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Glioblastoma (GBM) is a highly aggressive brain cancer with poor clinical outcome. Unfortunately, chemotherapy with temozolomide (TMZ) has a limited efficacy due to resistance mainly attributed to O6-methylguanine methyl transferase (MGMT) activity. Recently, miR-603 and miR-221 have been identified to target MGMT, thus improving the efficacy of temozolomide (TMZ) in the treatment of GBM. Previously, self-assembling nanoparticles (SANPs) have been proposed to deliver miRNAs into the brain. Here, SANP co-encapsulating miRNA-603 (miR-603) and miRNA-221 (miR-221) have been developed to enhance the efficacy of TMZ in the treatment of GBM by preventing the occurrence of chemoresistance. Preliminarily, SANPs encapsulating miRNAs were optimized in terms of lipid composition to assure physical stability and no hemolytic activity. Subsequently, SANPs with the lowest cytotoxicity and excellent internalization efficiency of miRNAs were selected through MTT assay and real-time PCR, respectively. To evaluate a potential synergistic effect between TMZ and miRNAs, MTT and clonogenic assays were performed. In our biological model, miRNA delivery via SANPs in combination with TMZ treatment strongly reduced cell viability and tumorigenic potential. Finally, in vivo assays were carried out on orthotopic xenograft mouse models. The treatment with SANPs encapsulating both miRNAs in combination with TMZ greatly decreased tumour growth, and even more significantly increased animal survival. In conclusion, this strategy provides the rationale for the development of new therapeutic approaches based on SANP technology to deliver miRNAs that play a key role in suppressing tumour., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Aims: Mineralocorticoid receptor antagonists (MRA) improve outcomes in heart failure with reduced ejection fraction (HFrEF) but are underused. Point prevalent use has been described, but the kinetics of discontinuation and the extent of reinitiation have not been studied., Methods and Results: Patients with HFrEF enrolled in the Swedish Heart Failure Registry between 2006 and 2021 were linked to the Prescribed Drug Register. The rate of discontinuation during the first year of treatment and reinitiation the year after discontinuation were estimated using the Kaplan-Meier method. Multivariable Cox proportional hazards models were used to assess the predictors of discontinuation. Of 11 474 MRA new users, 71% remained on therapy at 1 year. Baseline characteristics independently associated with discontinuation were: estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m 2 (hazard ratio [HR] 1.75, 95% confidence interval [CI] 1.34-2.27), hyperkalaemia (HR 1.73, 95% CI 1.25-2.40), eGFR 30-60 ml/min/1.73 m 2 (HR 1.51, 95% CI 1.37-1.66), age ≥80 years (HR 1.26, 95% CI 1.10-1.43), enrolment as inpatient (HR 1.25, 95% CI 1.14-1.38), a diagnosis of atrial fibrillation (HR 1.24, 95% CI 1.10-1.39), living alone (HR 1.23, 95% CI 1.13-1.34), ischaemic heart disease (HR 1.20, 95% CI 1.09-1.31), anaemia (HR 1.17, 95% CI 1.07-1.29), diabetes mellitus (HR 1.15, 95% CI 1.04-1.27) and New York Heart Association class III-IV (HR 1.13, 95% CI 1.02-1.24). Reinitiation within a year occurred in 46% of cases, mostly within 3 months after discontinuation., Conclusion: Among patients with HFrEF initiated on MRA, 71% remained on therapy at 1 year. Discontinuation occurred early and was more common in patients with advanced kidney disease, hyperkalaemia, lack of follow-up in specialty care, more severe heart failure, comorbidities, and markers of sociodemographic frailty. Among those who discontinued, almost half reinitiated treatment the year following discontinuation., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Long-term outcome of contemporary stress echocardiography has not been systematically assessed., Objective: To evaluate the association between results of stress echocardiography and patients' outcomes with suspected coronary artery disease using randomised controlled trials., Methods: Multiple electronic databases were searched for studies evaluating long-term outcome (>12 months) of stress echocardiography in patients suspected of coronary artery disease since year 2000. A common-effect model was used to derive pooled estimates. The primary outcome was a composite of all-cause mortality or cardiovascular death and non-fatal myocardial infarction, depending on the definition applied in individual trials, termed as major adverse cardiovascular event (MACE). Secondary outcome was all-cause mortality. Positive stress echocardiography result was defined as inducible ischaemia in at least one of the 17 left ventricular segments and negative stress echocardiography with no inducible ischaemia., Results: Among a total of six trials, 16 581 subjects underwent either pharmacological or treadmill stress echocardiography, a median follow-up of 31 months (range 21-101). The annual event rate was 1.76% for the composite MACE and 1.35% for all-cause mortality. Compared with negative stress echocardiography, positive stress echocardiography was associated with an increased risk of the MACE and all-cause mortality with an annual event rate of 1.99% vs 1.54% (OR 2.04, 95% CI 1.79 to 2.33) and 1.68% vs 1.02% (OR 2.06, 95% CI 1.80 to 2.35), respectively., Conclusion: Positive stress echocardiography results were associated with poorer long-term MACE and all-cause mortality. Stress echocardiography results may provide a useful long-term guidance in intensifying preventative treatment in patients with suspected coronary artery disease., Prospero Registration Number: CRD42023416766., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/objective: Balanced reciprocal translocations are structural chromosomal anomalies that involve a mutual exchange of segments between two non-homologous chromosomes with a consequent 50-80% risk of conceiving fetuses with unbalanced chromosomal anomalies. This study describes a 37-year-old woman, at 13 + 5 weeks of gestation, who is a balanced reciprocal translocation 46,XX,t(9;18)(q34;q11.2) carrier, with a high-risk non-invasive prenatal screening test, NIPT, for chromosome 18 aneuploidy., Methods: The highlighted aneuploidy was characterized with cytogenetic, FISH and SNP-array techniques., Results: Cytogenetic analysis, performed on flask-cultured amniocytes, indicated a 48,XX,+2mar karyotype on 50 metaphases. SNP array analysis showed a 15.3 Mb duplication of chromosome 18p (arr[hg19]18p11.32-p11.21(12,842-15,303,932)x4), consistent with a partial tetrasomy 18p, and a 926 kbp duplication of chromosome 9q (arr[GRCh37]9q34.3(140,118,286-141,044,489)x3), consistent with partial trisomy 9q. FISH analysis with a 9q34.3 probe was performed on flask-cultured amniocytes' metaphases, highlighting the presence of a third signal on one of the two marker chromosomes (18p11.32-p11.21)., Conclusions: The evidence of such partial aneuploidies suggests that different mutational events may be possible at meiotic segregation or probably post-meiotic segregation. The results obtained highlight the high sensitivity of the screening test, NIPT, with massive parallel sequencing, and the usefulness of cytogenetics, cytogenomics and molecular biology techniques, in synergy, to characterize and confirm positive NIPT results.

Aims: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) are prevalent comorbidities associated with significant morbidity/mortality. We assessed prevalence of, patient profiles and outcomes associated with COPD across the ejection fraction (EF) spectrum., Methods: HF patients enrolled in the Swedish HF registry between 2005 and 2021 were considered. Multivariable logistic regression models were fitted to assess patient characteristics independently associated with COPD and Cox regression models for investigating the associations between COPD and outcomes, that is, morbidity/mortality., Results: Among 97 904 HF patients, COPD prevalence was 13%, highest in HF with preserved EF [HFpEF: 16%, HF with mildly reduced EF (HFmrEF): 12%, HF with reduced EF (HFrEF): 11%]. Key patient characteristics independently associated with a diagnosis of COPD included higher EF, female sex, smoking, obstructive sleep disorder, peripheral artery disease, a lower educational level, more severe HF, more likely mineralocorticoid receptor antagonist and diuretic use but less likely use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin-receptor-neprilysin inhibitors (not in HFrEF), beta-blockers, HF device therapies, and follow-up in HF nurse-led clinics. COPD was independently associated with a 15% higher risk of cardiovascular (CV) death/HF hospitalization [hazard ratio: 1.15 (95% confidence interval: 1.11-1.18)], CV death, non-CV death, all-cause death and HF hospitalizations, regardless of EF., Conclusions: COPD was present in every eight patient with HF, and more common with preserved EF. Patients with COPD had more severe HF, heavier comorbidity burden and worse morbidity/mortality regardless of EF. Our results call for improved diagnostic and management strategies in patients with HF and COPD., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Data from US have shown a reversal in the improvement of heart failure (HF)-related mortality over the last ~10 years. It is unknown whether these trends generalize to European universal healthcare systems. We assessed temporal trends in (i) HF-related mortality in the overall national population; and (ii) all-cause mortality following an incident HF diagnosis, overall and stratified by ejection fraction (EF), in Sweden between 1997 and 2022., Methods and Results: Annual mortality rates with a HF diagnosis as underlying cause were extracted from the Cause of Death Register. All-cause mortality following incident HF was assessed in two HF cohorts derived from the National Patient Register (NPR) and the Swedish HF Registry (SwedeHF). Temporal trends were presented as average annual percentage change (AAPC). Between 1997 and 2022, age-adjusted HF-related mortality in the general population declined from 33.4 to 23.8 per 100 000 individuals (AAPC -2.15%, p < 0.001). In the HF cohort from NPR (n = 423 092), all-cause mortality at 1, 3, and 5 years following a first diagnosis of HF was 25%, 46%, and 58%, respectively, in 2022; 1-year mortality declined (AAPC -1.10%, p < 0.001) over time regardless of age or sex. In SwedeHF (n = 63 753), the decline in 1-year mortality was less steep with increasing EF (AAPC -2.64%, p < 0.001; -2.30%, p = 0.062; and -2.16%, p = 0.032 in EF <40%, 40-49%, and ≥50%, respectively)., Conclusions: Heart failure-related mortality has declined over the last ~25 years in Sweden. All-cause mortality in patients with HF has also declined, more in HF with reduced than preserved EF, mirroring the different availability of life-saving treatments across the EF spectrum., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The HeartLogic algorithm (Boston Scientific, St Paul, MN) integrates data from implantable cardioverter-defibrillator (ICD) sensors to predict heart failure (HF) decompensation: first (S1) and third (S3) heart sounds, intrathoracic impedance, respiration rate, ratio of respiration rate to tidal volume (RSBI), and night heart rate., Objective: This study assessed the relative changes in ICD sensors at the onset of HeartLogic alerts, their association with patient characteristics, and outcomes., Methods: The study included 568 patients with HF carrying ICDs (CRT-D, n = 410) across 26 centers, with a median follow-up of 26 months. HeartLogic alerts triggered patient contact and potential treatment., Results: A total of 1200 HeartLogic alerts were recorded in 370 patients. The sensor with the highest change at the alert's onset was S3 in 27% of alerts, followed by S3/S1 (25%). Patients with atrial fibrillation (AF) and chronic kidney disease (CKD) at implantation had higher prevalence of alerts (AF, 84% vs no AF, 58%; CKD, 72% vs no CKD, 59%; P < .05) and rate (AF, 1.51 per patient-year vs no AF, 0.88 per patient-year; CKD, 1.30 per patient-year vs no CKD, 0.89 per patient-year; P < .05). During follow-up, 247 patients experienced more than 1 alert; in 85%, the sensor with the highest change varied between successive alerts. Of the 88 (7%) alerts associated with HF hospitalization or death, respiration rate or RSBI (11%, P = .007 vs S3/S1) and night heart rate (11%, P = .031 vs S3/S1) were more commonly the sensors showing the highest change. Clinical events were more common with the first alert (12.6%) than subsequent alerts (5.2%, P < .001)., Conclusion: HeartLogic alerts are mostly triggered by changes in heart sounds, but clinical events are more linked to respiration rate, RSBI, and night heart rate. Recurrent alerts often involve different sensors, indicating diverse mechanisms of HF progression., Competing Interests: Disclosures Dr Dello Russo is consultant for Abbott, Biosense Webster, and Boston Scientific. Dr Santini is consultant for Abbott, Boston Scientific, Medtronic, and Biotronik and is a speaker for Medtronic, Boston Scientific, Abbott, Microport, and Biotronik. Dr Bertini is a consultant for Boston Scientific and Microport; speaker and tutor in training courses for Boston Scientific, Microport, Medtronic, Abbott, Biotronik, Pfizer, Bayer, Daiichi-Sankyo, and Boehringer Ingelheim. Dr Casella has received speaker honoraria from Biosense Webster. Dr Averina, Dr Campari, and Dr Valsecchi are employees of Boston Scientific. The remaining authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims: We explored timing, settings and predictors of angiotensin receptor-neprilysin inhibitor (ARNI) initiation in a large, nationwide cohort of patients with heart failure (HF) with reduced ejection fraction (HFrEF)., Methods and Results: Patients with HFrEF (ejection fraction <40%) registered in the Swedish HF Registry in 2017-2021 and naïve to ARNI were evaluated for timing and location of, and their characteristics at ARNI initiation. ARNI use increased from 8.3% in 2017 to 26.7% in 2021. Among 3892 hospitalized patients, 8% initiated ARNI in-hospital or ≤14 days after discharge, 4% between 15 and 90 days, and 88% >90 days after discharge or never initiated. Factors associated with earlier initiation included follow-up in specialized HF care, more severe HF, previous HF treatment use and higher income, whereas older age, higher comorbidity burden and living alone were associated with later/no initiation. Of 16 486 HFrEF patients, 8.1% inpatients and 5.9% outpatients initiated an ARNI at the index date. Factors associated with initiation in outpatients were overall consistent with those linked with an in-hospital/earlier ARNI initiation; 4.9% of 10 209 with HF duration <6 months and 9.1% of 5877 with HF duration ≥6 months initiated ARNI. Predictors of ARNI initiation in HF duration <6 months were inpatient status, lower ejection fraction, hypertension, whereas previous angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use was associated with less likely initiation. Discontinuation at 1 year ranged between 13% and 20% across the above-reported analyses., Conclusions: In-hospital and early initiation of ARNI are limited in real-world care but still slightly more likely than in outpatients. ARNI were more likely initiated in patients with more severe HF, which might suggest its use as a second-line treatment and only following worsening of clinical status. One-year discontinuation rates were consistent regardless of the timing/setting of ARNI initiation., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Many patients with heart failure (HF) are managed in primary care, and comorbidities are common. Anemia is one frequent comorbidity. The aim of this study was to assess the prevalence, comorbidities, and prognosis of HF patients in primary care who have anemia., Method: We linked data on 9300 patients managed in primary care from the nationwide SwedeHF registry with other Swedish national register data. A multivariable logistic regression model with anemia as a dependent variable was performed. Multivariate Cox proportional hazards regression analysis was used to model the time to event., Results: The median age (IQR) was 81 (74-86) years, and 45 % of the patients were female. A total of 2852 (30.7 %) had anemia. Anemia was more common in men, in those ≥75 years, and in those with kidney dysfunction. A total of 695 (10.8 %) of patients without and 520 (18.2 %) with anemia had cancer. Cancer was independently associated with anemia (OR 1.5, 95 % CI 1.3-1.7). Other comorbidities significantly associated with anemia were peripheral artery disease (OR 1.39, 95 % CI 1.18-1.65), diabetes (OR 1.29, 95 % CI 1.16-1.44), and liver disease (OR 1.64, 95 % CI 1.09-2.46). If anemia was present, prognosis was worse. Risk of all-cause hospitalization was higher (adjusted HR 1.3, 95 % CI 1.2-1.4), as was risk of all-cause mortality (adjusted HR 1.4, 95 % CI 1.3-1.5)., Conclusions: Anemia is common in primary care patients with HF. It is associated with worse prognosis and comorbidities, most notably cancer., Competing Interests: Declaration of competing interest ME none, PW none, AUM none, LB none, BE none. LHL: research grants to author's institution, speakers and consulting fees, Astra-Zeneca, Inc.; Novartis, Inc. UD reports grants from Pfizer, Boehringer Ingelheim, AstraZeneca, Vifor Pharma, Boston Scientific, and Roche Diagnostics, and honoraria/consultancies from Amgen, Pfizer, and AstraZeneca, all outside the submitted work. Grants: AstraZeneca, Vifor, Boston Scientific, Boehringer Ingelheim, Novartis, MSD; Consulting: Vifor, AstraZeneca, Bayer, Pharmacosmos, MSD, MedScape, Sanofi, Lexicon, Myokardia, Boehringer Ingelheim, Servier, Edwards Life Sciences, Alleviant; Speaker's honoraria: Abbott, OrionPharma, MedScape, Radcliffe, AstraZeneca, Novartis, Boehringer Ingelheim, Bayer; Patent: AnaCardio; Stock ownership: AnaCardio. GS: None related to the present work. GS reports grants and personal fees from Vifor, personal fees from Societa’ Prodotti Antibiotici, grants and personal fees from AstraZeneca, personal fees from Roche, personal fees from Servier, grants and personal fees from Novartis, personal fees from GENESIS, grants and personal fees from Cytokinetics, personal fees from Medtronic, grants from Boston Scientific, grants and personal fees from PHARMACOSMOS, grants from Merck, grants from Bayer, personal fees from Edwards Life Sciences outside the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: Real-world data show that guidelines are insufficiently implemented, and particularly guideline-directed medical therapies (GDMT) are underused in patients with heart failure and reduced ejection fraction (HFrEF) in clinical practice. The Council for Cardiology Practice and the Heart Failure Association of the European Society of Cardiology (ESC) developed a survey aiming to (i) evaluate the perspectives of the cardiology community on the 2021 ESC heart failure (HF) guidelines, (ii) pinpoint disparities in disease management, and (iii) propose strategies to enhance adherence to HF guidelines., Methods and Results: A 22-question survey regarding the diagnosis and treatment of HFrEF was delivered between March and June 2022. Of 457 physicians, 54% were general cardiologists, 19.4% were HF specialists, 18.9% other cardiac specialists, and 7.7% non-cardiac specialists. For diagnosis, 52.1% employed echocardiography and natriuretic peptides (NPs), 33.2% primarily used echocardiography, and 14.7% predominantly relied on NPs. The first drug class initiated in HFrEF was angiotensin-converting enzyme inhibitors/angiotensin receptor-neprilysin inhibitor (ACEi/ARNi) (91.2%), beta-blockers (BB) (73.8%), mineralocorticoid receptor antagonists (MRAs) (53.4%), and sodium-glucose cotransporter 2 (SGLT2) inhibitors (48.1%). The combination ACEi/ARNi + MRA+ BB was preferred by 39.3% of physicians, ACEi/ARNi + SGLT2 inhibitors + BB by 33.3%, and ACEi/ARNi + BB by 22.2%. The time required to initiate and optimize GDMT was estimated to be <1 month by 8.3%, 1-3 months by 52%, 3-6 months by 31.8%, and >6 months by 7.9%. Compared to general cardiologists, HF specialists/academic cardiologists reported lower estimated time-to-initiation, and more commonly preferred a parallel initiation of GDMT rather than a sequential approach., Conclusion: Participants generally followed diagnostic and treatment guidelines, but variations in HFrEF management across care settings or HF specialties were noted. The survey may raise awareness and promote standardized HF care., (© 2024 European Society of Cardiology.)

Aims: We analysed baseline characteristics and guideline-directed medical therapy (GDMT) use and decisions in the European Society of Cardiology (ESC) Heart Failure (HF) III Registry., Methods and Results: Between 1 November 2018 and 31 December 2020, 10 162 patients with acute HF (AHF, 39%, age 70 [62-79], 36% women) or outpatient visit for HF (61%, age 66 [58-75], 33% women), with HF with reduced (HFrEF, 57%), mildly reduced (HFmrEF, 17%) or preserved (HFpEF, 26%) ejection fraction were enrolled from 220 centres in 41 European or ESC-affiliated countries. With AHF, 97% were hospitalized, 2.2% received intravenous treatment in the emergency department, and 0.9% received intravenous treatment in an outpatient clinic. AHF was seen by most by a general cardiologist (51%) and outpatient HF most by a HF specialist (48%). A majority had been hospitalized for HF before, but 26% of AHF and 6.1% of outpatient HF had de novo HF. Baseline use, initiation and discontinuation of GDMT varied according to AHF versus outpatient HF, de novo versus pre-existing HF, and by ejection fraction. After the AHF event or outpatient HF visit, use of any renin-angiotensin system inhibitor, angiotensin receptor-neprilysin inhibitor, beta-blocker, mineralocorticoid receptor antagonist and loop diuretics was 89%, 29%, 92%, 78%, and 85% in HFrEF; 89%, 9.7%, 90%, 64%, and 81% in HFmrEF; and 77%, 3.1%, 80%, 48%, and 80% in HFpEF., Conclusion: Use and initiation of GDMT was high in cardiology centres in Europe, compared to previous reports from cohorts and registries including more primary care and general medicine and regions more local or outside of Europe and ESC-affiliated countries., (© 2024 European Society of Cardiology.)

Aims: This survey investigates natriuretic peptide (NP) testing in community and hospital settings, assessing awareness, accessibility, and utilization., Methods and Results: This investigator-initiated survey, conceived within the HFA of the European Society of Cardiology, comprised 14 questions. It underwent validation and pilot testing to ensure question readability and online system functionality. The survey was accessible for 87 days, from 5 April 2023 to 1 July 2023 via a web platform. There were 751 healthcare professionals across 99 countries who responded. Of them, 92.5% had access to NPs testing in hospital whereas 34.3% had no access to NTproBNP in community settings. Access to point of care NP testing was uncommon (9.6%). Public insurance fully covered NPs testing in 31.0% of cases, with private insurance providing coverage in 37.9%. The majority (84.0%) of participants believed that the medical evidence supporting NPs testing was strong, and 54.7% considered it cost-effective. Also, 35.8% found access, awareness, and adoption to be in favour of NPs testing both in hospital and community settings. Strategies to optimize NP testing involved regular guideline updates (57.9%), prioritizing NPs testing for dyspnoea assessment (36.4%), and introducing clinician feedback mechanisms (21.2%). Notably, 40% lacked a community-based HF diagnostic pathway for referring high-NP patients for echocardiography and cardiology evaluation., Conclusions: This survey reveals NP awareness, access, and adoption across several countries. Highlighting the importance of community-based early heart failure diagnosis and optimizing HF diagnostic pathways remains a crucial, unmet opportunity to improve patient outcomes., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Little is known either about either physical activity patterns, or other lifestyle-related prevention measures in heart transplantation (HTx) recipients. The history of HTx started more than 50 years ago but there are still no guidelines or position papers highlighting the features of prevention and rehabilitation after HTx. The aims of this scientific statement are (i) to explain the importance of prevention and rehabilitation after HTx, and (ii) to promote the factors (modifiable/non-modifiable) that should be addressed after HTx to improve patients' physical capacity, quality of life and survival. All HTx team members have their role to play in the care of these patients and multidisciplinary prevention and rehabilitation programmes designed for transplant recipients. HTx recipients are clearly not healthy disease-free subjects yet they also significantly differ from heart failure patients or those who are supported with mechanical circulatory support. Therefore, prevention and rehabilitation after HTx both need to be specifically tailored to this patient population and be multidisciplinary in nature. Prevention and rehabilitation programmes should be initiated early after HTx and continued during the entire post-transplant journey. This clinical consensus statement focuses on the importance and the characteristics of prevention and rehabilitation designed for HTx recipients., (© The Authors. Published by John Wiley & Sons Limited and Oxford University Press on behalf of the European Society of Cardiology, and Frontiers Media SA on behalf of the European Society for Organ Transplantation.)

Malignancies of the parotid gland are relatively uncommon and in most cases are primary neoplasms; intraparotid metastases are rare. Oral and oropharyngeal squamous cell carcinoma (O- and OP-SCC) can potentially metastasize to the parotid gland or intraparotid lymph nodes. Fine-needle aspiration cytology (FNAC) serves as the initial diagnostic approach for this purpose. HPV status in FNAC specimens is relevant and can guide the diagnostic workup, indicating a potential oropharyngeal origin of the primary tumor. A small series of occult SCC metastases is presented below, in which HPV-DNA testing of FNAC specimens helped identify primary neoplasms located in the oropharynx. US-guided FNAC of parotid nodules was conducted by an experienced interventional cytopathologist in three cases. Each patient underwent assessment of direct smears, cell blocks, and liquid-based samples for HPV testing. The morphological and immunocytochemical features of SCC were documented, and real-time PCR was employed for the detection and genotyping of HPV. The role of HPV testing on FNAC specimens in pinpointing the primary neoplasms in the oropharynx is highlighted. Consequently, FNAC samples emerge as valuable diagnostic and prognostic tools in this context, providing essential insights for patient management., (© 2024 Wiley Periodicals LLC.)

Aims: Heart failure (HF) with preserved ejection fraction (HFpEF) is characterized by growing incidence and poor outcomes. A large majority of HFpEF patients are cared by non-cardiologists. The availability of sodium-glucose cotransporter 2 inhibitors (SGLT2i) as recommended therapy raises the importance of prompt and accurate identification and treatment of HFpEF across diverse healthcare settings. We evaluated HFpEF management across specialties through a survey targeting cardiologists, HF specialists, and non-cardiologists., Methods and Results: An independent web-based survey was distributed globally between May and July 2023. We performed a post-hoc analysis, comparing cardiologists, HF specialists, and non-cardiologists. A total of 1460 physicians (61% male, median age 41[34-49]) from 95 countries completed the survey; 20% were HF specialists, 65% cardiologists, and 15% non-cardiologists. Compared with HF specialists, non-cardiologists and cardiologists were less likely to use natriuretic peptides (p = 0.003) and HFpEF scores (p = 0.004) for diagnosis, and were also less likely to have access to or consider specific echocardiographic parameters (p < 0.001) for identifying HFpEF. Diastolic stress tests were used in less than 30% of the cases, regardless of the specialty (p = 1.12). Multidrug treatment strategies were similar across different specialties. While SGLT2i and diuretics were the preferred drugs, angiotensin receptor blockers and angiotensin receptor-neprilysin inhibitors were the least frequently prescribed in all three groups. However, when constrained to choose one drug, the proportion of physicians favoring SGLT2i varied significantly among specialties (66% HF specialists, 52% cardiologists, 51% non-cardiologists). Additionally, 10% of non-cardiologists and 8% of cardiologists considered beta blocker the drug of choice for HFpEF., Conclusion: Significant differences among specialty groups were observed in HFpEF management, particularly in the diagnostic work-up. Our results highlight a substantial risk of underdiagnosis and undertreatment of HFpEF patients, especially among non-HF specialists., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Direct oral anticoagulants (DOACs) are increasingly used off-label to treat patients with left ventricular thrombus (LVT). We analysed available meta-data comparing DOACs and vitamin K antagonists (VKAs) for efficacy and safety., Methods: We conducted a systematic search and meta-analysis of observational and randomized data comparing DOACs vs. VKAs in patients with LVT. Endpoints of interest were stroke or systemic embolism, thrombus resolution, all-cause death, and a composite bleeding endpoint. Estimates were pooled using a random-effects model meta-analysis, and their robustness was investigated using sensitivity and influential analyses., Results: We identified 22 articles (18 observational studies, 4 small randomized clinical trials) reporting on a total of 3587 patients (2489 VKA vs. 1098 DOAC therapy). The pooled estimates for stroke or systemic embolism [odds ratio (OR): 0.81; 95% confidence interval (CI): 0.57, 1.15] and thrombus resolution (OR: 1.12; 95% CI: 0.86, 1.46) were comparable, and there was low heterogeneity overall across the included studies. The use of DOACs was associated with lower odds of all-cause death (OR: 0.65; 95% CI: 0.46, 0.92) and a composite bleeding endpoint (OR: 0.67; 95% CI: 0.47, 0.97). A risk of bias was evident particularly for observational reports, with some publication bias suggested in funnel plots., Conclusion: In this comprehensive analysis of mainly observational data, the use of DOACs was not associated with a significant difference in stroke or systemic embolism, or thrombus resolution, compared with VKA therapy. The use of DOACs was associated with a lower rate of all-cause death and fewer bleeding events. Adequately sized randomized clinical trials are needed to confirm these findings, which could allow a wider adoption of DOACs in patients with LVT., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Heart failure (HF) and atrial fibrillation (AF) often coexist. We explored AF incidence, prevalence, and treatment strategies in patients with versus without HF across the ejection fraction (EF) spectrum., Methods and Results: We analysed patients with HF from the Swedish HF Registry (1 December 2005-31 December 2021), matched 1:1 by sex, age, and county of residence to patients without HF from Statistics Sweden. Two study cohorts were derived (i) to assess AF prevalence and treatments, and (ii) to evaluate AF incidence and related predictors. Overall, 195 106 patients were considered, 50% of them with HF (of whom 54% with HF with reduced [HFrEF], 23% mildly reduced [HFmrEF], and 23% with preserved EF [HFpEF]). From 2006 to 2021, AF prevalence increased in both patients with (57% to 58%) and without HF (8% to 11%). HF patients, particularly if with HFrEF, were more likely receiving AF treatments than those without HF. Over time, antiarrhythmic use decreased, while rate control drugs and oral anticoagulant use, and AF-related procedures increased, regardless of HF and EF. During a median follow-up of 3.7 years, in 86 210 patients without AF, incident AF risk was two-fold higher in HF versus non-HF (hazard ratio [HR] 2.76, 95% confidence interval [CI] 2.45-3.12), highest in HFpEF (HR 3.12, 95% CI 2.65-3.67) versus HFrEF (HR 2.68, 95% CI 2.34-3.06) and HFmrEF (HR 2.53, 95% CI 2.17-2.94)., Conclusions: Atrial fibrillation prevalence, anticoagulant use, and AF-related procedures increased over time regardless of HF, with HF patients more likely receiving AF treatments. In HF, despite higher AF prevalence and incidence in HFpEF, AF treatment use remained modest, calling for further implementation., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Despite the progress in the care of individuals with heart failure (HF), important sex disparities in knowledge and management remain, covering all the aspects of the syndrome, from aetiology and pathophysiology to treatment. Important distinctions in phenotypic presentation are widely known, but the mechanisms behind these differences are only partially defined. The impact of sex-specific conditions in the predisposition to HF has gained progressive interest in the HF community. Under-recruitment of women in large randomized clinical trials has continued in the more recent studies despite epidemiological data no longer reporting any substantial difference in the lifetime risk and prognosis between sexes. Target dose of medications and criteria for device eligibility are derived from studies with a large predominance of men, whereas specific information in women is lacking. The present scientific statement encompasses the whole scenario of available evidence on sex-disparities in HF and aims to define the most challenging and urgent residual gaps in the evidence for the scientific and clinical HF communities., (© 2024 European Society of Cardiology.)

Aims: Several mechanisms have been identified in the aetiopathogenesis of heart failure with preserved ejection fraction (HFpEF). Among these, coronary microvascular dysfunction (CMD) may play a key pathophysiological role. We performed a systematic review and meta-analysis to investigate the prevalence, echocardiographic correlates, and prognostic implications of CMD in patients with HFpEF., Methods and Results: A systematic search for articles up to 1 May 2023 was performed. The primary aim was to assess the prevalence of CMD. Secondary aims were to compare key echocardiographic parameters (E/e' ratio, left atrial volume index [LAVi], and left ventricular mass index [LVMi]), clinical outcomes [death and hospitalization for heart failure (HF)], and prevalence of atrial fibrillation (AF) between patients with and without CMD. Meta-regressions according to baseline patient characteristics and study features were performed to explore potential heterogeneity sources. We identified 14 observational studies, enrolling 1138 patients with HFpEF. The overall prevalence of CMD was 58%. Compared with patients without CMD, patients with HFpEF and CMD had larger LAVi [mean difference (MD) 3.85 confidence interval (CI) 1.19-6.5, P < 0.01)], higher E/e' ratio (MD 2.76 CI 1.54-3.97; P < 0.01), higher prevalence of AF (odds ratio 1.61 CI 1.04-2.48, P = 0.03) and higher risk of death or hospitalization for HF [hazard ratio 3.19, CI 1.04-9.57, P = 0.04]., Conclusions: CMD is present in little more than half of the patients with HFpEF and is associated with echocardiographic evidence of more severe diastolic dysfunction and a higher prevalence of AF, doubling the risk of death or HF hospitalization., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Patients with heart failure (HF) remain often undertreated for multiple reasons, including treatment inertia, contraindications, and intolerance. The OPTIimal PHARMacological therapy for patients with Heart Failure (OPTIPHARM-HF) registry is designed to evaluate the prevalence of evidence-based medical treatment prescription and titration, as well as the causes of its underuse, in a broad real-world population of consecutive patients with HF across the whole ejection fraction spectrum and among different clinical phenotypes., Methods: The OPTIPHARM-HF registry (NCT06192524) is a prospective, multicenter, observational, national study of adult patients with symptomatic HF, as defined by current international guidelines, regardless of ejection fraction. Both outpatients and inpatients with chronic and acute decompensated HF will be recruited. The study will enroll up to 2500 patients with chronic HF at approximately 35 Italian HF centres. Patients will be followed for a maximum duration of 24 months. The primary objective of the OPTIPHARM-HF registry is to assess prescription and adherence to evidence-based guideline-directed medical therapy (GDMT) in patients with HF. The primary outcome is to describe the prevalence of GDMT use according to target guideline recommendation. Secondary objectives include implementation of comorbidity treatment, evaluation of sequence of treatment introduction and up-titration, description of GDMT implementation in the specific HF population, main causes of GDMT underuse, and assessment of cumulative rate of cardiovascular events., Conclusion: The OPTIPHARM-HF registry will provide important implications for improving patient care and adoption of recommended medical therapy into clinical practice among HF patients., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: The detailed sub-categories of death and hospitalization, and the impact of comorbidities on cause-specific outcomes, remain poorly understood in heart failure (HF) with preserved ejection fraction (HFpEF). We sought to evaluate rates and predictors of cardiovascular (CV) and non-CV outcomes in HFpEF., Methods: The Karolinska-Rennes study was a bi-national prospective observational study designed to characterize HFpEF (ejection fraction ≥45%). Patients were followed for cause-specific death and hospitalization. Baseline characteristics were pre-selected based on clinical relevance and potential eligibility criteria for HFpEF trials. The associations between characteristics and cause-specific outcomes were assessed with univariable and multivariable Cox regressions., Results: Five hundred thirty-nine patients [56% females; median (inter-quartile range) age 79 (72-84) years; NT-proBNP/BNP 2448 (1290-4790)/429 (229-805) ng/L] were included. Over 1196 patient-years follow-up [median (min, max) 744 days (13-1959)], there were 159 (29%) deaths (13 per 100 patient-years: CV 5.1 per 100, dominated by HF 3.9 per 100; and non-CV 5.8 per 100, dominated by cancer, 2.3 per 100). There were 723 hospitalizations in 338 patients (63%; 60 per 100 patient-years: CV 33 per 100, dominated by HF 17 per 100; and non-CV 27 per 100, dominated by lung disease 5 per 100). Higher age and natriuretic peptides, lower serum natraemia and NYHA class III-IV were independent predictors of CV death; lower serum natraemia, anaemia and stroke of non-CV death; and anaemia and lower serum natraemia of non-CV death or hospitalizations. There were no apparent predictors of CV death or hospitalization., Conclusions: In a clinical cohort hospitalized and diagnosed with HFpEF, death and hospitalization rates were roughly similar for CV and non-CV causes. CV deaths were predicted primarily by severity of HF; non-CV deaths primarily by anaemia and prior stroke. Lower serum sodium predicted both. Hospitalizations were difficult to predict., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: In recent decades, the topic of gender differences has become central to many areas of study, including medicine. The present study explored gender differences in empathy, gender role ideologies, and gender sensitivity among medical students, highlighting significant variations that can inform medical education and training programs., Materials and Methods: The study involved 155 students (52.1% male; mean age: 22.68±2.48 years) from the Department of Medicine, Surgery, and Dentistry of the University of Salerno in Baronissi, Southern Italy. Participants completed two standardized scales: the Jefferson Scale of Empathy (JSE) to assess empathy, and the Nijmegen Gender Awareness in Medicine Scale (N-GAMS) to evaluate gender awareness. Six open-ended questions were also included in the gender-based violence representations., Results: The ANOVA analysis reveals significant differences in scores between male and female students across the N-GAMS scales, indicating a strong role of gender in these variations. These findings suggest the necessity for further research to understand the contributing factors and inform targeted interventions in medical education. Additionally, there are significant differences in compassionate care (Factor 2) and walking in the patient's shoes (Factor 3), highlighting the substantial impact of gender on these latter aspects of empathy., Conclusions: These gender differences have significant implications for medical education. Training programs should be tailored to address the specific needs and characteristics of both male and female students. For example, encouraging male students to maintain their gender sensitivity while challenging traditional gender role ideologies can promote a more inclusive approach to patient care. For female students, fostering confidence in their compassionate care abilities and providing opportunities to express empathy in diverse ways can help overcome societal constraints., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Independent committee of the Psychological Counseling Center (Centro di Counseling Psicologico) of the University of Salerno issued approval 1/2021. The study was conducted in accordance with the Declaration of Helsinki (1964) and the recommendations of the Association Italian School of Psychology (AIP). Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Savarese et al.)

Aims: To assess the use and associations with outcomes of glucagon-like peptide-1 receptor agonists (GLP-1 RA) in a real-world population with heart failure (HF) and type 2 diabetes mellitus (T2DM)., Methods and Results: The Swedish HF Registry was linked with the National Diabetes Registry and other national registries. Independent predictors of GLP-1 RA use were assessed by multivariable logistic regressions and associations with outcomes were assessed by Cox regressions in a 1:1 propensity score-matched cohort. Of 8188 patients enrolled in 2017-21, 9% received a GLP-1 RA. Independent predictors of GLP-1 RA use were age <75 years, worse glycaemic control, impaired renal function, obesity, and reduced ejection fraction (EF). GLP-1 RA use was not significantly associated with a composite of HF hospitalization (HHF) or cardiovascular (CV) death regardless of EF, but was associated with a lower risk of major adverse CV events (CV death, non-fatal stroke/transient ischaemic attack, or myocardial infarction), and CV and all-cause death. In patients with body mass index ≥30 kg/m2, GLP-1 RA use was also associated with a lower risk of HHF/CV death and HHF alone., Conclusions: In patients with HF and T2DM, GLP-1 RA use was independently associated with more severe T2DM, reduced EF, and obesity and was not associated with a higher risk of HHF/CV death but with longer survival and less major CV adverse events. An association with lower HHF/CV death and HHF was observed in obese patients. Our findings provide new insights into GLP-1 RA use and its safety in HF and T2DM., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The growing understanding of cancer biology and the establishment of new treatment modalities has not yielded the expected results in terms of survival for Laryngeal Squamous Cell Cancer (LSCC). Early diagnosis, as well as prompt identification of patients with high risk of relapse would ensure greater chance of therapeutic success. However, this goal remains a challenge due to the absence of specific biomarkers for this neoplasm., Methods: Serum samples from 45 LSCC patients and 23 healthy donors were collected for miRNA expression profiling by TaqMan Array analysis. Additional 20 patients and 42 healthy volunteers were included for the validation set, reaching an equal number of clinical samples for each group. The potential diagnostic ability of the such identified three-miRNA signature was confirmed by ROC analysis. Moreover, each miRNA was analyzed for the possible correlation with HNSCC patients' survival and TNM status by online databases Kaplan-Meier (KM) plotter and OncomiR. In silico analysis of common candidate targets and their network relevance to predict shared biological functions was finally performed by PANTHER and GeneMANIA software., Results: We characterized serum miRNA profile of LSCC patients identifying a novel molecular signature, including miR-223, miR-93 and miR-532, as circulating marker endowed with high selectivity and specificity. The oncogenic effect and the prognostic significance of each miRNA was investigated by bioinformatic analysis, denoting significant correlation with OS. To analyse the molecular basis underlying the pro-tumorigenic role of the signature, we focused on the simultaneously regulated gene targets-IL6ST, GTDC1, MAP1B, CPEB3, PRKACB, NFIB, PURB, ATP2B1, ZNF148, PSD3, TBC1D15, PURA, KLF12-found by prediction tools and deepened for their functional role by pathway enrichment analysis. The results showed the involvement of 7 different biological processes, among which inflammation, proliferation, migration, apoptosis and angiogenesis., Conclusions: In conclusion, we have identified a possible miRNA signature for early LSCC diagnosis and we assumed that miR-93, miR-223 and miR-532 could orchestrate the regulation of multiple cancer-related processes. These findings encourage the possibility to deepen the molecular mechanisms underlying their oncogenic role, for the desirable development of novel therapeutic opportunities based on the use of short single-stranded oligonucleotides acting as non-coding RNA antagonists in cancer., (© 2024. The Author(s).)