Analysis Of Individual Participant Data Research Articles

Retrospective composite analysis of StartReact data indicates sex differences in simple reaction time are not attributable to response preparation

Simple reaction time (RT) can vary by sex, with males generally displaying faster RTs than females. Although several explanations have been offered, the possibility that response preparation differences may underlie the effect of sex on simple RT has not yet been explored. A startling acoustic stimulus (SAS) can involuntarily trigger a prepared motor response (i.e., StartReact effect), and as such, RT latencies on SAS trials and the proportion of these trials demonstrating startle-reflex EMG in the sternocleidomastoid (SCM) muscle are used as indirect measures of response preparation. The present study employed a retrospective analysis of composite individual participant data (IPD) from 25 datasets published between 2006 and 2019 to examine sex differences in response preparation. Linear mixed effects models assessed the effect of sex on control and SAS RT as well as the proportion of SAS trials with SCM activation while controlling for study design. Results indicated significantly longer control RT in female participants as compared to males (p = .017); however, there were no significant sex differences in SAS RT (p = .441) or the proportion of trials with startle reflex activity (p = .242). These results suggest that sex differences in simple RT are not explained by variations in levels of response preparation but instead may be the result of differences in perceptual processing and/or response initiation processes.

Incorporating Baseline Outcome Data in Individual Participant Data Meta-Analysis of Non-randomized Studies.

BackgroundIn non-randomized studies (NRSs) where a continuous outcome variable (e.g., depressive symptoms) is assessed at baseline and follow-up, it is common to observe imbalance of the baseline values between the treatment/exposure group and control group. This may bias the study and consequently a meta-analysis (MA) estimate. These estimates may differ across statistical methods used to deal with this issue. Analysis of individual participant data (IPD) allows standardization of methods across studies. We aimed to identify methods used in published IPD-MAs of NRSs for continuous outcomes, and to compare different methods to account for baseline values of outcome variables in IPD-MA of NRSs using two empirical examples from the Thyroid Studies Collaboration (TSC).MethodsFor the first aim we systematically searched in MEDLINE, EMBASE, and Cochrane from inception to February 2021 to identify published IPD-MAs of NRSs that adjusted for baseline outcome measures in the analysis of continuous outcomes. For the second aim, we applied analysis of covariance (ANCOVA), change score, propensity score and the naïve approach (ignores the baseline outcome data) in IPD-MA from NRSs on the association between subclinical hyperthyroidism and depressive symptoms and renal function. We estimated the study and meta-analytic mean difference (MD) and relative standard error (SE). We used both fixed- and random-effects MA.ResultsTen of 18 (56%) of the included studies used the change score method, seven (39%) studies used ANCOVA and one the propensity score (5%). The study estimates were similar across the methods in studies in which groups were balanced at baseline with regard to outcome variables but differed in studies with baseline imbalance. In our empirical examples, ANCOVA and change score showed study results on the same direction, not the propensity score. In our applications, ANCOVA provided more precise estimates, both at study and meta-analytical level, in comparison to other methods. Heterogeneity was higher when change score was used as outcome, moderate for ANCOVA and null with the propensity score.ConclusionANCOVA provided the most precise estimates at both study and meta-analytic level and thus seems preferable in the meta-analysis of IPD from non-randomized studies. For the studies that were well-balanced between groups, change score, and ANCOVA performed similarly.

Relative contribution of low-density and asymptomatic infections to Plasmodium vivax transmission in the Amazon: pooled analysis of individual participant data from population-based cross-sectional surveys

SummaryBackgroundLow-density and asymptomatic Plasmodium vivax infections remain largely undetected and untreated and may contribute significantly to malaria transmission in the Amazon.MethodsWe analysed individual participant data from population-based surveys that measured P vivax prevalence by microscopy and polymerase chain reaction (PCR) between 2002 and 2015 and modelled the relationship between parasite density and infectiousness to vectors using membrane feeding assay data. We estimated the proportion of sub-patent (i.e., missed by microscopy) and asymptomatic P vivax infections and examined how parasite density relates to clinical manifestations and mosquito infection in Amazonian settings.FindingsWe pooled 24,986 observations from six sites in Brazil and Peru. P vivax was detected in 6·8% and 2·1% of them by PCR and microscopy, respectively. 58·5% to 92·6% of P vivax infections were asymptomatic and 61·2% to 96·3% were sub-patent across study sites. P vivax density thresholds associated with clinical symptoms were one order of magnitude higher in children than in adults. We estimate that sub-patent parasite carriers are minimally infectious and contribute 12·7% to 24·9% of the community-wide P vivax transmission, while asymptomatic carriers are the source of 28·2% to 79·2% of mosquito infections.InterpretationAsymptomatic P vivax carriers constitute a vast infectious reservoir that, if targeted by malaria elimination strategies, could substantially reduce malaria transmission in the Amazon. Infected children may remain asymptomatic despite high parasite densities that elicit clinical manifestations in adults.FundingUS National Institutes of Health, Fundação de Amparo à Pesquisa do Estado de São Paulo, and Belgium Development Cooperation.

J-shape relation of blood pressure reduction and outcome in acute intracerebral hemorrhage: A pooled analysis of INTERACT2 and ATACH-II individual participant data.

The aim of this study was to better define the shape of association between the degree ("magnitude") of early (< 1 h) reduction in systolic blood pressure (SBP) and outcomes in patients with acute intracerebral hemorrhage (ICH) through pooled analysis of the second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2) and second Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-II) datasets. Association of the continuous magnitude of SBP reduction described using cubic splines and an ordinal measure of the functional outcome on the modified Rankin scale (mRS) scores at 90 days were analyzed in generalized linear mixed models. Models were adjusted for achieved (mean) and variability (standard deviation, SD) of SBP between 1 and 24 h, various baseline covariates, and trial as a random effect. Among 3796 patients (mean age 63.1 (SD = 13.0) years; female 37.4%), with a mean magnitude (< 1 h) of SBP reduction of 28.5 (22.8) mmHg, those with larger magnitude were more often non-Asian and female, had higher baseline SBP, received multiple blood pressure (BP) lowering agents, and achieved lower SBP levels in 1-24 h. Compared to those patients with no SBP reduction within 1 h (reference), the adjusted odds of unfavorable functional outcome, according to a shift in mRS scores, were lower for SBP reductions up to 60 mmHg with an inflection point between 32 and 46 mmHg, but significantly higher for SBP reductions > 70 mmHg. Similar J-shape associations were evident across various time epochs across 24 h and consistent according to baseline hematoma volume and SBP and history of hypertension. A moderate degree of rapid SBP lowering is associated with improved functional outcome after ICH, but large SBP reductions over 1 h (e.g. from > 200 to target < 140 mmHg) were associated with reduction, or reversal, of any such benefit.

Home Non-Invasive Ventilation in COPD: A Global Systematic Review.

Uncertainty remains around the benefit of home non-invasive ventilation (NIV) for stable chronic obstructive pulmonary disease (COPD) patients and those with a recent exacerbation (post-hospital). The aim of this systematic review was to: (1) update the evidence base with studies published in any language, including Chinese language studies not indexed in standard medical databases, and (2) explore the impact of additional studies on the evidence base. Standard systematic review methodology was used for identifying and appraising studies. Randomized controlled trials (RCTs) and non-randomized studies reporting mortality, hospitalizations, exacerbations, quality of life, adverse events, or adherence were included. Random effects meta-analysis was undertaken for mortality and hospitalizations, with studies sub-grouped by population and study design. Sensitivity analysis was performed to explore the effect of including studies from Western and non-Western countries. A total of 103 studies were included, substantially more than in previous reviews. There was no significant effect on mortality for the stable population. There was a benefit from NIV for the post-hospital population based on non-randomized studies, or RCTs from non-Western countries. There was a small but significant reduction in hospital admissions (1-2/year) with NIV across all sub-groups, and a variable reduction in duration of stay with greater reductions in studies from China. The evidence base on home NIV is considerably larger than previously presented. While NIV may reduce hospital admissions and improve quality of life, there is still little evidence of a reduction in mortality, regardless of country. Individual participant data analysis may clarify which patients would benefit most from NIV.

Re: “Commentary” by Rothrock et al. “Meta-Analyses Did Not Establish Improved Mortality With Ivermectin Use in COVID-19”

Re: “Commentary” by Rothrock et al. “Meta-Analyses Did Not Establish Improved Mortality With Ivermectin Use in COVID-19”

Dapagliflozin and new-onset type 2 diabetes in patients with chronic kidney disease or heart failure: pooled analysis of the DAPA-CKD and DAPA-HF trials

BackgroundChronic kidney disease and heart failure are insulin resistant states associated with a high incidence of diabetes. We assessed the effect of dapagliflozin on new-onset type 2 diabetes in a pooled analysis of patient-level data from the DAPA-CKD and DAPA-HF trials. MethodsThis study is a pooled analysis of individual participant data from two phase 3, randomised, double-blind, placebo-controlled, multicentre, clinical trials. Participants with no history of diabetes and HbA1c less than 6·5% (48 mmol/mol) at baseline were included in this pooled analysis. New-onset type 2 diabetes was a prespecified exploratory endpoint in both DAPA-CKD and DAPA-HF trials and is the focus of this analysis. New-onset type 2 diabetes was identified by serial trial measurements of HbA1c (two consecutive values ≥6·5% [≥48 mmol/mol]) or following a clinical diagnosis of diabetes between trial visits. Time to new-onset type 2 diabetes was analysed in a Cox proportional Hazards model from random assignment to end of treatment. Findings4003 participants (1398 [34·9%] from the DAPA-CKD trial and 2605 [65·1%] from the DAPA-HF trial) were included in our analysis: 1995 (49·8%) had received dapagliflozin and 2008 (50·2%) had received placebo. Over a median follow-up of 21·2 months (IQR 16·0 to 25·4), 126 (6·3%) of 2008 patients in the placebo group (event rate 3·9 per 100 patient-years) and 85 (4·3%) of 1995 patients in the dapagliflozin group (event rate 2·6 per 100 patient-years) developed type 2 diabetes (hazard ratio 0·67 [95% CI 0·51 to 0·88]; p=0·0040). There was no heterogeneity between studies (p interaction 0·77) and there was no clear evidence that the effect of dapagliflozin varied in prespecified subgroups including sex, age, glycaemic status, BMI, glomerular filtration rate, systolic blood pressure, and baseline cardiovascular medication use. More than 90% of the participants who developed type 2 diabetes had prediabetes at baseline (HbA1c 5·7% to 6·4% [39 to 46 mmol/mol]). Mean HbA1c remained unchanged (placebo-adjusted change in the dapagliflozin group of −0·01% [95% CI −0·03 to 0·01], −0·1 mmol/mol [95% CI −0·3 to 0·1] at 12 months). InterpretationTreatment with dapagliflozin reduced the incidence of new-onset type 2 diabetes in participants with chronic kidney disease and HF without a reduction in HbA1c. FundingAstraZeneca.

Breakfast Skipping Is Associated with Vitamin D Deficiency among Young Adults entering Initial Military Training

BackgroundVitamin D deficiency (VDD), defined as serum 25-hydroxyvitamin D (25[OH]D) levels < 20 ng/mL [to convert 25[OH]D ng/mL to nmol/L, multiply by 2.5]) is prevalent in young adults and has been associated with adverse health outcomes, including stress fracture during periods of increased physical activity such as military training. Foods commonly consumed at breakfast provide an important source of vitamin D, yet breakfast skipping is common among young adults. However, whether breakfast skipping is associated with VDD in young adults is unclear. ObjectivesThis study aimed to determine whether breakfast skipping is associated with odds of VDD among recruits entering initial military training (IMT), and with changes in serum 25(OH)D during IMT. In addition, whether diet quality and vitamin D intake mediated these associations was determined. DesignSecondary analysis of individual participant data collected during five IMT studies. Breakfast skipping (≥ 3 times/week) was self-reported. Dietary intake was determined using food frequency questionnaires, and vitamin D status was assessed using circulating 25(OH)D concentrations pre- and post-IMT. Participants and settingParticipants were healthy US Army, US Air Force, and US Marine recruits (N = 1,569, 55% male, mean ± standard deviation age 21 ± 4 years) entering military service between 2010 and 2015 at Fort Jackson, SC; Fort Sill, OK; Lakeland Air Force Base, TX; or the Marine Corps Recruit Depot, Parris Island, SC. Main outcome measuresPrimary outcomes were VDD pre-IMT and change in 25(OH)D from pre- to post-IMT. Statistical analysis performedAssociations were determined using multivariate-adjusted logistic and linear regression and mediation models. ResultsForty-six percent of military recruits were classified as breakfast skippers pre-IMT, and 30% were VDD. Breakfast skipping was associated with a higher odds of pre-IMT VDD (odds ratio 1.5, 95% CI 1.1 to 1.9), and lower vitamin D intake and diet quality were partial mediators of the association. Serum 25(OH)D concentrations improved (P = 0.01) among habitual breakfast skippers versus nonskippers during IMT; however, regression to the mean could not be ruled out. Neither change in diet quality nor vitamin D intake were associated with change in 25(OH)D concentrations during IMT. ConclusionsBreakfast skipping is prevalent among incoming military recruits and is associated with VDD. This relationship may be mediated by lower diet quality and vitamin D intake.

The Effect of Hemodiafiltration on Inflammatory Biomarkers in Comparison to High Flux Dialyzers in Prevalent Hemodialysis Patients

Abstract Introduction Inflammation in patients with ESRD undergoing HD is an increasing concern for physicians and has been related to increase the rates of morbidity and mortality. Interestingly, patients with ESRD in conventional HD have frequent infections and a suboptimal response to vaccines; this is probably related to an immune inflammatory disorder associated either with uremia and/or nutritional status. In addition to CRP, which seems to be the most important marker for the identification and control of inflammation in clinical practice, many other markers are also available for the evaluation of inflammatory state. Decreased renal clearance clearly accounts for higher levels of circulating cytokines, although increased production has also been described. Hemodiafiltration has been shown to improve cardio-protection and the immunologic system and reduces infection and mortality compared with conventional HD. A recent study showed that hemodiafiltration compared with conventional HD reduced the risk of mortality in ESRD patients. Analysis of pooled individual participant data from randomized controlled trials has shown survival benefits of high volume-HDF on all-cause mortality and especially cardiovascular mortality rate. The mechanisms that lead to improved outcomes are not clear, but it is thought that HDF may reduce the production of inflammatory mediators through the use of biocompatible dialysers and ultrapure dialysate and also improve clearance of larger molecular weight substances, many of which are associated with oxidative stress, inflammation and endothelial dysfunction. Objective The aim of this study is to detect, prospectively, the effect of 3 months dialysis with Hemodiafiltration on inflammatory and nutritional biomarkers in comparison to conventional dialysis with high flux dialyzer in stable HD patients. Patients and methods 30 adults aged 20-75 years who were selected from Dialysis Unit, Kobary El-Kobba Military Hospital. 30 male patients known to have chronic kidney disease and are on dialysis with high flux dialyzer more than 3 months were divided into 2 groups:15 Patients are shifted to be on dialysis with HDF and 15 Patients are continued to be on Regular Hemodialysis with high flux dialyzer. Full medical history and clinical examination. Anthropometric measurements and Laboratory investigations including Complete Blood Picture (WBCs, platelets, Hb), Coagulation profile PT, PTT&amp;INR, Liver function tests (ALT, AST, T. Bilirubin and S. Albumin), Lipid profile (Triglycerides, total cholesterol, VLDL), S. creatinine, BUN, Na, K, Uric acid, Total Proteins, Serum Calcium, Serum Phosphorus, PTH, Serum ferritin, High sensitivity CRP (Enzyme- Linked Immunosorbent Assay (ELISA)) and IL6 (ELISA). Results The current study was conducted on 30 patients with chronic kidney disease on regular dialysis. The patients were divided into two groups A representing patients on hemodiafiltration (n = 15) and group B representing patients on dialysis with high flux dialyzer (n = 15). A high statistical significant difference (P &amp;lt; 0.01) was found regarding K 4.3±0.6 meq/l in group A while it is 5.2±0.5 meq/l in group B, a high statistical significant difference (P &amp;lt; 0.01) was found regarding phosphorus 4.6±1.0 mg/dl in group A while it is 6.1±0.9 mg/dl in group B and no statistical significant difference (P &amp;gt; 0.05) was found as regard the uric acid. A statistical significant difference (P &amp;lt; 0.05) was found regarding CRP 63.5±40.9 mg/dl in group A while it is 73.4±33.2 mg/dl in group B, a statistical significant difference (P &amp;lt; 0.01) was found regarding IL6 85.3±37.6 mg/dl in group A while it is 156.7±151.9 mg/dl in group B after 3 months and no statistical significant difference (P &amp;gt; 0.05) was found as regard those inflammatory markers before 3 months. A statistical significant difference (P &amp;lt; 0.05) was found regarding CRP. A statistical significant difference (P &amp;lt; 0.05) was found regarding IL6. Conclusion The present study revealed that there was no significant change in CRP and IL6 in patients on HDF compared to patients undergoing hemodialysis with high flux dialyzer before 3 months but there was a significant decrease in CRP and IL6 in patients on HDF compared to patients undergoing hemodialysis with high flux dialyzer after 3 months.

Intensive blood pressure lowering with nicardipine and outcomes after intracerebral hemorrhage: An individual participant data systematic review.

Nicardipine has strong, rapidly acting antihypertensive activity. The effects of acute systolic blood pressure levels achieved with intravenous nicardipine after onset of intracerebral hemorrhage on clinical outcomes were determined. A systematic review and individual participant data analysis of articles before 1 October 2020 identified on PubMed were performed (PROSPERO: CRD42020213857). Prospective studies involving hyperacute intracerebral hemorrhage adults treated with intravenous nicardipine whose outcome was assessed using the modified Rankin Scale were eligible. Outcomes included death or disability at 90 days, defined as the modified Rankin Scale score of 4-6, and hematoma expansion, defined as an increase ≥6 mL from baseline to 24-h computed tomography. Three studies met the eligibility criteria. For 1265 patients enrolled (age 62.6 ± 13.0 years, 484 women), death or disability occurred in 38.2% and hematoma expansion occurred in 17.4%. Mean hourly systolic blood pressure during the initial 24 h was positively associated with death or disability (adjusted odds ratio (aOR) 1.12, 95% confidence interval (CI) 1.00-1.26 per 10 mmHg) and hematoma expansion (1.16, 1.02-1.32). Mean hourly systolic blood pressure from 1 h to any timepoint during the initial 24 h was positively associated with death or disability. Later achievement of systolic blood pressure to ≤140 mmHg increased the risk of death or disability (aOR 1.02, 95% CI 1.00-1.05 per hour). Rapid lowering of systolic blood pressure by continuous administration of intravenous nicardipine during the initial 24 h in hyperacute intracerebral hemorrhage was associated with lower risks of hematoma expansion and 90-day death or disability without increasing serious adverse events.

Comparison of invasive treatment strategies in patients with non–ST elevation acute coronary syndrome: A systematic review and meta-analysis

ObjectiveTo compare the mortality associated with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with non–ST elevation acute coronary syndrome (NSTE-ACS). MethodsWe searched publications from PubMed, Embase, Web of Science, and the Cochrane Library from inception until December 23, 2020. All randomized clinical trials (RCTs) and observational studies comparing all-cause mortality after treatment with CABG versus PCI for patients with NSTE-ACS with minimum follow-up of 6 months were included. Restricted mean survival time (RMST) differences from RCTs and adjusted RMST differences from observational studies were computed by reconstructing time-to-event data from published Kaplan–Meier curves. Extracted hazard ratios (HRs) were also assessed as a secondary analysis. ResultsOur systematic review included an individual participant data analysis of 3 RCTs and 8 observational studies. A meta-regression showed a significant association between log-transformed HRs and duration of follow-up (−0.009 [95% confidence interval (CI), −0.002 to −0.016] log-HR per 1-year longer follow-up; P = .037), suggesting a violation of the proportional hazard assumption. Analysis of 6 studies with available RMST data showed a significant inverse association between adjusted RMST differences and cutoff years (slope, −0.028 [95% CI, −0.042 to −0.013] year difference per 1-year longer cutoff; P < .005), suggesting a longer survival benefit in the CABG arm compared with the PCI arm with longer follow-up. ConclusionsThere was a trend toward a benefit of CABG compared with PCI in the longer follow-up in patients with NSTE-ACS. A large, well-designed RCT with longer follow-up is needed to obtain definitive evidence on this topic.

Association of Thyroid Dysfunction With Cognitive Function

In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings. To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia. This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021. Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values. The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated. Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia. In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.

Association of peri-procedural myocardial infarction with mortality after stenting true coronary bifurcation lesions: A pooled individual participant data analysis from four randomized controlled trials.

Five definitions of peri-procedural myocardial infarction (PMI) following percutaneous coronary intervention (PCI) are used in clinical trials; their clinical relevance in coronary bifurcation stenting remains unclear. To understand the correlation between PMI and mortality in bifurcation lesions from the DKCRUSH studies. PMI was defined using serum creatine kinase-myocardial band (CK-MB) values within 48 h of PCI according to the SYNTAX, Fourth Universal Definition of MI (4th UDMI), ISCHEMIA, SCAI, and EXCEL definitions. Overall, 1300 patients with both CK and CK-MB measurements pre- and post-stenting were evaluated. The association of each PMI type and all-cause death or cardiac death at a median of 5.58 years of follow-up was analyzed using Cox regression. In total, 56 (4.3%) patients had PMI. According to SYNTAX, 4th UDMI or ISCHEMIA, SCAI, and EXCEL definitions, PMI occurred in 21 (1.6%), 56 (4.3%), 29 (2.2%), and 32 (2.5%) patients, respectively. All definitions were significantly correlated with unadjusted mortality at the end of follow-up but not at 30 days or 1-year after stenting. PMI using SYNTAX, SCAI, and EXCEL definitions rather than 4th UDMI definition was strongly associated with adjusted all-cause death. By adjusted analysis, PMI according to 4th UDMI, SCAI, and EXCEL definitions but not SYNTAX definition was positively correlated with cardiac death at a median of 5.58 years of follow-up. CK-MB ≥ 5 x UNL strongly enhanced the correlation of CK-MB values with mortality. PMI rate varies with the definition following stenting for bifurcation lesions. PMI defined by SCAI and EXCEL definitions is strongly correlates with adjusted all-cause and cardiac death.

Longitudinal development of incident gout from low-normal baseline serum urate concentrations: individual participant data analysis

IntroductionElevated serum urate (SU) concentration is the central risk factor for the development of gout. The aim of this study was to examine the incidence of gout in people with low and normal SU levels (< 7.00 mg/dL).MethodsLongitudinal cohort data from the Atherosclerosis Risk in Communities Study (ARIC), Coronary Artery Risk Development in Young Adults Study (CARDIA), and both the Original and Offspring cohorts of the Framingham Heart Study (FHS) were used to determine incident gout by baseline SU over 3, 5, 10, 12 and 15 year periods. A Cox proportional hazards model with covariables of age, gender, ethnicity, and cohort was calculated to report the hazard ratios (HR) for incident gout.ResultsThe incidence of gout at 15 years for a baseline SU < 4.00 mg/dL was 0.59%, 4.00–4.49 mg/dL was 1.28%, 4.50–4.99 mg/dL was 0.86%, 5.00–5.49 mg/dL was 0.94%, 5.50–5.99 mg/dL was 1.52%, 6.00–6.49 mg/dL was 2.91%, 6.50–6.99 mg/dL was 3.2%, and > 7.00 mg/dL was 12.2%. In an adjusted Cox proportional hazards model, compared to the referent baseline SU < 4.00 mg/dL, there was a non-significant increase in incident gout for baseline SU bands between 4.00–5.49 mg/dL, whereas incident gout was significantly increased for SU 5.50–5.99 mg/dL (HR 2.60), 6.00–6.49 mg/dL (HR 3.70), 6.50–6.99 mg/dL (HR 5.24) and > 7.00 mg/dL (HR 18.62).ConclusionA baseline SU of 5.50 mg/dL or more is a risk factor for development of gout over 15 years. However, incident gout does occur over time in a small proportion of people with lower baseline SU levels.

Uric acid-lowering effect of dotinurad, a novel selective urate reabsorption inhibitor, in hypertensive patients with gout or asymptomatic hyperuricemia: a pooled analysis of individual participant data in phase II and III trials

ABSTRACT Background: Hyperuricemia is a risk factor for the development of hypertension and is comorbid in many hypertensive patients. According to Japanese hypertension management guidelines published in 2019, a target serum uric acid level of ≤6.0 mg/dL is recommended in hypertensive patients with gout or asymptomatic hyperuricemia. Dotinurad is a novel uric acid-lowering drug classified as a selective urate reabsorption inhibitor. A pooled analysis was performed on the uric acid-lowering effect of dotinurad in 222 hypertensive patients with gout or asymptomatic hyperuricemia in four clinical trials (NCT02344862, NCT02416167, NCT03100318, NCT03372200). Moreover, we analyzed the long-term uric acid-lowering effect of dotinurad in 154 hypertensive patients with gout or asymptomatic hyperuricemia (NCT03006445). Results: In the pooled analysis, the percent change in the decrease of serum uric acid with the use of dotinurad was 42.17 ± 12.42% at a dose of 2 mg and 60.42 ± 8.03% at a dose of 4 mg; the percentage of patients who achieved a serum uric acid level of ≤6.0 mg/dL was 82.8% and 100.0%. The long-term uric acid-lowering effect of dotinurad showed almost the same results. In this study, the concomitant use of diuretics or angiotensin II receptor blockers affected the uric acid-lowering effect of dotinurad at only a dose of 2 mg in the pooled analysis. Conclusions: In the pooled analysis, dotinurad lowered serum uric acid levels. Dotinurad has an achievement rate of over 80% for serum uric acid level of ≤6.0 mg/dL in both analyses, and will be clinically useful for the management of hyperuricemic states in hypertensive patients.

Antidepressant treatment effects and country income: meta-regression analysis of individual participant data from duloxetine trials.

In recent decades, significant numbers of pharmaceutical trials have gradually been relocated to low- and middle-income countries. However, there is little evidence regarding the transferability of trial outcomes across countries. Analysing duloxetine randomised controlled trials (RCTs) conducted in different countries, we investigated whether per capita gross national income (GNI) and healthcare expenditure (HE) are associated with pre-post mean changes of depression severity and differences in duloxetine-placebo effect sizes. Meta-analyses included RCTs investigating duloxetine efficacy in patients with depression. Individual participant data (IPD) from multi-centre duloxetine trials were provided by the manufacturer. Data extracted from published reports also entered analyses in case of trials conducted in only one country. A meta-regression approach was applied to analyse associations of GNI and HE with standardised pre-post mean change using raw score standardisation (SMCR) and comparative effect size, that is, the mean differences (MD) in pre-post effect size between duloxetine and placebo treatment. 23 trials with 8417 randomised participants entered analyses. Regression coefficients indicated a negative linear relationship of SMCR with GNI (z-standardised β=-3.61, R2 =14.8%, p < 0.001) and HE (β=-4.72, R2 =24.8%, p < 0.001) for participants treated with duloxetine. Similar associations were found for placebo treatment (GNI: β=-3.52, R2 =23.8%, p < 0.001; β=-3.34, R2 =21.0% p < 0.001). Neither GNI nor HE was associated with the MD between duloxetine and placebo pre-post differences. Findings challenge the idea of the universal transferability of antidepressant trial outcomes across countries. Understanding the results of antidepressant RCTs demands more sophisticated clarification of context factors involved in determining effectiveness of antidepressant medication and should be discussed with a view to socio-economic context in their countries of origin.

The development and validation of a prognostic model to PREDICT Relapse of depression in adult patients in primary care: protocol for the PREDICTR study

BackgroundMost patients who present with depression are treated in primary care by general practitioners (GPs). Relapse of depression is common (at least 50% of patients treated for depression will relapse after a single episode) and leads to considerable morbidity and decreased quality of life for patients. The majority of patients will relapse within 6 months, and those with a history of relapse are more likely to relapse in the future than those with no such history. GPs see a largely undifferentiated case-mix of patients, and once patients with depression reach remission, there is limited guidance to help GPs stratify patients according to risk of relapse. We aim to develop a prognostic model to predict an individual’s risk of relapse within 6–8 months of entering remission. The long-term objective is to inform the clinical management of depression after the acute phase.MethodsWe will develop a prognostic model using secondary analysis of individual participant data drawn from seven RCTs and one longitudinal cohort study in primary or community care settings. We will use logistic regression to predict the outcome of relapse of depression within 6–8 months. We plan to include the following established relapse predictors in the model: residual depressive symptoms, number of previous depressive episodes, co-morbid anxiety and severity of index episode. We will use a “full model” development approach, including all available predictors. Performance statistics (optimism-adjusted C-statistic, calibration-in-the-large, calibration slope) and calibration plots (with smoothed calibration curves) will be calculated. Generalisability of predictive performance will be assessed through internal-external cross-validation. Clinical utility will be explored through net benefit analysis.DiscussionWe will derive a statistical model to predict relapse of depression in remitted depressed patients in primary care. Assuming the model has sufficient predictive performance, we outline the next steps including independent external validation and further assessment of clinical utility and impact.Study registrationClinicalTrials.gov ID: NCT04666662

Low protein intake, physical activity, and physical function in European and North American community-dwelling older adults: a pooled analysis of four longitudinal aging cohorts

ABSTRACTBackgroundDietary protein may slow the decline in muscle mass and function with aging, making it a sensible candidate to prevent or modulate disability progression. At present, studies providing reliable estimates of the association between protein intake and physical function, and its interaction with physical activity (PA), in community-dwelling older adults are lacking.ObjectivesWe investigated the longitudinal relation between protein intake and physical function, and the interaction with PA.MethodsWe undertook a pooled analysis of individual participant data from cohorts in the PROMISS (PRevention Of Malnutrition In Senior Subjects in the European Union) consortium (the Health Aging and Body Composition Study, Quebec Longitudinal Study on Nutrition and Successful Aging, Longitudinal Aging Study Amsterdam, and Newcastle 85+) in which 5725 community-dwelling older adults were followed up to 8.5 y. The relation between protein intake and walking speed was determined using joint models (linear mixed-effects and Cox proportional hazards models) and the relation with mobility limitation was investigated using multistate models.ResultsHigher protein intake was modestly protective of decline in walking speed in a dose-dependent manner [e.g., protein intake ≥1.2 compared with 0.8 g/kg adjusted body weight (aBW)/d: β = 0.024, 95% CI: 0.009, 0.032 SD/y], with no clear indication of interaction with PA. Participants with protein intake ≥0.8 g/kg aBW/d had also a lower likelihood of incident mobility limitation, which was observed for each level of PA. This association seemed to be dose-dependent for difficulty walking but not for difficulty climbing stairs. No associations between protein intake and other mobility limitations transitions were observed.ConclusionsHigher daily protein intake can reduce physical function decline not only in older adults with protein intake below the current RDA of 0.8 g/kg BW/d, but also in those with a protein intake that is already considered sufficient. This dose-dependent association was observed for each level of PA, suggesting no clear synergistic association between protein intake and PA in relation to physical function.

Mucinous Adenocarcinoma Predicts Poor Response and Prognosis in Patients With Locally Advanced Rectal Cancer: A Pooled Analysis of Individual Participant Data From 3 Prospective Studies

PurposeTo evaluate the predictive implications and prognosis of mucinous adenocarcinoma (MAC) in locally advanced rectal cancer (LARC) with intensified neoadjuvant treatment. MethodsIndividual patient data of LARC patients from 3 prospective clinical trials was analyzed. Neoadjuvant treatment regimens comprised chemoradiotherapy (CRT) with fluorouracil (5-FU) or mFOLFOX6, neoadjuvant chemotherapy alone with mFOLFOX6 or mFOLFOXIRI. The postoperative pathological result, local recurrence and disease-free survival (DFS) were retrospectively analyzed in patients with MAC and adenocarcinoma (AC) with neoadjuvant treatment. ResultsTotally, 743 patients were recruited, with 620 patients eligible for analysis. Fifty-three (8.5%) patients were MAC. The pathological complete response (pCR) rate and tumor downstaging rate (ypStage 0-I) between MAC and AC patients was 7.5% vs. 22.0% (P = .01) and 20.8% vs. 48.7% (P < .001), respectively. Among patients receiving preoperative CRT with 5FU or mFOLFOX6, the pCR rate and tumor downstaging rate between MAC and AC patients was 11.1% vs. 27.3% (P = .03) and 23.7% vs. 52.6% (P = .001), respectively. Regarding neoadjuvant chemotherapy alone with mFOLFOX6 or mFOLFOXIRI, the pCR rate and tumor downstaging rate was 0 vs.13.2% (P = .11) and 11.8% vs. 42.5% (P = .03) between MAC and AC group, respectively. With the median follow-up time of 38.9 months, the 3-year DFS and 3-year locoregional recurrence rate was 58.4% vs. 77.6% (P = .02) and 26.0% vs. 5.7% (P = .001) in the MAC and AC group, respectively. MAC (hazard ratio [HR] 1.85, 95% confidence interval [CI], 1.15-2.98), PNI (HR 3.23, 95% CI, 1.85-5.72) and LVI (HR 2.04, 95% CI, 1.02-4.08) were independent prognosis factors and were associated with worse DFS. ConclusionsPatients with MAC of the rectum are associated with a lower pCR rate and tumor downstaging rate, higher incidence of local recurrence, and poorer DFS with neoadjuvant treatment.

Effect of intra-arrest trans-nasal evaporative cooling in out-of-hospital cardiac arrest: a pooled individual participant data analysis

BackgroundRandomized trials have shown that trans-nasal evaporative cooling initiated during CPR (i.e. intra-arrest) effectively lower core body temperature in out-of-hospital cardiac arrest patients. However, these trials may have been underpowered to detect significant differences in neurologic outcome, especially in patients with initial shockable rhythm.MethodsWe conducted a post hoc pooled analysis of individual data from two randomized trials including 851 patients who eventually received the allocated intervention and with available outcome (“as-treated” analysis). Primary outcome was survival with favourable neurological outcome at hospital discharge (Cerebral Performance Category [CPC] of 1–2) according to the initial rhythm (shockable vs. non-shockable). Secondary outcomes included complete neurological recovery (CPC 1) at hospital discharge.ResultsAmong the 325 patients with initial shockable rhythms, favourable neurological outcome was observed in 54/158 (34.2%) patients in the intervention and 40/167 (24.0%) in the control group (RR 1.43 [confidence intervals, CIs 1.01–2.02]). Complete neurological recovery was observed in 40/158 (25.3%) in the intervention and 27/167 (16.2%) in the control group (RR 1.57 [CIs 1.01–2.42]). Among the 526 patients with initial non-shockable rhythms, favourable neurological outcome was in 10/259 (3.8%) in the intervention and 13/267 (4.9%) in the control group (RR 0.88 [CIs 0.52–1.29]; p = 0.67); survival and complete neurological recovery were also similar between groups. No significant benefit was observed for the intervention in the entire population.ConclusionsIn this pooled analysis of individual data, intra-arrest cooling was associated with a significant increase in favourable neurological outcome in out-of-hospital cardiac arrest patients with initial shockable rhythms. Future studies are needed to confirm the potential benefits of this intervention in this subgroup of patients.