Comparison of rTMS and esketamine for treatment-resistant depression: A target trial emulation.

Evolution of Clinical Trial Design in ADPKD.

No epidemiological studies have yet explored the relationship between TZD use and epilepsy incidence within a population context. This study aimed to evaluate the association between TZD use and risk of epilepsy in a Chinese population by using a target trial emulation framework with active-comparator new-user (ACNU) design. We emulated a target trial comparing the risk of epilepsy between use of TZDs and alpha glucosidase inhibitors (AGIs) in patients with type 2 diabetes mellitus (T2DM). Participants aged between 18 and 100years, who were new users of TZDs or AGIs were included. The primary outcome was incident epilepsy identified by using ICD-10 codes. A Cox model with inverse probability of treatment weighting (IPTW) was used to estimate the hazard ratio (HR) and confidence interval (CI). Various subgroup analyses and sensitivity analyses were conducted. The final cohort included 22,128 new users of TZDs and 79,166 new users of AGIs. The mean age was 60.3 (SD, 12.8) years and 47.2% of participants were female. The incidence of epilepsy was 140.1 per 100,000 person-years in users of TZDs and 208.2 per 100,000 person-years for AGIs users, respectively. After adjusting for potential confounders using stabilized IPTW, use of TZDs was associated with a 23% (HR 0.77; 95% CI, 0.64-0.93) decrease in incidence of epilepsy. This association was consistent in various subgroup analyses and sensitivity analyses. Our results indicated that use of TZDs was associated with reduced risk of epilepsy in the study population. More studies are needed to confirm and replicate the study results in other settings and populations..

Clinical outcomes of early fast compared to slow sodium correction rate in adults with severe hypernatremia: A comparative effectiveness study.

Optimising lipid monitoring interval for primary prevention of cardiovascular disease in patients with type-2 diabetes: A target trial emulation study.

Health services research faces the challenge of providing sound recommendations for action for the further development of health systems and care. The application of causal inference methods offers health services researchers an excellent opportunity to identify causal relationships under everyday conditions. The role of clinical trials with a classic randomised controlled trial (RCT) design is recognised as suitable for gaining insights that help establish causal inference, but other methodological approaches to generating evidence also play an important role in health services research.The discussion paper presents key concepts and assumptions of causal inference and highlights their relevance for health services research. The paper makes it clear that in order to fulfil the assumptions, it is necessary to integrate theory, contextual knowledge, understanding of mechanisms and formal concepts, such as directed acyclic graphs (DAGs), into a suitable empirical study design. To this end, RCTs, quasi-experimental methods, causal machine learning, target trial emulation, in silico trials and the mixed-methods approach of integrated inference are presented and discussed in terms of their applicability in health services research and their internal and external validity.All of the approaches presented here can contribute to the estimation of causal effects when used in a targeted manner and in accordance with the central assumptions. Their suitability depends largely on the research question, data quality, theoretical modelling and contextual knowledge. The combination of complementary designs and high quality data sources can increase the robustness of causal conclusions.Causal inference in health services research is not only a methodological procedure, but an integrative process that systematically combines theory, methodology and contextual knowledge. By consistently linking these aspects, health services research can generate differentiated and actionable insights that go beyond correlative analyses and enable an understanding of the mechanisms of causal processes. This can lead, for example, to evidence-supported recommendations that critically examine the often non-evidence-based status quo and reliably evaluate the benefits of new models.

This cohort study uses target trial emulation to explore the comparative effectiveness of buprenorphine-naloxone and methadone for opioid overdose among youths in Canada.

High serum low-density lipoprotein cholesterol (LDL-C) levels are associated with increased risk of fracture; however, it remains unclear whether lowering LDL-C reduces fracture risk, and, if so, whether the magnitude of LDL-C reduction is linearly associated with fracture risk. This study aimed to evaluate the relation between the degree of LDL-C reduction and fracture risk. This population-based cohort study included individuals aged 40 to 90 years who initiated statins for hyperlipidaemia from IQVIA Medical Research Data primary care database in the UK (2000 to 2022). The primary outcome was hip fracture. Secondary outcomes included composite fracture and major osteoporotic fracture. A hypothetical target trial was emulated to assess the effect of achieving a LDL-C level of 1.8 to 2.6 mmol/L or < 1.8 mmol/L versus > 2.6 mmol/L induced by statin initiation within one year on the risk of incident and recurrent fractures over five years. Among 165,242 people with hyperlipidaemia initiating statins (mean age 62.6 years, 51.1% female), the five-year risk of incident hip fracture was lower in the 1.8 to 2.6 mmol/L arm (0.53%) and in the < 1.8 mmol/L arm (0.52%) than the > 2.6 mmol/L LDL-C arm (0.65%). The corresponding hazard ratios (HRs) were 0.77 (95% CI 0.65 to 0.91) and 0.68 (95% CI 0.54 to 0.86), respectively. A similar decreased risk of recurrent hip fracture was observed for the 1.8 to 2.6 mmol/L arm (HR = 0.79, 95% CI 0.39 to 1.58) and < 1.8 mmol/L arm (HR = 0.32, 95% CI 0.15 to 0.66), respectively. Additionally, lowering LDL-C levels reduced the risks of composite fracture and major osteoporotic fracture. In this population-based cohort study, LDL-C lowering was associated with a decreased risk of fracture in individuals with hyperlipidaemia. This decreased risk appeared to be associated with the extent of LDL-C lowering, suggesting that the therapeutic paradigm of 'lower is better' could be advantageous for fracture prevention in individuals with hyperlipidaemia.

Chemotherapy is given for early-stage breast cancer; however, some patients discontinue before completing all planned cycles. This study investigated the impact of early chemotherapy discontinuation on treatment outcomes. This retrospective cohort study used a target trial emulation framework to conduct a causal analysis of the all-cause mortality impact of completing a standard course of chemotherapy. Early-stage breast cancer patients treated with chemotherapy in England between 01/01/2014 and 31/12/2015 were identified from the National Disease Registration Service and Systemic Anti-Cancer Therapy datasets. Five-year OS was estimated for patients completing greater than or equal to six chemotherapy cycles relative to discontinuing chemotherapy early (less than six cycles), representing standard treatment during the study period. A clone-censor-weight approach was used to account for time-related bias and baseline confounding. Absolute risk and hazard ratios (HRs) were calculated. A total of 10 253 patients were included: 68% (n = 7014) received greater than or equal to six chemotherapy cycles, and 32% (n = 3239) received fewer than six cycles. Individuals completing greater than or equal to six cycles showed superior 5-year OS compared with discontinuation less than six cycles (absolute risk difference -1.6, 95% confidence interval [CI], -3.2, -0.1; HR 0.85, 95% CI 0.74, 0.98). Subgroup analyses showed OS benefit in patients diagnosed at stage 2 relative to Stage 3 (HR 0.82, 95% CI 0.69, 0.98), ER+/HER2+ histology (HR 0.46, 95% CI 0.24, 0.96) and Non-White ethnicity (HR 0.56, 95% CI 0.34, 0.91) when receiving six cycles. Patients who completed greater than or equal to six cycles showed improved OS compared with those who discontinued before receiving six cycles. These findings support the identification and pre-emptive management of patients at high risk of discontinuing chemotherapy prematurely, to maximize treatment benefit.

Evaluating the real-world effectiveness of the newly approved malaria vaccines, RTS,S/AS01 and R21/Matrix-M, is critical for informing vaccine policy, especially in areas not represented in the original clinical trials. Observational study designs such as cohort studies using the target trial emulation framework or the test-negative design offer promising approaches for estimating vaccine effectiveness in the real world. However, both designs require accurate, individual-level vaccination data, which remains a major challenge in many African countries. Strengthening electronic immunization registries, alongside continued efforts to improve the quality and completeness of paper-based immunization records, is essential in African countries, not only for the evaluation of current vaccines such as RTS,S/AS01 and R21/Matrix-M, but also in preparation for future malaria vaccines, to support robust vaccine monitoring and decision-making.

Protocol for a multicentre target trial emulation comparing ketamine and propofol in critically ill adults undergoing emergency intubation.

GLP-1 RA initiation versus metformin and risk of cardiomyopathy in patients with cancer and diabetes treated with chemotherapy, radiation, or immunotherapy: a target trial emulation.

Natural history of self-reported symptoms following SARS-CoV-2 infection: A target trial emulation in a prospective community-recruited cohort.

Recent studies have suggested potential effects on magnesium homeostasis associated with sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RA). We sought to determine whether these effects lead to a reduced risk of hypomagnesemia among adults with type 2 diabetes in clinical practice. We conducted a target trial emulation study using the multi-institutional cohort data from the TriNetX Global Collaborative Network. We compared 1:1 propensity score-matched patients with type 2 diabetes newly initiating SGLT2 inhibitors versus dipeptidyl peptidase-4 (DPP4) inhibitors (n = 718,798), GLP-1 RAs versus DPP4 inhibitors (n = 623,390), and SGLT2 inhibitors versus GLP-1 RAs (n = 702,808) from 2016 to 2024. Propensity scores were estimated using logistic regression models that included baseline covariates such as age, sex, race, comorbidities, and medication and laboratory data. In each comparison, patients receiving DPP4 inhibitors were considered the active-comparator group. The primary outcome was incident hypomagnesemia, defined by clinical diagnosis or serum magnesium <1.80 mg/dL. Patients were followed until the occurrence of an outcome of interest, last clinical visit, death, or the end of database period (March 31, 2025), whichever came first. We found that initiation of SGLT2 inhibitors was associated with a significantly lower risk of hypomagnesemia, compared with both DPP4 inhibitors (Hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.79, 0.82; p < 0.05) and GLP-1 RAs (HR: 0.92; 95% CI: 0.91, 0.93; p < 0.05). Similarly, GLP-1 RA use was associated with a lower risk of hypomagnesemia, compared with DPP4 inhibitors (HR: 0.89; 95% CI: 0.88, 0.91; p < 0.05). These associations were consistent across individual agents within each drug class. The main limitation of our study is that residual confounding inherent to retrospective observational research cannot be completely ruled out. Treatment with SGLT2 inhibitors and GLP-1 RAs was associated with a lower risk of hypomagnesemia, compared with DPP4 inhibitors. These findings suggest that SGLT2 inhibitors and GLP-1 RAs may be preferable options for patients at risk of hypomagnesemia.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) lower serum urate and are associated with a lower risk of recurrent gout flares. We used target trial emulation to compare rates of allopurinol initiation and use of anti-inflammatories (high-dose glucocorticoids, nonsteroidal anti-inflammatory drugs [NSAIDs], colchicine) and diuretics (prototypic serum urate-raising medication) among patients with gout using SGLT2is versus dipeptidyl peptidase 4 inhibitors (DPP-4is) (primary comparator), with glucagon-like peptide 1 receptor agonists (GLP-1RAs) as an alternative comparator. From a general population database, we identified patients with gout and comorbid type 2 diabetes and used Cox proportional hazards and Poisson regressions with inverse probability of treatment weighting to emulate randomization to SGLT2i or DPP-4i/GLP-1RA. We also replicated the analysis in an electronic health record data set with further adjustment for serum urate and BMI. Among 26,739 adults with gout and type 2 diabetes (mean age 66 years), 67% had polypharmacy. Allopurinol initiation was lower among SGLT2i initiators than DPP-4i, with a hazard ratio of 0.62 (95% CI 0.52-0.73). Associations were stronger among those using diuretics at baseline (P for interaction = 0.03) and persisted when comparing SGLT2i with GLP-1RA and accounting for serum urate and BMI in the secondary data set. SGLT2i was also associated with lower rates of high-dose glucocorticoid, NSAID, colchicine, and diuretic dispensing, with rate ratios of 0.78 (95% CI 0.74-0.83), 0.85 (95% CI 0.80-0.92), 0.87 (95% CI 0.83-0.92), and 0.87 (95% CI 0.85-0.89), respectively. For patients with gout and type 2 diabetes, SGLT2is may reduce gout-related medication use, which could, in turn, reduce exposure to the harmful cardiovascular-kidney-metabolic effects of NSAIDs and glucocorticoids in this high-risk population.

Association between glucagon-like peptide-1 receptor agonists and femur fracture risk in type 2 diabetes: A large-scale target trial emulation.

In 2018, France withdrew reimbursement for cholinesterase inhibitors (ChEIs) in Alzheimer's disease, citing modest efficacy, lack of long-term benefit, and safety concerns. This policy shift provided a unique opportunity to assess ChEI effectiveness in real-world settings, by evaluating, among patients treated with ChEI between 01/08/2017 and 01/08/2018, the impact of treatment discontinuation on cognitive decline (MMSE score) and survival. Using the French National Alzheimer's Database (BNA) and Meotis databases, we emulated a pragmatic, intention-to-treat trial comparing patients who discontinued ChEIs after delisting to those who continued treatment, under quasi-experimental conditions. To model cognitive trajectories, we used the inverse probability treatment-weighted (IPTW) cohort and applied mixed-effects models with random intercepts across all follow-up visits. Survival was estimated with a pooled logistic regression including treatment group, follow-up time, and an interaction between treatment and time. The mean difference in MMSE decline between discontinuers and continuers after one year was 0·97 points (95% CI 0·68-1·27, p < 0·001), reaching 1·81 points (0·91-2·71, p < 0·001), after four years. No significant difference in mortality (RR 1·10, 95% CI [0·95-1·29]) was observed over a five-year period. Our findings confirm and extend prior trials by demonstrating the sustained cognitive benefits of ChEIs in a real-world setting. While acknowledging the limitations associated with its retrospective nature, our study argues for reconsidering the 2018 delisting decision, as ChEIs remain safe and clinically relevant for mild-to-moderate Alzheimer's disease. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Early-life socioeconomic status (SES) increases the risk of poor mental health outcomes in adulthood. However, the mechanistic pathways underlying this relationship remain poorly understood. While addressing socioeconomic inequalities remains a long-term goal, identifying specific mediating pathways could reveal more immediate opportunities for effective interventions. Using linked administrative data from New South Wales, Australia (1990-2022), we will emulate a target trial examining the relationship between SES at birth and acute mental health admissions and presentations between the ages of 18 and 25 years. An interventional mediation analysis will be used to examine the effect of multiple mediating pathways, including education, housing stability, child protection contact, parental incarceration and justice system involvement, on the outcome. The analysis will estimate direct and indirect interventional effects, quantifying how much of the SES-mental health relationship could be modified by interventions on specific mediators. This study has received ethics approval from the University of Newcastle (H-2024-0015) and Aboriginal Health and Medical Research Council (2265/24) Human Research Ethics Committees. All dissemination activities will be conducted in accordance with data access agreements and following approval from all relevant data custodians (New South Wales Health System Data Services). Key findings will be communicated to relevant government agencies and policymakers through policy briefs and stakeholder meetings, and publication in appropriate academic journals.

Observational studies have suggested that air pollution is associated with impaired glucose metabolism; yet randomized controlled trials to confirm the causality of this association are ethically and practically unfeasible. We emulated a hypothetical trial to evaluate the effects of sustained reductions in ambient air pollutants on homeostasis model assessment for insulin resistance (HOMA-IR) and fasting glucose (FG) in children and adolescents. Combining target trial emulation with g-computation, we estimated the effects of sustained hypothetical reductions of air pollutants on HOMA-IR and FG compared to no intervention (natural course). Our sample comprised 1417 children aged 2-9 years at baseline (2007/2008) participating in the pan-European IDEFICS/I.Family cohort. Ambient annual average levels of particulate matter<2.5μm (PM2.5), black carbon (BC), and NO2 were estimated at residential addresses using land use regression models. We found a clear dose-response relationship between sustained reductions in PM2.5 and BC and decreasing levels of HOMA-IR and FG. Hypothetically reducing PM2.5 to WHO's recommended annual level of 5μg/m3, the mean HOMA-IR z-score declined by -0.95 (95% CI: -1.65; -0.44). Similarly, lowering BC to 0.8×10-5/m reduced HOMA-IR by -0.36 (95% CI: -0.61; -0.12) and FG by -0.28 (95% CI: -0.50; -0.04). We found no clear evidence of NO2 reductions on HOMA-IR and FG. Even at relatively low pollution levels in our cohort, further reductions in PM2.5 and BC can improve HOMA-IR and FG levels in children and adolescents. Our findings provide evidence for the development of BC recommendations for air quality guidelines.

Background: The efficacy of corticosteroids in septic shock remains a subject of intense debate, with the two largest randomized trials ADRENAL and APROCCHSS yielding conflicting results regarding mortality. We hypothesized that hydrocortisone specifically confers a survival benefit in patients with high disease severity and refractory shock. We tested this hypothesis using a Target Trial Emulation framework on a large real-world cohort. Methods: We conducted a retrospective cohort study using the MIMIC-IV v3.1 database (2008–2019). We identified adult patients with septic shock requiring high-dose vasopressors (norepinephrine equivalent &gt; 0.25 mcg/kg/min). Patients were classified into two treatment strategies: (1) Hydrocortisone Group (initiation of intravenous hydrocortisone ~200 mg/day within 12 hours of shock onset) versus (2) Standard Care (no corticosteroids). The primary endpoint was 28-day all-cause mortality. We employed Inverse Probability of Treatment Weighting (IPTW) to adjust for confounding by indication, balancing baseline characteristics including SOFA score and lactate levels. Results: The final analyzable cohort included 4,200 patients. The Hydrocortisone group (n=1,680) exhibited significantly higher baseline severity (mean SOFA score 12.0 vs. 9.0) compared to the Standard Care group (n=2,520). After weighting, standardized mean differences for all covariates were &lt; 0.1, indicating excellent balance. Early hydrocortisone initiation was associated with a significant reduction in 28-day mortality (Adjusted Hazard Ratio [HR] 0.60; 95% CI, 0.50–0.72; p &lt; 0.001). Sensitivity analysis yielded an E-value of 2.73, suggesting robustness to unmeasured confounding. Subgroup analysis demonstrated that the survival benefit was most pronounced in patients with SOFA scores &gt; 10. Conclusion: In this large emulation of a target trial, early hydrocortisone administration was associated with a significant survival benefit in patients with severe, refractory septic shock. These findings support the use of corticosteroids in high-acuity patients, aligning with the results of the APROCCHSS trial.