Vetrano D, De Pascalis A, Tomassetti A
… +6 more, Comai G, Di Nunzio M, Barbuto S, Sinagra G, La Manna G, Cianciolo G
Eur J Intern Med
· 2026 Jun · PMID 42288441
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BACKGROUND AND AIMS: Fibroblast growth factor 23 (FGF23) has been implicated in the excess cardiovascular risk of chronic kidney disease (CKD), but its prognostic value remains uncertain. We conducted a systematic review...BACKGROUND AND AIMS: Fibroblast growth factor 23 (FGF23) has been implicated in the excess cardiovascular risk of chronic kidney disease (CKD), but its prognostic value remains uncertain. We conducted a systematic review and meta-analysis to assess the association of FGF23 with all-cause mortality, heart failure (HF), and atherosclerotic cardiovascular (aCV) events across the CKD spectrum. METHODS: PubMed/MEDLINE and Embase were searched from inception to February 9, 2026. Observational studies enrolling adults with CKD G1-G5, end-stage kidney disease (ESKD), or kidney transplant were eligible if they reported adjusted hazard ratios for baseline intact FGF23 (iFGF23) or C-terminal FGF23 (cFGF23). Random-effects models were used for quantitative synthesis. RESULTS: Forty-one studies were included in the systematic review and 31 studies (25,104 patients) in the meta-analysis. Higher continuous FGF23 was associated with increased all-cause mortality (HR 1.52, 95% CI 1.26-1.83), HF (HR 1.34, 95% CI 1.22-1.58), and aCV events (HR 1.23, 95% CI 1.08-1.41). Assay type contributed importantly to heterogeneity. For mortality, cFGF23 showed a robust association, whereas iFGF23 did not (P<0.001). A similar pattern was observed for HF, with stronger associations for cFGF23. For aCV events, no significant assay-related subgroup difference emerged. Sensitivity analyses using categorical FGF23 were consistent, and in ESKD the highest FGF23 category was associated with higher mortality. CONCLUSIONS: Higher FGF23 levels are associated with adverse cardiovascular outcomes and mortality across the CKD spectrum, but the strength and consistency of these associations vary by assay type. cFGF23 showed more consistent associations, particularly for mortality and HF, although the clinical utility of this finding remains to be established.
Mari PV, Coppola A, Ielo S
… +6 more, Scala R, de Corso E, Ojetti V, Ricci A, Baglioni S, Carriera L
Eur J Intern Med
· 2026 Jun · PMID 42288440
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OBJECTIVE: Biologic therapies for eosinophilic COPD require a blood eosinophil count (BEC) ≥300 cells/µL for eligibility. Landmark trials used a single screening measurement, yet BEC exhibits substantial within-patient v...OBJECTIVE: Biologic therapies for eosinophilic COPD require a blood eosinophil count (BEC) ≥300 cells/µL for eligibility. Landmark trials used a single screening measurement, yet BEC exhibits substantial within-patient variability. The study aimed to evaluate the optimal number of measurements to reliably detect the eosinophilic phenotype in COPD. METHODS: We developed a decision-analytic simulation model using pooled estimates of BEC variability from independent COPD cohorts, with intraclass correlation coefficients (ICCs) pooled using Fisher's z transformation. Persistence data from five cohorts - ECLIPSE, COSYCONET, CHAIN, BODE, and a Swedish cohort - comprising a total of 3347 patients, were used to estimate the probability of detecting BEC ≥300 cells/µL at least once according to the number of serial measurements. RESULTS: Using the ≥300 cells/µL threshold, the pooled COPD population was classified as persistent eosinophilia, 9.2%; intermittent eosinophilia, 32.5%; and never eosinophilic, 58.3%. Among patients with intermittent eosinophilia, one measurement detected BEC ≥300 cells/µL in 43% of cases. Two measurements at 6-month intervals increased detection to 67%, three measurements over 12 months to 81%, and five measurements over 24 months to 94%. Weighted pooled ICCs declined from 0.784 at ≤3 months to 0.570 at ≥36 months, supporting greater variability over longer intervals. CONCLUSIONS: Intermittent eosinophilia affects approximately one-third of patients with COPD and may be missed by single-BEC screening. In this model, three measurements over 12 months achieved ≥80% detection. Integrating historical and prospective BEC values may improve biologic eligibility assessment without delaying treatment decisions.
Eur J Intern Med
· 2026 Jun · PMID 42288439
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The climate crisis is an escalating public health emergency that demands urgent, systemic action from the healthcare sector. This article presents a solution-oriented framework for integrating climate health into clinica...The climate crisis is an escalating public health emergency that demands urgent, systemic action from the healthcare sector. This article presents a solution-oriented framework for integrating climate health into clinical practice, medical education, and health system operations. It outlines the dual role of healthcare as both a contributor to and victim of climate change, with the global healthcare sector responsible for approximately 4.6% of national greenhouse gas emissions. Drawing on the Sustainable Initiatives to Guide Healthcare Transformation (SIGHT) report and the existing evidence base, the article offers actionable strategies for decarbonizing healthcare systems through energy efficiency, sustainable procurement, waste reduction, and climate-resilient infrastructure It also emphasizes the critical role of leadership, interprofessional engagement, and equity-centered design in driving institutional change, while simultaneously acknowledging the importance of aligned policies and transparent reporting to affect change. These strategies reflect a new vision for healthcare leadership, grounded in environmental stewardship, social justice, and a commitment to healing both people and planet.
Serrano-Combarro A, Atienza-Mateo B, Martín-Gutierrez A
… +13 more, Paino LI, Casafont-Solé I, Loarce-Martos J, Blanco-Madrigal JM, Ortega-Castro R, Mena-Vázquez N, Fernández-Díaz C, Loricera J, Ferrer-Pargada D, Ferraz-Amaro I, Castañeda S, Blanco R, Spanish Collaborative Group of Interstitial Lung Disease Associated with Rheumatoid Arthritis
Eur J Intern Med
· 2026 Jun · PMID 42276922
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BACKGROUND: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a major cause of morbidity and mortality, and optimal treatment strategies remain unclear. Abatacept (ABA) is supported by observational e...BACKGROUND: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a major cause of morbidity and mortality, and optimal treatment strategies remain unclear. Abatacept (ABA) is supported by observational evidence, but the impact of early initiation on pulmonary outcomes is unknown. METHODS: We conducted a national multicentre observational cohort including 526 patients with RA-ILD treated with ABA across 40 Spanish hospitals. Patients were classified as early (ABA within 6 months of ILD diagnosis) or late (ABA ≥24 months after diagnosis). Longitudinal changes in forced vital capacity (FVC), diffusing capacity for carbon monoxide (DLCO), high-resolution CT (HRCT), dyspnoea, RA activity, glucocorticoid use, safety, and drug retention were analysed using mixed-effects models adjusted for confounders. Timing of ABA initiation was evaluated both categorically and continuously. FINDINGS: Median follow-up was 24 [8-48] months. Pulmonary function remained stable: 77% of patients showed improvement or stabilisation in FVC and 72% in DLCO, while HRCT improved or stabilised in 69%. No significant differences were observed between early and late groups in FVC or DLCO. However, each additional month of delay in ABA initiation was associated with greater DLCO decline (β=-0.002402; 95% CI -0.004287 to -0.000517; p = 0.013), equivalent to an additional 2-3% annual loss per year of delay. No association was found for FVC. DAS28-ESR decreased and prednisone dose was reduced. ABA retention was 83% with a favourable safety profile. INTERPRETATION: ABA stabilised lung function, improved RA control, and reduced glucocorticoid use. Earlier initiation was associated with better DLCO preservation in adjusted analyses, suggesting a possible pulmonary 'window of opportunity' in RA-ILD that warrants confirmation in future prospective studies.
Guldan M, Shah E, Al-Shiab R
… +3 more, Ozbek L, Covic A, Kanbay M
Eur J Intern Med
· 2026 Jun · PMID 42276920
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BACKGROUND: Frailty is a state of vulnerability that emerges from cumulative, non-genetic influences acting across the life course. This review applies an exposome lens, integrating general external exposures, specific e...BACKGROUND: Frailty is a state of vulnerability that emerges from cumulative, non-genetic influences acting across the life course. This review applies an exposome lens, integrating general external exposures, specific external exposures, and internal biologic processes. We aimed to synthesize how social, environmental, behavioural, clinical, and biological exposures contribute to frailty and identify clinically actionable prevention targets. METHODS: This structured narrative review synthesized epidemiological, clinical, environmental, and mechanistic evidence linking exposome-related exposures to frailty in older adults. Literature was identified through targeted searches of PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, supplemented by reference screening. Evidence was organized across exposome domains and narratively appraised according to study design, temporality, consistency, biological plausibility, and clinical relevance. RESULTS: Socioeconomic disadvantages, loneliness, and social isolation are consistently associated with higher frailty risk, whereas green and walkable environments may support healthier aging through mobility and social participation. Protective factors include specific high-quality dietary patterns and physical activity, whereas ultra-processed foods, sedentary behaviour, air pollution, climate stressors, infections, and selected chemical exposures are linked to adverse outcomes. Cardiometabolic, cardiorespiratory, and neurological vulnerability further connect external exposures with frailty progression. Internal pathways, including chronic inflammation, mitochondrial dysfunction, endocrine-metabolic dysregulation, gut microbiome dysbiosis, and epigenetic aging support plausible mechanistic pathways through which exposures may contribute to frailty. CONCLUSION: Exposome-informed frailty care should combine validated frailty assessment with brief screening for actionable risks, including social connection, diet, physical activity, pollution and temperature vulnerability, infection history, vaccination status, and chronic disease burden. Practical strategies include social prescribing, healthier dietary patterns (e.g., Mediterranean-style diets), physical activity in green and low-pollution spaces, seasonal health planning, vaccination, and cardiometabolic optimization.
Acevedo Monsanto MA, Zuberi EC, Bui A
… +4 more, Coutinho MV, Lopez CM, Mao MA, Shair K
Eur J Intern Med
· 2026 Jun · PMID 42270491
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Accurate assessment of kidney function is essential in hospitalized patients. However, serum creatinine does not always reflect true kidney function because it can be influenced by factors such as muscle mass, diet, and...Accurate assessment of kidney function is essential in hospitalized patients. However, serum creatinine does not always reflect true kidney function because it can be influenced by factors such as muscle mass, diet, and medications. When creatinine-based estimates are unreliable, cystatin C may serve as a useful complementary marker for internists. Compared with creatinine, cystatin C is less affected by these factors and may respond more rapidly to changes in glomerular filtration, which can improve recognition of kidney dysfunction and help refine chronic kidney disease (CKD) staging in hospitalized patients. In addition, cystatin C has prognostic value in heart failure, where elevated levels have been associated with higher risks of mortality and hospitalization. Together, these findings support the selective use of cystatin C for risk stratification and clinical decision-making in appropriate inpatient settings.
Brucato F, Tognola C, De Censi L
… +10 more, Andrian E, Tacchetto A, Invernici B, D'alesio S, Gheda S, Capsoni N, Galbiati F, Michele B, Giannattasio C, Maloberti A
Eur J Intern Med
· 2026 Jun · PMID 42270489
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BACKGROUND: Cardiological Hypertensive Emergencies (CHE) are characterized by markedly elevated blood pressure (BP) values associated with acute cardiac hypertension-mediated organ damage (acute coronary syndrome, acute...BACKGROUND: Cardiological Hypertensive Emergencies (CHE) are characterized by markedly elevated blood pressure (BP) values associated with acute cardiac hypertension-mediated organ damage (acute coronary syndrome, acute heart failure, acute pulmonary edema, or aortic dissection). This study aimed to evaluate the prevalence, clinical features and real-world BP management of CHE and to assess adherence to guideline recommendations by comparing ED practice before and after recent guideline release (2017 vs 2019). METHODS: This single-center retrospective analysis included all adult patients admitted to the ED of Niguarda Hospital, Milan, during 2017 and 2019 with severely elevated BP (SBP ≥180 mmHg and/or DBP ≥120 mmHg) and acute cardiological organ damage. Target achievement was defined as ≥25% SBP reduction for 2017 and SBP <140 mmHg (<120 mmHg for aortic dissection) for 2019. RESULTS: 282 CHE were analysed representing nearly half of all hypertensive emergencies in both years. Nitroglycerin was the predominant intravenous therapy used. Short-acting nifedipine use strongly decrease from 2017 to 2019. Baseline BP values were 193.2/95.2 ± 14.2/17.4 mmHg and decreased significantly during the ED stay (∆ 37.4/17.1 vs 26.0/20.4 mmHg). The proportion of patients achieving guideline-defined targets was lower in 2019, reflecting the introduction of more stringent BP goals. CONCLUSIONS: This real-world analysis demonstrates a persistent gap between guideline recommendations and clinical practice in the management of CHE. The reduced target achievement in 2019 suggests that the adoption of aggressive BP targets remains incomplete, potentially due to concerns regarding hypoperfusion, limited dissemination of guideline updates or differences in documentation.
Marques P, Vasques-Nóvoa F, Pintalhão M
… +11 more, Bergantim R, Mendonça L, Neves JS, Friões F, Sharma A, Filipatos G, Butler J, Anker S, Zannad F, Packer M, Ferreira JP
Eur J Intern Med
· 2026 Jun · PMID 42259701
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BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) use increase hemoglobin, and some patients may develop or aggravate polycythemia. Whether the presence or development of polycythemia impact the cardiorenal...BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) use increase hemoglobin, and some patients may develop or aggravate polycythemia. Whether the presence or development of polycythemia impact the cardiorenal benefits of SGLT2i across different cardio-kidney-metabolic (CKM) populations is unknown. AIMS: Assess the proportion of patients with polycythemia both at baseline and during follow-up, study the risk factors for its occurrence, and whether the SGLT2i effect may vary by polycythemia status. METHODS: Pooled analysis of placebo-controlled trials: EMPEROR-Preserved, EMPEROR-Reduced, EMPA-REG OUTCOME, CANVAS-R, and CREDENCE. Polycythemia was defined as a hemoglobin>16.5g/dL in men or >16.0g/dL in women. Multivariable-adjusted Cox models were applied, stratified by trial, to study the association of polycythemia at baseline and week 52 on clinical outcomes, including treatment-by-polycythemia interaction. Primary outcome was the composite of non-fatal stroke or myocardial infarction or cardiovascular mortality. RESULTS: 26,064 patients were included with 723 (2.8%) and 1,324 (6.3%) presenting polycythemia at baseline and 52 weeks, respectively. Smoking and obstructive lung disease associated with polycythemia at baseline, and randomization to SGLT2i (vs placebo) associated with a 6-fold increased risk of polycythemia at week-52 (OR 6.44 95%CI 5.42-7.65). Polycythemia (vs no polycythemia) at baseline and week-52 was associated with an increased risk of the primary outcome (HR 1.35 95%CI 1.09-1.66 and HR 1.42 95%CI 1.15-1.74, respectively), but not with heart failure (HF) hospitalizations. No statistical evidence of treatment effect modification (SGLT2i vs placebo) was observed in patients with pre-existing of incident polycythemia across cardiovascular outcomes (interactionP>0.1 for all cardiovascular outcomes). CONCLUSION: Polycythemia was associated with higher risk of atherosclerotic events. While careful evaluation is warranted, the benefits of SGLT2i were not modified in a significant manner among those with pre-existing or who develop polycythemia after treatment initiation.
Dankl D, Bruno RR, Beil M
… +18 more, Flaatten H, Kelm M, Sigal S, Szczeklik W, Elhadi M, Joannidis M, Koköfer A, Schreiber B, Singhartinger F, Oeyen S, Marsh B, Moreno R, Leaver S, De Lange DW, Guidet B, Boumendil A, Jung C, Wernly B
Eur J Intern Med
· 2026 Jun · PMID 42250989
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BACKGROUND: Evidence on sex-related mortality differences in critically ill older adults is inconsistent, and frailty is rarely incorporated despite its major prognostic relevance in geriatric intensive care. METHODS: We...BACKGROUND: Evidence on sex-related mortality differences in critically ill older adults is inconsistent, and frailty is rarely incorporated despite its major prognostic relevance in geriatric intensive care. METHODS: We performed a pooled analysis of acute ICU admissions from three prospective multinational cohorts within the Very Old Intensive Care Patients project: VIP1 and VIP2, which enrolled patients aged 80 years or older, and COVIP, which enrolled patients aged 70 years or older with COVID-19. Frailty was assessed before the acute illness using the Clinical Frailty Scale. The primary endpoint was 30-day mortality. Associations between sex and mortality were examined using robust Poisson regression adjusted for age, frailty, Sequential Organ Failure Assessment score, organ support, and treatment limitations, with Bayesian models used to estimate posterior probabilities of clinically relevant effect sizes. RESULTS: Among 10,363 acute ICU admissions, 43% were women. Women were older and more often frail, whereas men more frequently received invasive mechanical ventilation, vasopressors, and renal replacement therapy. Crude 30-day mortality was higher in men than in women (44%vs. 40%). Frailty was a strong independent predictor of mortality, with each 1-point increase in the Clinical Frailty Scale associated with an 8% increase in adjusted mortality risk (incidence-rate ratio 1.08, 95% CI 1.06-1.10). After multivariable adjustment for frailty and clinical covariates, male sex remained associated with a small residual increase in 30-day mortality (incidence-rate ratio 1.08; 95% CI 1.01-1.15). This association was attenuated with greater illness severity and more intensive organ support. Bayesian analyses yielded adjusted posterior median incidence-rate ratios of 1.04 to 1.06, and the probability of at least 10% excess mortality in men was low after adjustment (2% to 13%). CONCLUSIONS: In older critically ill adults, pre-admission frailty is a major driver of mortality. After explicit adjustment for frailty and illness severity, male sex was associated with only a small residual increase in 30-day mortality. Bayesian analyses suggest that large clinically meaningful sex-based mortality differences are unlikely after accounting for case mix and treatment intensity.
Scalvini S, Donati V, Zanelli E
… +5 more, Giudici V, Viscardi L, D'Isa S, Trevisan R, Bernocchi P
Eur J Intern Med
· 2026 Jun · PMID 42250988
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BACKGROUND: Heart failure (HF) and type 2 diabetes (T2DM) are significant public health concerns. This study evaluated a 6-month home-based telemedicine program for older patients with combined HF and T2DM. The primary o...BACKGROUND: Heart failure (HF) and type 2 diabetes (T2DM) are significant public health concerns. This study evaluated a 6-month home-based telemedicine program for older patients with combined HF and T2DM. The primary outcome was exercise tolerance evaluated at the 6-minute walk test (6MWT). Secondary outcomes included improvements in the physical activity profile (PASE), quality of life, clinical parameters, and biomarkers. METHODS: Patients were randomized into an Intervention (IG) or a Control (CG) Group. The IG received teleassistance from a nurse case manager, including telemonitoring and an app for medication adherence and symptom reporting. The CG received the usual care. RESULTS: 163 patients (84% male) were included 82 (71 ± 9 years) in the IG and 81 (74 ± 8 years) in the CG. After six months, the IG showed a mean increase of 12.4 meters (95% CI [1.7, 23.1]; p = 0.0168) in the distance walked at 6MWT, while the CG experienced a decrease of -22.4 meters (95% CI [-36, -8.9]; p = 0.0029), with a significant difference between groups of p = 0.0001. The PASE scores in the IG revealed a slight increase (p = 0.2914). Conversely, the CG significantly decreased their PASE scores (p = 0.0242), indicating a meaningful difference (p = 0.0164). No significant changes were observed in the quality-of-life questionnaires. Positive results were obtained on clinical parameters. CONCLUSIONS: The study proposed a home-based Phase III telerehabilitation program to help patients with HF and T2DM to maintain a healthy lifestyle. While technology can be complex for the elderly, its acceptance improves when seen as beneficial.
Esteve-Garcia A, Madrigal I, Aguilera C
… +12 more, Sau C, Aquino V, Barberà JA, Sánchez A, Morte B, Rodríguez-Revenga L, Alvarez-Mora MI, Ribas J, Torres-Iglesias R, Medina AP, Riera-Mestre A, Padró-Miquel A
Eur J Intern Med
· 2026 Jun · PMID 42250987
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BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder most commonly caused by pathogenic variants in ACVRL1 or ENG. Most pathogenic variants are coding missense, nonsense, sp...BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder most commonly caused by pathogenic variants in ACVRL1 or ENG. Most pathogenic variants are coding missense, nonsense, splice-site variants, or small insertions/deletions, as well as exon-level deletions or duplications, and are typically detectable by next-generation sequencing (NGS). However, balanced structural rearrangements and deep intronic variants are not reliably detected by standard exome-based approaches and may contribute to genetically unresolved cases. METHODS: We investigated four unrelated families with clinical features of HHT in whom prior whole exome sequencing (WES) was inconclusive. All affected individuals reported recurrent miscarriages, and further clinical review identified prior karyotype analyses. These cytogenetic findings prompted targeted reanalysis of WES datasets to assess potential disruption of HHT-associated genes. RESULTS: All four families carried an apparently balanced translocation, t(9;12)(p21.2;q13.13). Breakpoint mapping revealed disruption of a CT-rich region within intron 9 of ACVRL1, a known mutational hotspot. Reanalysis of WES data supported ACVRL1 disruption as the likely pathogenic mechanism. The translocation co-segregated with disease in all families and was absent in unaffected relatives. All carriers fulfilled clinical diagnostic criteria for HHT. A history of recurrent miscarriages emerged as a key clinical clue that prompted cytogenetic investigation and enabled molecular diagnosis. CONCLUSIONS: We identify a recurrent translocation, t(9;12)(p21.2;q13.13), that disrupts intron 9 of ACVRL1 and is undetectable by standard exome-based approaches, as a previously unrecognised cause of HHT in genetically unresolved patients. Our findings highlight and support the need to extend genomic testing beyond conventional exome sequencing in unresolved HHT cases.