Estimating individualized treatment effects using an individual participant data meta-analysis.

BACKGROUND: One key aspect of personalized medicine is to identify individuals who benefit from an intervention. Some approaches have been developed to estimate individualized treatment effects (ITE) with a single randomized control trial (RCT) or observational data, but they are often underpowered for the ITE estimation. Using individual participant data meta-analyses (IPD-MA) might solve this problem. Few studies have investigated how to develop risk prediction models with IPD-MA, and it remains unclear how to combine those methods with approaches used for ITE estimation. In this article, we compared different approaches using both simulated and real data with binary and time-to-event outcomes to estimate the individualized treatment effects from an IPD-MA in a one-stage approach. METHODS: We compared five one-stage models: naive model (NA), random intercept (RI), stratified intercept (SI), rank-1 (R1), and fully stratified (FS), built with two different strategies, the S-learner and the T-learner constructed with a Monte Carlo simulation study in which we explored different scenarios with a binary or a time-to-event outcome. To evaluate the performance of the models, we used the c-statistic for benefit, the calibration of predictions, and the mean squared error. The different models were also used on the INDANA IPD-MA, comparing an anti-hypertensive treatment to no treatment or placebo ( N = 40 237 , 836 events). RESULTS: Simulation results showed that using the S-learner led to better ITE estimation performances for both binary and time-to-event outcomes. None of the risk models stand out and had significantly better results. For the INDANA dataset with a binary outcome, the naive and the random intercept models had the best performances. CONCLUSIONS: For the choice of the strategy, using interactions with treatment (the S-learner) is preferable. For the choice of the method, no approach is better than the other.

Olaparib in recurrent isocitrate dehydrogenase mutant high-grade glioma: A phase 2 multicenter study of the POLA Network.

Background: Based on preclinical studies showing that IDH-mutant (IDHm) gliomas could be vulnerable to PARP inhibition we launched a multicenter phase 2 study to test the efficacy of olaparib monotherapy in this population. Methods: Adults with recurrent IDHm high-grade gliomas (HGGs) after radiotherapy and at least one line of alkylating chemotherapy were enrolled. The primary endpoint was a 6-month progression-free survival rate (PFS-6) according to response assessment in neuro-oncology criteria. Pre-defined threshold for study success was a PFS-6 of at least 50%. Results: Thirty-five patients with recurrent IDHm HGGs were enrolled, 77% at ≥ 2nd recurrence. Median time since diagnosis and radiotherapy were 7.5 years and 33 months, respectively. PFS-6 was 31.4% (95% CI [16.9; 49.3%]). Two patients (6%) had an objective response and 14 patients (40%) had a stable disease as their best response. Median PFS and median overall survival were 2.05 and 15.9 months, respectively. Oligodendrogliomas (1p/19q codeleted) had a higher PFS-6 (53.4% vs. 15.7%, P = .05) than astrocytomas while an initial diagnosis of grade 4 astrocytoma tended to be associated with a lower PFS-6 compared to grade 2/3 gliomas (0% vs 31.4%, P = .16). A grade 2 or 3 treatment-related adverse event was observed in 15 patients (43%) and 5 patients (14%), respectively. No patient definitively discontinued treatment due to side effects. Conclusions: Although it did not meet its primary endpoint, the present study shows that in this heavily pretreated population, olaparib monotherapy was well tolerated and resulted in some activity, supporting further PARP inhibitors evaluation in IDHm HGGs, especially in oligodendrogliomas.

Diabetes, periodontitis, and cardiovascular disease: towards equity in diabetes care.

Type 2 diabetes and its associated cardiovascular risk is an escalating epidemic that represents a significant public health burden due to increased morbidity and mortality, disproportionately affecting disadvantaged communities. Poor glycaemic control exacerbates this burden by increasing retinal, renal, and cardiac damage and raising healthcare costs. This predicament underscores the urgent need for research into cost-effective approaches to preventing diabetes complications. An important but often overlooked strategy to improve metabolic control in diabetic patients is the treatment of periodontitis. Our aim is to assess whether the inclusion of periodontitis treatment in diabetes management strategies can effectively improve metabolic control, and to advocate for its inclusion from an equity perspective. We conducted a comprehensive review of the literature from 2000 to 2023. We analyzed the pathophysiological links between periodontitis, diabetes, and atherosclerotic cardiovascular disease, all of which have inflammation as a central component. We also examined the inequalities in health care spending in this context. Our findings suggest that incorporating routine screening and treatment of periodontitis into national health programs, with coordinated efforts between physicians and dentists, is a cost-effective measure to improve metabolic control, reduce complications and improve the overall quality of life of people with diabetes.

Pharmacotherapy for mild hypertension

BACKGROUND: People with no previous cardiovascular events or cardiovascular disease represent a primary prevention population. The benefits and harms of treating mild hypertension in primary prevention patients are not known at present. This review examines the existing randomized controlled trial (RCT) evidence. OBJECTIVE: Primary objective: To quantify the effects of antihypertensive drug therapy on mortality and morbidity in adults with mild hypertension (systolic blood pressure (BP) 140-159 mmHg and/or diastolic BP 90-99 mmHg) and without cardiovascular disease. METHODS: Search: We searched CENTRAL (2011, Issue 1), MEDLINE (1948 to May 2011), EMBASE (1980 to May 2011) and reference lists of articles. The Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effectiveness (DARE) were searched for previous reviews and meta-analyses of anti-hypertensive drug treatment compared to placebo or no treatment trials up until the end of 2011. Selection criteria: RCTs of at least 1 year duration. Data collection and analysis: The outcomes assessed were mortality, stroke, coronary heart disease (CHD), total cardiovascular events (CVS), and withdrawals due to adverse effects. MAIN RESULTS: Of 11 RCTs identified 4 were included in this review, with 8,912 participants. Treatment for 4 to 5 years with antihypertensive drugs as compared to placebo did not reduce total mortality (RR 0.85, 95% CI 0.63, 1.15). In 7,080 participants treatment with antihypertensive drugs as compared to placebo did not reduce coronary heart disease (RR 1.12, 95% CI 0.80, 1.57), stroke (RR 0.51, 95% CI 0.24, 1.08), or total cardiovascular events (RR 0.97, 95% CI 0.72, 1.32). Withdrawals due to adverse effects were increased by drug therapy (RR 4.80, 95% CI 4.14, 5.57), ARR 9%. AUTHORS' CONCLUSIONS: Antihypertensive drugs used in the treatment of adults (primary prevention) with mild hypertension (systolic BP 140-159 mmHg and/or diastolic BP 90-99 mmHg) have not been shown to reduce mortality or morbidity in RCTs. Treatment caused 9% of patients to discontinue treatment due to adverse effects. More RCTs are needed in this prevalent population to know whether the benefits of treatment exceed the harms.