Hypertensive disorders complicate approximately 5-10% of pregnancies globally, significantly impacting maternal and foetal health. To address the distinct impacts of chronic hypertension and pregnancy-induced hypertension (PIH) on foeto-maternal health, this review delineated their associated distinct risk factors and diagnostic markers, providing evidence-based insights to guide targeted, patient-centred management of hypertensive pregnancies. A systematic search of Web of Science, PubMed, and SCOPUS was conducted using predefined criteria. Observational studies were rigorously screened and quality assessed. Data were extracted and narratively synthesised, with an emphasis on maternal and foetal outcomes, diagnostic modalities, and risk modifiers. The analysis confirmed that intrauterine foetal demise, intrauterine growth restriction, low birth weight, and neonatal as well as maternal mortality are major adverse outcomes of hypertensive pregnancies. The evidence demonstrates that whilst chronic hypertension and PIH confer considerable risk, PIH often results in more sudden and severe clinical deterioration, especially in the absence of vigilant prenatal monitoring and timely intervention. The findings underscored the value of targeted, patient-centred care: women with chronic hypertension benefit from early and sustained surveillance, whereas those with PIH require prompt escalation of monitoring following diagnosis, especially in the second trimester. Notably, comorbid systemic illnesses and advanced maternal age compound risks across hypertension categories, and diagnostic modalities, particularly ultrasound Doppler, are pivotal for early risk stratification and management. Effective management of hypertensive pregnancies requires early identification and individualised monitoring, recognising that chronic hypertension and pregnancy-induced hypertension differ in onset and progression, but both pose significant risks to maternal and foetal health.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a systemic cardiometabolic disorder arising from the convergence of metabolic stress, chronic low-grade (smoldering) inflammation, and vascular pathology. MASLD extends beyond hepatic fat accumulation, and is tightly linked to arterial hypertension and cardiovascular disease, with arterial hypertension acting as a disease modifier that accelerates fibrosis progression and deteriorates long-term outcomes. Emerging evidence suggests that chronic infections, particularly Helicobacter pylori infection, may further amplify this cardiometabolic continuum by sustaining inflammatory signaling, oxidative stress, insulin resistance, and endothelial damage. These mechanisms substantially overlap with crucial pathogenic pathways implicated in MASLD progression and hypertension onset. At the molecular level, AMP-activated protein kinase (AMPK) signaling represents a key integrative axis linking energy homeostasis, inflammation, and blood pressure regulation. Pharmacological AMPK activation, exemplified by imeglimin targeting presenilin enhancer-2, highlights the translational potential of therapies addressing hepatic and vascular injury simultaneously. This perspective summarizes clinical and mechanistic evidence supporting an integrated, systems-based framework in which chronic infection and metabolic stress converge along a shared axis to drive hypertension and MASLD. It underscores the need to incorporate metabolic regulation, cardiovascular risk modification, and selected infectious determinants into future risk stratification models and therapeutic strategies.
Cardiopulmonary transit time (CPTT), the time for blood to circulate from the right to the left ventricle, can be assessed on dynamic Rubidium-82 ([82Rb]) cardiac PET/CT. Given its association with cardiac and pulmonary function, CPTT holds potential as a screening marker for pulmonary hypertension. This study investigated the relationship between CPTT and echocardiographic markers of cardiac function, as well as its association with pulmonary hypertension. In this retrospective single-center study, 111 patients (72 male, 39 female) referred for [82Rb]RbCl-PET/CT and echocardiography within 31 days were included. CPTT, normalized to heart rate (NCPTT), was calculated from peak right and left ventricular [82Rb] activity and examined in relation to patient characteristics and echocardiographic parameters, which were further used to categorize left and right ventricular systolic dysfunction, left ventricular diastolic dysfunction, and signs of elevated pulmonary arterial pressure. Prolonged NCPTT was significantly associated with lower left ventricular ejection fraction and increased body weight (p < 0.05). NCPTT was significantly associated with left and right ventricular systolic dysfunction (OR = 1.21, 95%CI:1.04-1.42, p < 0.05; OR = 1.18, 95%CI:1.04-1.34, p < 0.01), elevated pulmonary arterial pressure (OR = 1.21, 95%CI:1.02-1.44, p < 0.05), and possible pulmonary hypertension (p < 0.05), but not with left ventricular diastolic dysfunction. Our findings suggest that NCPTT may serve as a useful additional marker for assessing cardiac function, particularly ejection fraction, and could help in the evaluation of patients with suspected cardiac systolic dysfunction, as well as the detection of pulmonary hypertension.
Bronchopulmonary dysplasia is a frequent complication of preterm birth and is often associated with the development of pulmonary hypertension (BPD-PH). BPD-PH is a multifactorial disease with variable hemodynamic phenotypes typically characterized by underdeveloped pulmonary vascular networks with altered microvascular function, carrying significant morbidity and mortality in infancy. Advances in neonatal care have improved the survival of preterm infants. Amongst survivors, there is a trend toward resolution of BPD-PH with adequate respiratory support and somatic growth, highlighting the importance of early recognition and intervention to optimize vascular growth potential. However, as this population ages the idea of "resolution" has been brought into question. There is increasing awareness of subclinical or recurrent pulmonary hypertension as survivors of prematurity from childhood through early adulthood suggesting that the vasculature remains at risk throughout life. The natural history of pulmonary vasculature is one of development, growth and aging. Each window presents unique opportunities and potential insults that impact overall BPD-PHseverity and progression. Here we review care of the BPD-PH patient across the lifespan highlighting windows of opportunity to reduce lifetime exposure to pulmonary hypertension.
The study investigates the relationship between sortilin levels and the ApoB/ApoA ratio in military personnel with arterial hypertension. A cross-sectional analytical study involving 120 male military personnel was conducted. Biochemical, hematological, and ELISA measurements were performed. Sortilin, ApoB, ApoB/ApoA ratio, and hs-CRP levels were significantly higher in the hypertensive group and correlated with systolic blood pressure. ROC analysis confirmed their discriminatory performance. Sortilin, ApoB, and hs-CRP are associated with hypertension and may be considered potential markers related to cardiovascular risk. However, due to the cross-sectional design, causal relationships cannot be established, and further large-scale prospective studies are required.
Pulmonary arterial hypertension (PAH) is a hemodynamic disorder that can progress to right heart failure and result in death. This study investigated the molecular mechanisms underlying the onset and progression of PAH to identify potential therapeutic targets. Peripheral blood samples from PAH patients were analyzed to assess serum levels of DKK1 and CKAP4, as well as NF-κB pathway activation. Supernatants from hypoxia-treated pulmonary artery endothelial cells (PAECs), plasmid-transfected cells, and SC75741-treated cells were used to modulate pulmonary artery smooth muscle cells (PASMCs). RT-qPCR, Western blot, and ELISA were employed to quantify DKK1 and CKAP4 expression and evaluate NF-κB pathway activation in PASMCs. EdU staining and CCK-8 viability assay were performed to assess cell proliferation, while DCFH-DA staining and ELISA were used to measure ROS, SOD, and MDA levels. DKK1 and CKAP4 expression were positively correlated, and both were upregulated with increasing pulmonary artery systolic pressure (PASP) in PAH patients. The supernatant from hypoxia-exposed PAECs induced NF-κB pathway activation, cell proliferation, and oxidative stress in PASMCs, effects that were inhibited by siDKK1, siCKAP4, and SC75741. Hypoxia stimulated PAECs to secrete DKK1, which in turn upregulated CKAP4 expression and activated the NF-κB pathway in PASMCs, promoting cell proliferation and oxidative stress.
We previously established an interpretable combinatorial data-mining framework to identify combinations of clinical factors predictive of heart failure. Because hypertension (HT) is a major contributor to heart failure, accurate prediction of new-onset HT is critically important for prevention. To identify combinations of clinical factors predictive of HT onset using a novel limitless-arity multiple-testing procedure (LAMP) and to estimate the probability of developing HT. We analyzed 2,610,286 individuals without HT who underwent annual health check-ups starting in 2005-2015 and were followed for 5 consecutive years without missing data. Using the LAMP method, we systematically identified statistically significant combinations of fewer than four clinical factors associated with HT onset. Among 28,618 subjects used for rule discovery, 4802 combinations predictive of HT onset were identified. The remaining 2,581,668 individuals were classified into one group with no predictive combinations (G0) and 20 groups (G1-G20) according to increasing numbers of predictive combinations. The incidence of HT increased stepwise with the number of predictive combinations, as confirmed by Kaplan-Meier analyses (p < 0.001). Receiver-operating characteristic analysis demonstrated a moderate discriminative performance (area under the curve = 0.69). We identified combinations of routine clinical parameters that predict new-onset HT in the general population. A greater number of matching predictive combinations was associated with a proportionally higher probability of developing HT. This interpretable combinatorial data-mining framework may enable risk stratification for HT and support early preventive strategies.
This study investigates the use of RADA16 hydrogels for delivering carnosic acid (CA) in glaucoma treatment. Rheological tests at 0.5% (w/v), 1% (w/v), and 2% (w/v) concentrations showed significant elasticity, with Young's moduli of 30.18 Pa, 16.22 Pa, and 26.66 Pa, respectively. The 1% (w/v) concentration had the lowest stiffness, ideal for intravitreal injection. SEM revealed the hydrogel's porous microstructure. The RADA16-CA system provided sustained CA release over 72 h, peaking at 6 h. In vitro, high CA concentrations (≥ 256 μg/mL) were cytotoxic, but RADA16 and RADA16-CA enhanced cell proliferation. RADA16-CA demonstrated superior efficacy and biocompatibility. In an acute ocular hypertension model, RADA16-CA improved retinal health in rats by reducing retinal nerve fiber layer thickness, ROS-positive cells, and pro-inflammatory cytokines, while boosting cell survival and antioxidant activity.These findings highlight the potential of the RADA16-CA sustained-release system as an optimized approach for glaucoma treatment.
Pulmonary hypertension (PH) associated with interstitial lung disease (ILD) represents a clinical phenotype of high morbidity and mortality. Early identification is essential to optimize management and improve patients' quality of life. The aim of this study was to describe the clinical, functional, and hemodynamic characteristics of patients with ILD and PH at a specialized center. A retrospective observational study was conducted in a cohort of 20 patients with ILD and PH. Demographic, clinical, pulmonary function, radiological, and hemodynamic data were analyzed, as well as treatment received. Mean age was 70 ± 11 years. The most frequent ILD diagnoses were nonspecific interstitial pneumonia (N:7, 40%) and combined pulmonary fibrosis and emphysema (N:6, 30%). The mean pulmonary artery pressure was 34 ± 9 mmHg. The mean six-minute walk distance was 285 ± 162 meters. Chronic oxygen therapy was required in 60% of patients. Regarding PH treatment, 80% received phosphodiesterase-5 inhibitors and 55% inhaled treprostinil. Patients with ILD and PH have high morbidity and significant functional impairment. Early detection and accurate characterization are key for clinical management. Further studies are needed to define more effective therapeutic strategies. Introducción: La hipertensión pulmonar (HP) asociada a enfermedades pulmonares intersticiales difusas (EPID) representa un fenotipo clínico de alta morbimortalidad. Su identificación temprana es importante para optimizar el manejo terapéutico y mejorar la calidad de vida de los pacientes. El objetivo de este estudio fue describir las características clínicas, funcionales y hemodinámicas de pacientes con EPID e HP en un centro especializado. Materiales y métodos: Estudio retrospectivo, observacional, en una cohorte de 20 pacientes con EPID e HP. Se analizaron datos demográficos, características clínicas, pruebas de función pulmonar, hallazgos radiológicos y hemodinámicos y tratamiento recibido. Resultados: La edad media fue 70 ± 11 años. Los diagnósticos de EPID más frecuentes fueron neumonía intersticial no específica (N: 7, 40%) y síndrome de combinación (N:6, 30%). La media de la presión media de la arteria pulmonar fue de 34 ± 9 mmHg. La distancia media en el test de marcha de seis minutos fue de 285 ± 162 metros. El 60% de los pacientes requería oxigenoterapia crónica. El 80% recibió inhibidores de la fosfodiesterasa tipo 5 y el 55% treprostinil inhalado. Discusión: Los pacientes con EPID e HP presentan una elevada carga de morbilidad y deterioro funcional significativo. La detección temprana de la HP y su caracterización adecuada en estos pacientes, son claves para su abordaje clínico, optimizar el tratamiento y mejorar los desenlaces. Se requieren estudios adicionales para definir estrategias terapéuticas más eficaces en esta población.
Systemic sclerosis (SSc) is a rare systemic disease characterised by progressive fibrosis, vasculopathy, and immune dysregulation, resulting in multiorgan damage. Independently of pulmonary arterial hypertension, cardiac involvement, encompassing myocardial fibrosis, coronary microvascular dysfunction, arrhythmias, conduction disorders, pericardial and valvular disease, and heart failure, represents a frequently underestimated cause of morbidity and mortality. Clinically manifest cardiac disease is observed in 15 to 35% of patients, while subclinical dysfunction is detectable in approximately 70% when advanced screening tools are employed. The annual incidence of sudden cardiac death is estimated at between 1.0% and 3.3%, exceeding the general-population risk by more than tenfold. The pathophysiological framework rests on coronary microvascular dysfunction driven by endothelial injury, ischaemia-reperfusion cycles, and TGF-β-mediated replacement fibrosis, potentiated by autonomic nervous system imbalance and activation of the renin-angiotensin-aldosterone system. Electrocardiographic abnormalities, detectable in 25 to 85% of patients, are independent predictors of mortality, while diastolic dysfunction, present in 18 to 62% of cases, constitutes a robust prognostic marker. Cardiac magnetic resonance imaging has transformed subclinical detection, revealing late gadolinium enhancement fibrosis in the majority of screened patients without a prior cardiovascular diagnosis. Management requires a multidisciplinary approach, integrating SSc-specific adaptation of guideline-directed heart failure therapies, immunosuppression targeting inflammatory and fibrotic pathways, arrhythmia management with implantable devices, and EULAR-recommended cardiovascular risk reduction. This narrative review synthesises current evidence on the epidemiology, pathogenesis, diagnostic evaluation, and therapeutic strategies of cardiac involvement in SSc, highlighting the need for early, systematic, risk-stratified screening and the establishment of dedicated multidisciplinary cardiac teams.
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Primary biliary cholangitis (PBC) is a liver disease frequently associated with extrahepatic manifestations. Although a relationship with kidney dysfunction has been reported, data about PBC and chronic kidney disease (CKD) are limited. We assessed the prevalence and incidence of CKD and identify associated risk factors in patients with PBC. This was a multicenter retrospective study involving 1058 consecutive PBC patients. The presence of metabolic comorbidities, including diabetes, hypertension, and dyslipidemia was collected. CKD was defined as eGFR < 60 mL/min/1.73 m2. Baseline CKD was found in 10% of patients. The number of metabolic factors was associated with progressively lower eGFR levels and higher rates of CKD. Hypertension[OR 2.77 (95%CI 1.60-4.82)], diabetes[OR 2.17(95%CI 1.13-4.18)], ALT[OR 0.92(95%CI 0.88-0.96)], albumin[OR 0.24(95%CI 0.13-0.43)], and platelets[OR 0.996(95%CI 0.992-0.999)] were associated with baseline CKD. CKD was associated with higher mortality (32.1% vs. 7.3%). Seven percent of patients developed CKD. Baseline FIB-4 was associated with CKD incidence: < 1.45: 3% (13/428), 1.45-3.25: 10.2% (31/303), > 3.25: 13.4% (11/82). Baseline eGFR values [OR 0.93(95%CI 0.90-0.96)], cirrhosis [OR 2.31(95%CI 1.09-4.88)], hypertension [OR 2.36 (95%CI 1.14-4.88)], and albumin [OR 0.31(95%CI 0.14-0.72)] were associated with CKD occurrence. Baseline eGFR values [OR 0.90 (95%CI 0.88-0.93)], hypertension at baseline [OR 2.01(95%CI 1.06-3.81)] and progression to cirrhosis [OR 4.50(95%CI 1.96-10.30)] were related to CKD incidence in non-cirrhotic patients. In the absence of comorbidities, maintaining treatment response after follow-up showed 0.9% of de novo CKD (vs. 8%). One of every ten PBC patients showed CKD, mainly related to metabolic factors (hypertension and diabetes), and advanced liver disease (albumin and platelets), increasing the risk of mortality. These conditions were also related to the CKD occurrence, even in non-cirrhotic patients.
To describe a case of inferior ST-segment elevation from massive bladder distension resolving with Foley catheterization in the absence of tachycardia, hypertension, or other hemodynamic evidence of sympathetic activation. A 73-year-old man presented with progressive abdominal distension and markedly decreased urination over several days. Vital signs were notable only for mild hypotension (blood pressure 99/75 mmHg) with heart rate 94 beats per minute and temperature 97.6 °F. Examination revealed a bladder palpable to the xiphoid. An electrocardiogram obtained in response to hyperkalemia (potassium 5.5 mEq/L) unexpectedly demonstrated inferior ST-segment elevation in leads II, III, and aVF with reciprocal depression in leads I and aVL. Computed tomography confirmed massive bladder distension extending to the xiphoid with no obstructing lesion. After discussion with interventional cardiology, Foley catheterization drained approximately 2 L of urine; a repeat electrocardiogram immediately after demonstrated complete resolution of ST-segment changes. Serial high-sensitivity troponin (peak 36 ng/L; reference <22 ng/L) showed no dynamic change. Blood cultures grew Escherichia coli, confirming bacteremic urosepsis. Unlike prior reports attributing bladder-distension-associated electrocardiographic changes to catecholamine surge with tachycardia and hypertension, this case occurred with entirely normal heart rate and no hypertension. A mechanical diaphragmatic mechanism from a bladder distended to the xiphoid is the more plausible explanation. Massive bladder distension can produce inferior ST-segment elevation mimicking ST-elevation myocardial infarction, resolving with decompression even without hemodynamic activation. Emergency physicians should consider this entity in the differential for reversible inferior ST-segment elevation.
This study investigated whether breastfeeding (BF) is associated with a reduction in persistent hypertension (PH) and glucose metabolism impairment in patients with polycystic ovary syndrome (PCOS) who experienced pregnancy-induced hypertension (PIH) and/or gestational diabetes mellitus (GDM). This secondary observational analysis utilized data from two prospective cohort studies involving 241 participants (101 PCOS patients; 140 controls) with a history of GDM and/or PIH. At 18 months post-delivery, patients underwent physical examinations, blood pressure monitoring, and biochemical assays, including oral glucose tolerance tests. Feeding practices were categorized as exclusive BF, partial BF, or formula feeding (FF). Patients with PCOS demonstrated significantly shorter BF durations (9.6 ± 7.0 vs. 12.6 ± 5.9 months; P < 0.001) and lower exclusive BF rates (39.6% vs. 62.9%; P < 0.001) compared to controls. At 18 months, the composite cardiometabolic outcome prevalence was 55.4% in the PCOS group versus 11.4% in controls (P < 0.001). Multivariate analysis identified exclusive BF as a potent independent factor associated with a significantly lower risk (adjusted OR 0.14, 95% CI 0.05-0.38; P < 0.001) of cardiometabolic impairment. Breastfeeding is associated with a significant reduction in long-term cardiometabolic risks in women with PCOS following complicated pregnancies. Supporting and optimizing lactation may represent a valuable non-pharmacological strategy to consider for this high-risk population.
Developmental programming is a key determinant of adult hypertension. Total parenteral nutrition (TPN) can exert nutritional stress during development and cause irreversible programming of metabolism via epigenetic modifications, often caused by imbalances in dietary methyl nutrients. Betaine and creatine (B+C) can increase the availability of methyl groups, but they are not included in commercial TPN formulations. We hypothesized that receiving TPN during early life would increase blood pressure in adulthood and that supplementing TPN with B+C would prevent this programming. Intrauterine growth-restricted neonates (IUGR) have been shown to develop hypertension in adult life; thus, we hypothesized that IUGR would exacerbate the TPN effect. We used 7-d-old normal birth weight female Yucatan miniature piglets (n = 24) that were randomly assigned to the following diets: sow-fed (SowFed), TPN control (TPN-control), and TPN with B+C (TPN-B+C), with 8 IUGR piglets fed TPN as a fourth group (TPN-IUGR). After 2 wk of the experimental diets, all pigs were fed a grower diet until adulthood. At 8 mo, a telemeter was implanted to measure 24-h blood pressure (BP) before and after a 2-wk high salt diet. Although BP was not different between TPN-control and SowFed adult pigs, the addition of B+C to neonatal TPN reduced mean (by 9.5 mmHg) and systolic (by 7.1 mmHg) arterial pressure (P<0.05; ANOVA, Dunnett's comparison to TPN-control) in adulthood. However, the expression of key renin-angiotensin system genes was not altered in adult pigs. The BP parameters increased in response to a high salt challenge in all pigs (by 6.2-15.4 mmHg; P<0.05; paired t-tests), but the neonatal diet did not affect the response. These data collectively suggest that TPN feeding in early life does not alter adult blood pressure but supplementing B+C in TPN may reduce the risk of hypertension.
Comprehensive telehealth is used effectively for treatment-resistant chronic diseases in certain integrated health systems but has seldom been implemented in systems that provide mainly fee-for-service (FFS) care. To examine the effectiveness and implementation of comprehensive telehealth delivered in an FFS environment for patients with uncontrolled type 2 diabetes (T2D) and comorbid hypertension. Pragmatic, randomized, effectiveness-implementation trial. (ClinicalTrials.gov: NCT05120544). 6 academic primary care or endocrinology clinics. Participants had both T2D with hemoglobin A1c (HbA1c) persistently at 8.0% or higher for at least 6 months and hypertension with at least 1 systolic blood pressure (BP) above 140 mm Hg or diastolic BP above 90 mm Hg in the past year. Two 12-month, mobile monitoring-enabled interventions: a self-monitoring control program and a nurse-delivered, comprehensive telehealth program incorporating self-management support and medication management. Primary (HbA1c) and secondary outcomes were evaluated at 12 months. Implementation analyses evaluated fidelity and barriers to intervention delivery. Participants were 64% female and 68% Black. The mean age was 54.5 years, mean HbA1c 9.8%, and mean BP 135/81 mm Hg. The estimated mean change in HbA1c from 0 to 12 months was -0.7 percentage points with self-monitoring and -1.1 percentage points with comprehensive telehealth; the estimated mean between-group difference in HbA1c change at 12 months was -0.4 percentage points (95% CI, -1.0 to 0.3 percentage points). Between-group differences in change in secondary outcomes did not reach statistical significance, except for diabetes self-care (0.4 [CI, 0.0 to 0.9], favoring comprehensive telehealth). The comprehensive program was delivered with suboptimal fidelity (median encounters per participant, 9; fidelity threshold, ≥12); analyses identified barriers to program delivery. Generalizability to dissimilar populations and systems lacking telehealth infrastructure may be limited. Comprehensive telehealth did not substantially lower HbA1c relative to control in this study. Population factors, intervention and control program design, and barriers to FFS implementation of comprehensive telehealth may have contributed to these findings. National Institute of Nursing Research and Duke Clinical & Translational Science Institute.
Patients with unresectable hepatocellular carcinoma have a poor prognosis and treatments with long-term benefits are needed. Anti-PD-L1 or anti-PD-1 plus anti-VEGF or anti-CTLA-4 double combinations are validated, first-line, systemic immunotherapies. We report the preplanned phase 2 results of the phase 2-3 PRODIGE 81-FFCD 2101-TRIPLET-HCC trial investigating the survival outcomes and safety profile of a triple combination of atezolizumab, bevacizumab, and ipilimumab in a first-line setting. This randomised, open-label, phase 2-3 trial enrolled patients aged 18 years or older with unresectable hepatocellular carcinoma without previous systemic therapy at 36 hospitals in France. Patients had at least one measurable untreated lesion per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1), Child-Pugh class A disease, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned (1:1) to receive intravenous treatment every 3 weeks for up to 2 years with atezolizumab 1200 mg plus bevacizumab 15 mg/kg (plus ipilimumab 1 mg/kg for up to four doses), or atezolizumab plus bevacizumab alone. Subsequent follow-up was for a further 2 years. Randomisation was done centrally by the study funder, via an electronic case report form, using the minimisation method, and stratified by centre, ECOG performance status, macrovascular invasion or extrahepatic spread (or both), and baseline α-fetoprotein. We report the non-comparative phase 2 results with a primary endpoint of objective response (complete or partial) within the first 24 weeks of treatment, assessed per investigator by RECIST v1.1, in patients who received at least the first dose of study medication (modified intention-to-treat population); 35 patients in the experimental group needed to have had an objective response at week 24 for the trial to progress to phase 3. Missing data were not replaced. The trial is registered with ClinicalTrials.gov (NCT05665348) and is complete. Between March 9, 2023, and Sept 20, 2024, 229 patients were randomly assigned to treatment and 226 received at least one dose of study medication; 113 patients received atezolizumab plus bevacizumab plus ipilimumab and 113 received atezolizumab plus bevacizumab. 206 (91%) patients were male and 20 (9%) were female. At 24 weeks, 34 (30% [80% CI 24-36]) patients in the atezolizumab plus bevacizumab plus ipilimumab group had an objective response as had 31 (27% [22-34]) patients in the atezolizumab plus bevacizumab group. The trial was therefore stopped and did not progress to phase 3. The most common (>2% of patients) investigator-assessed treatment-related, grade 3-4 adverse events in the atezolizumab plus bevacizumab plus ipilimumab group were colitis (four [4%] patients), confusional syndrome (three [3%]), arterial hypertension (11 [10%]), and asthenia (six [5%]); the most common in the atezolizumab plus bevacizumab group were acute renal failure (three [3%] patients), proteinuria (four [4%]), gastrointestinal bleeding (six [5%]), arterial hypertension (13 [12%]), increased aspartate aminotransferase (three [3%]), increased alanine aminotransferase (three [3%]), and increased lipasaemia (three [3%]). Serious adverse events were reported in 55 (49%) patients in the atezolizumab plus bevacizumab plus ipilimumab group and in 48 (42%) patients in the atezolizumab plus bevacizumab group. Treatment-related adverse events resulting in death occurred in six (5%) patients in the atezolizumab plus bevacizumab plus ipilimumab group and none in the atezolizumab plus bevacizumab group. The addition of ipilimumab to atezolizumab plus bevacizumab did not show any benefit in patients with previously untreated, unresectable hepatocellular carcinoma. These results do not support the addition of low-dose (1 mg/kg) ipilimumab to atezolizumab plus bevacizumab as a first-line treatment in this setting. Fédération Francophone de Cancérologie Digestive.
Aromatase inhibitors (AIs) are standard therapy for postmenopausal women with hormone receptor-positive breast cancer. However, prolonged AI use is associated with increased cardiovascular (CV) risk, including hypertension, and endothelial dysfunction. This study evaluated the longitudinal changes in endothelial function during AI therapy, and whether AI-induced endothelial dysfunction is reversible post-discontinuation. Patients were recruited before or within one month of AI initiation (Pre/early AI), during AI therapy, and after discontinuation (Post-AI) from two prospective studies. Patients with hypertension, hyperlipidemia, diabetes, or tobacco use were excluded. Vascular assessments included peripheral arterial tonometry (EndoPAT) for endothelial function (abnormal if ratio < 1.67) and artery elasticity indices. Estradiol, lipid profiles, and inflammatory markers were also measured. The study included 12 Pre/early AI patients, 67 visits from 41 patients during AI (median 2.89 years on AI), and 9 Post-AI patients (median 4.17 years follow-up). EndoPAT ratio was significantly impaired during AI therapy compared to the Pre/early AI (median: 0.86 vs 2.19). The EndoPAT ratio declined as early as six months and showed a progressive decline over time. Post-discontinuation, the EndoPAT ratio was only partially and not significantly restored (median: 1.08) despite full estradiol restoration and long follow-up. Arterial elasticity showed no significant changes. Systolic blood pressure increased modestly during AI therapy and returned to baseline after discontinuation, while diastolic pressure remained unchanged. Circulating interleukin-6 and tumor necrosis factor-α significantly decreased following AI discontinuation. AI therapy is associated with significant and progressive endothelial dysfunction, which does not fully recover after treatment cessation, highlighting the importance of CV monitoring in patients receiving long-term AI therapy.
Living with multiple long-term conditions (MLTC) is increasingly common, posing challenges for healthcare systems and individuals alike. Identifying clusters of co-occurring conditions has been proposed as key to understanding disease patterns and supporting patient-centred coordinated care. Latent class analysis (LCA) has been suggested as the optimal clustering method for MLTC, based on simulation studies where condition prevalence and correlations were assumed to be constant across clusters. However, real-world data demonstrate substantial variation in both prevalence and inter-condition correlations, particularly when highly prevalent conditions, such as hypertension, coexist with much rarer conditions. The objective of this methodological study was to evaluate the performance and robustness of LCA using real-world data from routinely-collected electronic health records for people hospitalised in North-East England. We investigated the performance and robustness of LCA using information on 60 long-term conditions (LTC). Four analytical approaches were assessed: 1) including all LTC, 2) excluding the most prevalent condition, 3) restricting analyses to the population living with the most prevalent condition and applying LCA to the remaining 59 conditions, and 4) restricting analyses to the population without the most prevalent condition and applying LCA to the remaining 59 conditions. LCA performance was examined using criteria including patient partitioning, condition clustering patterns, and dispersion of condition prevalence across clusters, with further assessment through bootstrap sampling to evaluate reproducibility. Across all approaches, LCA consistently demonstrated strong performance according to these criteria. Excluding or stratifying by the most prevalent condition led to only marginal improvements in the clustering accuracy and stability of the remaining conditions. These findings confirm that LCA remains a robust and reliable method for MLTC clustering in realistic settings where prevalence of different LTC varies markedly and a single dominant LTC is observed. This supports continued use of LCA to understand complex disease patterns and guide future MLTC research. Many people live with two or more long-term health conditions, which can make their care more complex. Researchers often group patients based on patterns of co-existing conditions to better understand these complexities and improve care planning. One commonly used method for this is called latent class analysis (LCA). Previous research has suggested that LCA is a useful way of identifying groups of patients with similar patterns of health conditions. However, this research made assumptions that do not reflect the complexity of real-world health data. In reality, some conditions are very common while others are rare, and the relationships between different conditions may vary. In this study, we used data from electronic health records from a hospital in the UK to test how well LCA performs under more realistic conditions. We also explored whether very common conditions, such as hypertension, affect the results. We found that LCA performs well even when there are large differences in how common conditions are and how they are related to each other. We found no evidence that the presence of one condition that is much more common than others influences the results. These findings suggest that LCA is a reliable method for identifying groups of patients with similar patterns of health conditions in real-world data. This can help researchers and clinicians better understand disease patterns and support more personalised and coordinated care for people living with MLTC.