Guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) reduces mortality rates but remains widely underused. A polypill for HFrEF has been proposed as an implementation strategy to improve GDMT delivery, but little is known about physicians' preferences in the design of HFrEF polypills. Discrete choice experiments (DCEs), in which survey respondents choose among hypothetical products, are a powerful tool in health economics research and can lend insight into key tradeoffs in HFrEF polypill design. However, the process of designing DCEs is complex and often poorly reported.

We developed a survey instrument, including a DCE, through a 5-stage mixed-methods process including (1) literature review; (2) physician interviews and surveys; (3) attribute generation; (4) expert review; and (5) pilot testing. We applied a D-efficient design approach using a multinomial logic model to determine the number of choice tasks for the DCE.

We designed a DCE with 4 attributes: HFrEF polypill out-of-pocket cost, inclusion of an angiotensin converting enzyme inhibitor, angiotensin receptor blocker, or sacubitril/valsartan, ancillary support for polypill prescribing, and pharmacy availability. The final survey will be distributed to cardiologists in academic and Veterans Administration medical centers across the United States.

Through a rigorous multistage design process leveraging mixed methods, we developed a DCE that elicits cardiologists' preferences about HFrEF polypills and key tradeoffs in their design. Results from this DCE study will directly inform future HFrEF polypill cluster-randomized clinical trials.

To investigate the prognostic value of the systemic inflammation response index (SIRI) for major adverse cardiovascular events (MACE) among adults with metabolic syndrome (MS), and to determine whether MS status modifies the association between SIRI and incident MACE.

This prospective cohort study enrolled 3,198 participants from Pudong New Area, Shanghai, with a median follow-up of 43 months. Baseline characteristics were compared across SIRI quartiles stratified by MS status. Multivariable Cox proportional hazards regression models were constructed to evaluate the independent association between SIRI and MACE. Restricted cubic spline (RCS) analysis was performed to examine the dose-response relationship. Interaction analyses were conducted to assess effect modification by key metabolic components.

Of 3,198 participants, 1,318 had MS and 1,880 did not. Higher SIRI quartiles were associated with unfavorable metabolic profiles in both groups. Compared with non-MS participants in the lowest SIRI quartile, participants with MS in the highest SIRI quartile exhibited the greatest risk of MACE (HR = 2.33, 95% CI: 1.64-3.30, P < 0.001). Among participants with MS, the highest quartile demonstrated a 38% elevated risk compared with the lowest quartile (HR = 1.38, 95% CI: 1.08-1.77, P = 0.01). RCS analysis indicated a linear positive association between SIRI and MACE risk among participants with MS (P for overall association = 0.02). A significant non-linear interaction was identified between SIRI and fasting plasma glucose (P for interaction = 0.04).

Elevated SIRI is independently associated with an increased risk of incident MACE, and MS status significantly modifies this association. SIRI represents a promising and readily available biomarker for cardiovascular risk stratification, especially among individuals with MS. Combined interventions targeting systemic inflammation and glycemic control may reduce the risk of MACE in this high-risk population.

Optimal management of patent ductus arteriosus (PDA) in premature infants remains debated, and the long-term impact of different strategies has not been well studied. We previously conducted a randomized clinical trial comparing nonintervention (NI) and oral ibuprofen (IBU) for hemodynamically significant PDA in preterm infants, which showed no significant difference in bronchopulmonary dysplasia or death during hospitalization. In this study, we aimed to present a prespecified longitudinal follow-up investigation to assess the outcomes of persistently open PDA at discharge, as well as growth and neurodevelopmental outcomes at 2 years' corrected age (CA), based on PDA management strategy.

Surviving infants from the original trial were evaluated at 2 years' CA. Examiners blinded to the management group assessed spontaneous ductal closure after hospital discharge, growth parameters, and neurodevelopmental outcomes.

Among 130 survivors, open PDA at discharge was present in 7/66 (11%) NI and 2/64 (3%) IBU infants; spontaneous closure occurred in 3/7 NI infants but 0/2 IBU infants. Device closure occurred in 6% (4/66) of the NI group and 3% (2/64) of the IBU group (P = 0.680) by 2 years' CA. Growth parameters-height, weight, and head circumference-did not differ significantly between groups. Neurodevelopmental impairment-defined as cerebral palsy, hearing or visual loss, or a Bayley Scales of Infant Development II mental or psychomotor development index below 70-was present in 15% (10/66) of the NI group and 22% (14/64) of the IBU group (P = 0.371).

This follow-up study demonstrated that NI for hemodynamically significant PDA in preterm infants resulted in growth and neurodevelopmental outcomes at 2 years' CA similar to those seen with IBU treatment. The high rate of spontaneous PDA closure and lack of significant differences in long-term morbidities support the safety of NI and raise questions about the benefit of routine pharmacologic closure.

To determine which primary endovascular revascularisation strategy represents the most clinical and cost-effective treatment for patients with chronic limb threatening ischaemia who require an endovascular femoro-popliteal, with or without an infra-popliteal revascularisation.

Three-arm open-label pragmatic multicentre randomised phase 3 superiority trial.

Thirty-five UK NHS vascular units.

Patients with chronic limb threatening ischaemia who required an endovascular femoro-popliteal with or without an infra-popliteal revascularisation.

Participants were randomly assigned (1 : 1 : 1) to either a femoro-popliteal plain balloon angioplasty with or without bare metal stenting (considered as control or reference), or a drug-coated balloon angioplasty with or without bare metal stenting, or a drug-eluting stenting first revascularisation strategy.

The primary outcome was amputation-free survival defined as time to first major amputation or death from any cause. Secondary outcomes included overall survival, limb salvage, major adverse limb events, major adverse cardiac events and other pre-specified clinical and patient reported outcome measures. Serious adverse events were collected up to 30 days following the first revascularisation procedure.

Between 29 January 2016 and 31 August 2021, 481 participants [167 (35%) women] of mean age 71.8 years (standard deviation 10.8) were randomised. Major amputation or death occurred in 106 of 160 (66%) participants in the plain balloon angioplasty ± bare metal stenting group, 97 of 161 (60%) participants in the drug-coated balloon angioplasty ± bare metal stenting, and 93 of 159 (58%) participants in the drug-eluting stenting group [adjusted hazard ratios: plain balloon angioplasty ± bare metal stenting vs. drug-coated balloon angioplasty ± bare metal stenting: 0.84 (97.5% confidence interval 0.61 to 1.16), p = 0.22; plain balloon angioplasty ± bare metal stenting vs. drug-eluting stenting: 0.83 (97.5% confidence interval 0.60 to 1.15), p = 0.20]. There were no differences in serious adverse events between the groups. There were no differences in mortality when drug technology arms were pooled versus plain balloon angioplasty ± bare metal stenting. When compared to plain balloon angioplasty, drug-eluting stenting was less costly [-£724 (95% confidence interval -£4975 to £2631)] and resulted in additional 0.048 quality-adjusted life-years (95% confidence interval -0.060 to 0.148). Drug-coated balloon angioplasty was unlikely to be a cost-effective option (probability 52% of being cost-effective at £20,000 per quality-adjusted life-year) while drug-eluting stenting was potentially cost-effective (probability 76% of being cost-effective at £20,000 per quality-adjusted life-year).

Neither drug-coated balloon angioplasty ± bare metal stenting, nor drug-eluting stenting, conferred significant clinical benefit over plain balloon angioplasty ± bare metal stenting when used in the femoro-popliteal segment in patients undergoing femoro-popliteal ± infra-popliteal endovascular revascularisation for chronic limb threatening ischaemia. Drug-eluting stenting and drug-coated balloon angioplasty in chronic limb threatening ischaemia patients were found to offer moderate benefits in health economic outcomes particularly when drug-eluting stenting was compared to plain balloon angioplasty.

This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 13/81/02.

While antihypertensive treatment prevents cardiovascular events, it may also increase risks such as falls in patients with frailty. The Optimising Treatment for Mild Systolic Hypertension in the Elderly (OPTiMISE) trial found that deprescribing one antihypertensive drug did not result in worse short-term blood pressure control and long-term follow-up showed no observed harm, but its generalisability to routine clinical practice remains uncertain.

This study aimed to calibrate the OPTiMISE effect to a representative primary care population in England.

We calibrated the OPTiMISE treatment effect using inverse probability weighting (IPW) based on trial inclusion likelihood. The trial enrolled 569 adults aged ≥80 years with controlled blood pressure on ≥2 antihypertensive drugs. A target population was reconstructed from electronic health records of 24 participating practices and extrapolated to all English adults aged ≥80 years, prescribed ≥2 antihypertensive drugs, using NHS Digital data. The primary outcome was all-cause hospitalisation or death. Weighted Cox models estimated calibrated hazard ratios (HRs).

The target population included 798 179 individuals (median age 84 years [81-87], 48% female). Compared with OPTiMISE participants, a higher proportion of individuals in target population were overtly frail (25% vs. 11%). After calibration using IPW, deprescribing was not associated with higher risk of hospitalisation or death [calibrated HR 0.94 (95% CI: 0.73-1.22)], similar to the long-term follow-up of OPTiMISE [HR 0.93 (95% CI: 0.76-1.12)], although with a slightly wider confidence interval.

Calibrating OPTiMISE findings to a representative primary care population frailer than the original participants suggests that the original trial findings could be translated into a real-world population.

Iatrogenic transmission of amyloid beta can cause cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD), but the relationship between these phenotypes is unclear.

We retrospectively analyzed standardized neuropsychological and neuroimaging data from 11 patients with iatrogenic CAA (iCAA). Brain MRI was assessed for medial temporal lobe atrophy (MTA), the posterior atrophy score for parietal atrophy, and global cortical atrophy (GCA).

All patients (mean age 42 ± 8.3 years) had childhood neurosurgery; 91% had confirmed cadaveric dura exposure. Six patients (55%) presented with intracerebral hemorrhage, and none showed MTA, parietal atrophy, or GCA at presentation. Over a median 5-year follow-up, 8/11 (73%) developed atrophy on at least one score, moderate to severe in three patients. Cognitive impairment was present in 9/11 (82%) at a median 3-year follow-up. AD was confirmed histopathologically in 2/4 (50%) examined cases.

Progressive brain atrophy and cognitive impairment are common in iCAA, suggesting frequent co-existing neurodegeneration and possible AD pathology. Vigilance for cognitive decline may enable earlier identification and management.

Obesity is a well-known heart failure (HF) risk factor, yet the biological pathways linking adiposity indices to HF remain unclear. This study aimed to identify proteomic mediators for five novel indices-waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHTR), body roundness index (BRI), weight-adjusted waist index (WWI), and translate mechanistic differences into clinical practice.

Using UK Biobank data, we applied Cox regression and linear regression to identify proteins associated with both HF and each index, followed by mediation and GO enrichment analyses.

All five indices were associated with HF, with WHR and WHTR showing the strongest links. Shared pathways included angiogenesis and cardiac development. Each index occupied a distinct position along a pathological continuum: BRI (cell surface-related) as the upstream driver of early adipose dysfunction; WHR (inflammatory-fibrotic cascade) and WHTR (developmental-metabolic-inflammatory-hormonal) as intermediate downstream markers; WWI (vascular development) and WC (extracellular matrix remodeling) as terminal downstream markers of established organ damage.

Each indicator occupies a distinct position in HF progression, offering unique mechanistic insights into its onset, and thus enabling individualized risk assessment and mechanism-based interventions for obese patients.

We aimed to examine the association between insulin resistance (IR) and target organ damage (TOD) in patients with hypertension. Three indices of IR (Triglyceride-Glucose index: TyG; triglyceride-to-HDL ratio: TG/HDL-C; Metabolic Score for Insulin Resistance: METS-IR) were examined for their association with TOD in 614 newly diagnosed patients with hypertension. Left ventricular mass index (LVMI), the intima-media thickness of the common carotid artery (IMT-CCA) and estimated Glomerular Filtration Rate (eGFR) were used as indices of cardiac, artery and renal damage. Receiver Operating Characteristic (ROC) analysis performed to estimate optimal cut-off for each index, while simple and multiple logistic regression models were applied to examine the indices as binary predictors of organ damage. Linear and non-linear associations were examined with continuous variables using linear regression and restricted cubic splines (RCS) models. After adjusting for confounders, logistic regression showed that high TG/HDL-C (OR:1.50, 95%CI:1.03-2.18) and METS-IR (OR:2.17, 95%CI:1.50-3.13) were associated with increased risk of left ventricular hypertrophy, while only high METS-IR was associated with increased risk of carotid plaque (OR:2.07, 95%CI:1.17-3.68) and only high TG/HDL-C was associated with renal damage (OR:2.33, 95%CI:1.02-5.36). Adjusted linear regression showed that none of the indices were significantly associated with LVMI. However, all indices were associated with CCA-IMT (p < 0.05), but none with eGFR (p > 0.05). Adjusted RCS models showed a significant non-linear association between TyG and CCA-IMT (p for non-linearity = 0.009). In conclusion, IR biomarkers are of clinical value in newly diagnosed patients with hypertension.

Aging remodels hippocampal transcriptional architecture by upregulating neuroinflammatory gene programmes and suppressing neuronal and metabolic networks, increasing ischemic injury susceptibility. Environmental enrichment (EE), a non-pharmacological intervention known to promote brain plasticity, has not previously been assessed at a systems level against aging- and stroke-associated co-expression programmes. Weighted gene co-expression network analysis (WGCNA) was applied to hippocampal RNA-seq data (GSE302188), yielding 45 modules, 24 of which were significantly age-associated (FDR < 0.05). Ten Age-UP modules were enriched for neuroinflammatory and immune activation pathways, nine Age-DOWN modules showed heterogeneous profiles including ribosomal RNA processing, and nominal enrichment for synaptic organisation pathways. Gene set enrichment analysis against an independent stroke dataset (GSE137482) identified 29 stroke-engaged modules (FDR < 0.05-0.25), 18 of which were Age-Neutral, indicating largely distinct aging and stroke transcriptional signatures. Cell-type deconvolution using MuSiC confirmed that age-associated module trajectories reflect coordinated within-cell transcriptional reprogramming rather than shifts in hippocampal cellular composition. In young adult mice (GSE95740; 3 months), EE did not preferentially reverse the concordantly dysregulated aging-stroke modules. To evaluate EE effects on established aging programmes, module eigengenes from an independent aged dataset (PRJEB58981;17 months) were projected onto the aging reference trajectory. EE partially opposed age-suppressed co-expression programmes but did not suppress the neuroinflammatory (turquoise) or interferon (sienna3) modules most strongly implicated in the aging-stroke overlap. Collectively, EE engaged hippocampal co-expression architecture principally through plasticity- and glial-related mechanisms. These findings identify complement and interferon signalling as priority targets for adjunctive pharmacological strategies in aged stroke-vulnerable populations. Adequately powered studies comparing young and aged animals across EE, stroke, and combined EE-plus-stroke conditions are required to determine EE's potential to suppress the concordant aging-stroke immune substrate represents a fundamental biological boundary or a tractable target in age-matched experimental designs.

Heart failure (HF) is a heterogeneous syndrome with diverse etiologies, yet the metabolic determinants specific to its subtype remain unclear. We performed an integrative multi-omics analysis combining metabolomics, genetics, and single-cell transcriptomics to characterize metabolic signatures of distinct HF subtypes. By applying Mendelian randomization of 1,091 circulating metabolites, we identified distinct metabolic patterns: lipid metabolites, particularly sphingolipids, were associated with increased HF risk, while tricarboxylic acid (TCA) cycle intermediates exhibited potential protective effects. Subtype-specific differences included lipid remodeling in coronary heart disease (CHD)-related HF, TCA metabolism in hypertension (HTN)-related HF, and amino acid pathways in overweight-related HF. Integrative analyses highlighted candidate regulators such as UPP1, NEU3, CBS, SHMT1, PLD2, OGDHL, and SULT1A1/2. Single-cell data revealed cardiomyocyte-enriched expression of OGDHL, which was consistently downregulated in experimental HF models. These findings provide insight into metabolic heterogeneity in HF and identify OGDHL as a potential regulator of cardiac metabolic remodeling.