroxine treatment.ConclusionsAmong older adults with SHypo, positive antithyroid antibodies are not associated with more benefits on clinical outcomes with LT4.

Background: An increased risk of intracranial hemorrhage (ICH) associated with statins has been reported, but data on the relationship between statin use and cerebral microbleeds (CMBs) in patients with atrial fibrillation (AF), a population at high bleeding and cardiovascular risk, are lacking. Aims: To explore the association between statin use and blood lipid levels with the prevalence and progression of CMBs in patients with AF with a particular focus on anticoagulated patients. Methods: Data of Swiss-AF, a prospective cohort of patients with established AF, were analyzed. Statin use was assessed during baseline and throughout follow-up. Lipid values were measured at baseline. CMBs were assessed using magnetic resonance imagining (MRI) at baseline and at 2 years follow-up. Imaging data were centrally assessed by blinded investigators. Associations of statin use and low-density lipoprotein (LDL) levels with CMB prevalence at baseline or CMB progression (at least one additional or new CMB on follow-up MRI at 2 years compared with baseline) were assessed using logistic regression models; the association with ICH was assessed using flexible parametric survival models. Models were adjusted for hypertension, smoking, body mass index, diabetes, stroke/transient ischemic attack, coronary heart disease, antiplatelet use, anticoagulant use, and education. Results: Of the 1693 patients with CMB data at baseline MRI (mean ± SD age 72.5 ± 8.4 years, 27.6% women, 90.1% on oral anticoagulants), 802 patients (47.4%) were statin users. The multivariable adjusted odds ratio (adjOR) for CMBs prevalence at baseline for statin users was 1.10 (95% CI = 0.83–1.45). AdjOR for 1 unit increase in LDL levels was 0.95 (95% CI = 0.82–1.10). At 2 years, 1188 patients had follow-up MRI. CMBs progression was observed in 44 (8.0%) statin users and 47 (7.4%) non-statin users. Of these patients, 64 (70.3%) developed a single new CMB, 14 (15.4%) developed 2 CMBs, and 13 developed more than 3 CMBs. The multivariable adjOR for statin users was 1.09 (95% CI = 0.66–1.80). There was no association between LDL levels and CMB progression (adjOR 1.02, 95% CI = 0.79–1.32). At follow-up 14 (1.2%) statin users had ICH versus 16 (1.3%) non-users. The age and sex adjusted hazard ratio (adjHR) was 0.75 (95% CI = 0.36–1.55). The results remained robust in sensitivity analyses excluding participants without anticoagulants. Conclusions: In this prospective cohort of patients with AF, a population at increased hemorrhagic risk due to anticoagulation, the use of statins was not associated with an increased risk of CMBs. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Guidelines and studies provide conflicting information on whether type 2 diabetes (T2D) should be considered a coronary heart disease risk (CHD) equivalent in older adults.We synthesized participant‐level data on 82,723 individuals aged ≥65 years from five prospective studies in two‐stage meta‐analyses. We estimated multivariable‐adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of T2D (presence versus absence) on a primary composite outcome defined as cardiovascular events or all‐cause mortality. Secondary outcomes were the components of the composite. We evaluated CHD risk equivalence by comparing outcomes between individuals with T2D but no CHD versus CHD but no T2D.The median age of participants was 71 years, 20% had T2D and 17% had CHD at baseline. A total of 29,474 participants (36%) experienced the composite outcome. Baseline T2D was associated with higher risk of cardiovascular events or all‐cause mortality versus no T2D (HR 1.44, 95% CI [1.40–1.49]). The association was weaker in individuals aged ≥75 years versus 65–74 years (HR 1.32 [1.19–1.46] vs. 1.56 [1.50–1.62]; p‐value for interaction = .032). Compared to individuals with CHD but no T2D, individuals with T2D but no CHD had a similar risk of the composite outcome (HR 0.95 [0.85–1.07]), but a lower risk of cardiovascular events (HR 0.76 [0.59–0.98]).T2D was associated with increased risk of cardiovascular events and all‐cause mortality in older adults, but T2D without CHD conferred lower risk of cardiovascular events compared to CHD without T2D. Our results suggest that T2D should not be considered a CHD risk equivalent in older adults. [ABSTRACT FROM AUTHOR]

Background: It is estimated that major depression disorders constitute 8.2% of years lived with disability (YLDs) globally. The repetitive Transcranial Magnetic Stimulation (rTMS) and Electroconvulsive Therapy (ECT) are two relative common interventions to treat major depressive disorders, especially for treatment resistant depression. In this study the cost- effectiveness and cost-utility of rTMS were compared with ECT in Iranian population suffering from major depressive disorder using a decision tree model. Methods: A decision tree model conducted to compare the cost-effectiveness ratio of rTMS with ECT in a health system prospective and 7 months' time horizon. The outcome variables were: response rate, remission rate and quality-adjusted life-years (QALYs) of the rTMS and ECT as primary and secondary outcomes extracted from systematic reviews and randomized control trials. The costs were also calculated through a field study in one clinic and one hospital; the direct costs have only been considered. Results: The total cost for rTMS and ECTstrategieswere11015000Rials (373US$) and 11742700 Rials (397.7US$), respectively. Also the rTMS/ECT ratio of costs per improved patients was 1194410Rials (40.5 US$); the ratio for costs per QALYs utility was 21017139 Rials (711.72 US$). The incremental cost- effectiveness ratio of rTMS versus ECT was 1194410 Rials (40.44 US$) after treatment and maintenance courses. Conclusion: Given the current prevalence of depressive disorders in Iranian population, the ECT is more cost-effective than TMS. The sensitivity analysis showed that if the prevalence of major depressive disorders declines to below 5% or the costs of rTMS decrease (rTMS provided by public sector), then the rTMS becomes more cost-effective compared with ECT. However, efficacy of rTMS depends on the frequency of pulsed magnetic field, the location of rTMS on the head, the number of therapeutic sessions and the length of each session. [ABSTRACT FROM AUTHOR]

Background: To reduce the health inequity, it is necessary to measure and monitor these inequalities. In this regard, in Iran a plan was developed and accordingly 52 indicators to measure equity in health were developed and announced by the Ministry of Health in collaboration with other sectors. This study aims to obtain a deeper understanding of the development of health equity indicators and identify their implementation challenges and proposed solutions from the perspective of policy makers and executives responsible for the indicators development and implementation. Methods: In this qualitative study, data were gathered using semi-structured interviews with 15 Stakeholders involved in the development and implementation of these health equity indicators (at national and provincial levels), and the review and analysis of relevant documents including meeting minutes, working plans and working progress reports. Data were analyzed using a framework analysis approach. Results: Four main themes were identified, including the concept of equity in health and its importance, the use of health equity indicators and process of indicators development, challenges of development and implementation of the indicators and laying the groundwork for the establishment of indicators. The findings showed that policy makers' viewpoint on concepts and indicators is different from those of executives and their perceptions have little in common. The establishment of indicators requires accurate stakeholders' understanding and accurate insight into the issue of equity in health, political will, financing, training and empowerment of organization's employees, legal requirements, and finally a clear action plan. Conclusion: The development of the indicators requires a shared understanding among policy makers and executives. As the attention has been focused recently on the issue, in addition to knowledge improvement, proper solutions with an intersect oral collaboration approach in order to tackle challenges should be considered. [ABSTRACT FROM AUTHOR]

Context: Subclinical thyroid dysfunction (ScTD) comprising subclinical hypothyroidism (SHypo) and subclinical hyperthyroidism (SHyper) has been associated with increased risk for cardiovascular events., Objective: To assess associations between ScTD and cardiovascular risk factors (cvRFs) according to age and sex., Design and Setting: Pooled individual participant data analysis of large prospective cohort studies from the Thyroid Studies Collaboration., Participants: Aged 18 to 103 years with SHypo (TSH >4.50 mU/l, normal fT4) and SHyper (TSH <0.45 mU/l, normal fT4) vs. euthyroid (TSH 0.45-4.50 mU/l)., Interventions: None as this is an observational study., Main Outcome Measures: cvRFs, i.e. blood pressure, lipid levels, hs-CRP., Results: Of 69,006 participants (mean age 62 years, 55% women, 25% current smokers) from 16 international cohorts, 3,748 (5.4%) had SHypo and 3,428 (5.0%) had SHyper. In both women and men, systolic and diastolic BP were similar regardless of thyroid status. Exceptions were lower diastolic BP in women with SHyper compared to euthyroids (adjusted mean difference [aMD] -1.3 mmHg, 95%CI -2.0 to -0.5), and lower systolic BP in men with SHyper compared to euthyroids (aMD -3.1 mmHg, 95%CI -4.8 to-1.4). In both women and men, lipid levels (total, HDL, LDL cholesterol, triglycerides) and hs-CRP were similar regardless of thyroid status. The only exception were women with SHyper who had a lower LDL cholesterol compared to euthyroids (aMD -0.17 mmol/l, 95%CI -0.29 to -0.05)., Conclusions: Participants with ScTD and euthyroids have similar cvRFs and differences are arguably too small to explain the increased cardiovascular risk in ScTD observed in previous studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Older and multimorbid adults with type 2 diabetes (T2D) are at high risk of cardiovascular disease (CVD) and chronic kidney disease (CKD). Estimating risk and preventing CVD is a challenge in this population notably because it is underrepresented in clinical trials. Our study aims to (1) assess if T2D and haemoglobin A1c (HbA1c) are associated with the risk of CVD events and mortality in older adults, (2) develop a risk score for CVD events and mortality for older adults with T2D, (3) evaluate the comparative efficacy and safety of novel antidiabetics., Methods and Analysis: For Aim 1, we will analyse individual participant data on individuals aged ≥65 years from five cohort studies: the Optimising Therapy to Prevent Avoidable Hospital Admissions in Multimorbid Older People study; the Cohorte Lausannoise study; the Health, Aging and Body Composition study; the Health and Retirement Study; and the Survey of Health, Ageing and Retirement in Europe. We will fit flexible parametric survival models (FPSM) to assess the association of T2D and HbA1c with CVD events and mortality. For Aim 2, we will use data on individuals aged ≥65 years with T2D from the same cohorts to develop risk prediction models for CVD events and mortality using FPSM. We will assess model performance, perform internal-external cross validation, and derive a point-based risk score. For Aim 3, we will systematically search randomized controlled trials of novel antidiabetics. Network meta-analysis will be used to determine comparative efficacy in terms of CVD, CKD, and retinopathy outcomes, and safety of these drugs. Confidence in results will be judged using the CINeMA tool., Ethics and Dissemination: Aims 1 and 2 were approved by the local ethics committee (Kantonale Ethikkommission Bern); no approval is required for Aim 3. Results will be published in peer-reviewed journals and presented in scientific conferences.

Background: The recognition of patient safety is now occupying a prominent place on the health policy agenda since medical errors can result in adverse events. The existence of confusing drug names is one of the most common causes of medication errors. In Iran, the General Office of Trademarks Registry (GOTR), for four years (2010-2014) was responsible for approving drug proprietary names. This study aimed to investigate the performance of the GOTR in terms of drug names orthographic similarity using the SOLAR model., Methods: First, 100 names were randomly selected from the GOTR's database. Then, each name was searched through pharmaceutical websites including Martindale (the Complete Drug Reference published by Pharmaceutical Press), Drugs.com and Medicines Complete. Pair of drugs whose names look orthographically similar with different indications were identified. Then, the SOLAR model was utilized to determine orthographic similarity between all pair of drug names., Results: The mean of match values of these 100 pairs of drug was 77% indicating the high risk of similarity. The match value for most of the reviewed pairs (92%) was high (≥66%). This value was medium (≥ 33% and <66%) just for 8% of the pairs of drug. These results indicate high risk of confusion due to similarity of drug names., Conclusion: The stewardship of the GOTR in patient safety considerations is fundamentally problematic. Thus, as a best practice, we recommend that proprietary names of drugs be evaluated by an entity within the health system. While an entity within the health system should address patient safety considerations, the GOTR is responsible for intellectual property rights., Competing Interests: Conflict of Interests The authors declare that there is no conflict of interest.

Background: Inequality in households' payments on food and health expenditures presents the accessibility and utilization patterns between them. This study investigated the Iranian rural and urban households' inequality in payments on food and Out-of-Pocket health expenditures from 1998 to 2012., Methods: This descriptive study was conducted through the analysis of Iranian Statistics Centre data on Iranian households' income and expenditures. The Gini Coefficients, Concentration and Kakwani indices have been calculated for Iranian rural and urban households' Out-of-Pocket health and food expenditures., Results: The means of Iranian rural and urban total consumption expenditures inequality were 0.48 and 0.48, respectively. The means of concentration index of food expenditures for rural and urban regions were 0.35 and 0.34, respectively. The means of Out-of-Pocket payments for health services for rural and urban regions were 0.51 and 0.5, respectively. Finally the means of Kakwani index of Out-of-Pocket health payments in rural and urban households were -0.005 and -0.018, respectively., Conclusion: There are relative high levels of inequality in Iranian households' payments on food and Out-of-Pocket health expenditures.