Search

Abstract Aims Approximately half of patients with heart failure and a reduced ejection fraction (HeFREF) are discharged from hospital on triple therapy [angiotensin‐converting enzyme inhibitors (ACE‐Is) or angiotensin receptor blockers (ARBs), beta‐blockers (BBs), and mineralocorticoid receptor antagonists (MRAs)]. We investigated what proportion of patients are on optimal doses prior to discharge and how many might be eligible for initiation of sacubitril–valsartan or sodium‐glucose co‐transporter‐2 inhibitors (SGLT2Is). Methods and results Between 2012 and 2017, 1277 patients admitted with suspected heart failure were enrolled at a single hospital serving a local community around Kingston upon Hull, UK. Eligibility for sacubitril–valsartan or SGLT2I was based on entry criteria for the PIONEER‐HF, DAPA‐HF, and EMPEROR‐Reduced trials. Four hundred fifty‐five patients had HeFREF with complete data on renal function, heart rate, and systolic blood pressure (SBP) prior to discharge. Eighty‐three per cent of patients were taking an ACE‐I or ARB, 85% a BB, and 63% an MRA at discharge. More than 60% of patients were eligible for sacubitril–valsartan and >70% for SGLT2I. Among those not already receiving a prescription, 37%, 28%, and 49% were eligible to start ACE‐I or ARB, BB, and MRA, respectively. Low SBP (≤105 mmHg) was the most frequent explanation for failure to initiate or up‐titrate therapy. Conclusions Most patients admitted for heart failure are eligible for initiation of life‐prolonging medications prior to discharge. A hospital admission may be a common missed opportunity to improve treatment for patients with HeFREF.

Abstract Aims We aim to characterize the clinical and proteomic profiles of patients at risk of developing heart failure (HF), with and without coronary artery disease (CAD) or prior myocardial infarction (MI). Methods and results HOMAGE evaluated the effect of spironolactone on plasma and serum markers of fibrosis over 9 months of follow‐up in participants with (or at risk of having) CAD, and raised natriuretic peptides. In this post hoc analysis, patients were classified as (i) neither CAD nor MI; (ii) CAD; or (iii) MI. Proteomic between‐group differences were evaluated through logistic regression and narrowed using backward stepwise selection and bootstrapping. Among the 527 participants, 28% had neither CAD or MI, 31% had CAD, and 41% had prior MI. Compared with people with neither CAD nor MI, those with CAD had higher baseline plasma concentrations of matrix metalloproteinase‐7 (MMP‐7), galectin‐4 (GAL4), plasminogen activator inhibitor 1 (PAI‐1), and lower plasma peptidoglycan recognition protein 1 (PGLYRP1), whilst those with a history of MI had higher plasma MMP‐7, neurotrophin‐3 (NT3), pulmonary surfactant‐associated protein D (PSPD), and lower plasma tumour necrosis factor‐related activation‐induced cytokine (TRANCE). Proteomic signatures were similar for patients with CAD or prior MI. Treatment with spironolactone was associated with an increase of MMP7, NT3, and PGLYRP1 at 9 months. Conclusions In patients at risk of developing HF, those with CAD or MI had a different proteomic profile regarding inflammatory, immunological, and collagen catabolic processes.

L’articolo racconta l’esperienza dell’introduzione del piano di lavoro matematico in due classi quinte della scuola primaria, con riflessioni di contesto e di metodo. Al centro di pratiche condivise da un gruppo di insegnanti di scuola primaria, il piano di lavoro costituisce una formula promettente di laboratorio matematico, in cui autonomia, apprendimento individualizzato e dimensione pratica e cooperativa si incontrano. Il racconto parte dalla descrizione dello strumento del piano di lavoro e procede con l’introduzione per gradi di questa pratica in classe e la sua articolazione negli spazi e tempi, cui fa seguito l’illustrazione del percorso della classe attraverso alcune esperienze significative collegate al problem solving. Si prende in considerazione, infine, l’evoluzione nel tempo degli atteggiamenti dei bambini verso la matematica, con alcune riflessioni in chiusura sulle possibilità d’uso dello strumento anche dopo la scuola primaria.

Abstract Introduction Unintentional dural puncture (UDP) occurs in 0.5–1.5% of labour epidural analgesia cases. To date, little is known about evidence of UDP-related complications. This work aimed to assess the incidence of intrapartum and postpartum complications in parturients who experienced UDP. Methods This is a 10-year retrospective observational study on parturients admitted to our centre who presented UDP. Data collection gathered UDP-related complications during labour and postpartum. All women who displayed UDP received medical therapy and bed rest. An epidural blood patch (EBP) was not used in this population. Once asymptomatic, patients were discharged from the hospital. Results Out of 7718 neuraxial analgesia cases, 97 cases of UDP occurred (1.25%). During labour, complications appeared in a small percentage of analgesia procedures performed, including total spinal anaesthesia (1.0%), extended motor block (3%), hypotension (4.1%), abnormal foetal heart rate (2%), inadequate analgesia (14.4%), and general anaesthesia following neuraxial anaesthesia failure (33.3% of emergency caesarean sections). During the postpartum period, 53.6% of parturients exhibited a postdural puncture headache, 13.4% showed neurological symptoms, and 14.4% required neurological consultation and neuroimaging. No patient developed subdural hematoma or cerebral venous sinus thrombosis; one woman presented posterior reversible encephalopathy syndrome associated with eclampsia. Overall, 82.5% of women experienced an extension of hospital stay. Conclusion Major complications occurred in a small percentage of patients during labour. However, since they represent high-risk maternal and neonatal health events, a dedicated anaesthesiologist and a trained obstetric team are essential. No major neurological complications were registered postpartum, and EBP was not performed. Nevertheless, all patients with UDP were carefully monitored and treated until complete recovery before discharge, leading to an extension of their hospitalization.

Abstract Aims Transferrin saturation (TSAT), a marker of iron deficiency, reflects both serum concentrations of iron (SIC) and transferrin (STC). TSAT is susceptible to changes in each of these biomarkers. Little is known about determinants of STC and its influence on TSAT and mortality in patients with heart failure. Accordingly, we studied the relationship of STC to clinical characteristics, to markers of iron deficiency and inflammation and to mortality in chronic heart failure (CHF). Methods and results Prospective cohort of patients with CHF attending a clinic serving a large local population. A total of 4422 patients were included (median age 75 (68–82) years; 40% women; 32% with left ventricular ejection fraction ≤40%). STC ≤ 2.3 g/L (lowest quartile) was associated with older age, lower SIC and haemoglobin and higher high‐sensitivity C‐reactive protein, ferritin and N‐terminal pro‐brain natriuretic peptide compared with those with STC > 2.3 g/L. In the lowest STC quartile, 624 (52%) patients had SIC ≤13 μmol/L, of whom 38% had TSAT ≥20%. For patients in the highest STC quartile, TSAT was 13 μmol/L in 185 (17%) patients. STC correlated inversely with ferritin (r = −0.52) and high‐sensitivity C‐reactive protein (r = −0.17) and directly with albumin (r = 0.29); all P 20% and serum ferritin >100 μg/L; such patients have a high prevalence of anaemia and a poor prognosis and might have iron deficiency but are currently excluded from clinical trials of iron repletion.

Background: Immune responses play a significant role in hypertension, though the importance of key inflammatory mediators remains to be defined. We used a systematic literature review and meta-analysis to study the associations between key cytokines and incident hypertension. Methods: We performed a systematic search of Pubmed/Medline, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL), for peer-reviewed studies published up to August 2022. Incident hypertension was defined as systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg and/or the use of antihypertensive medications. Random effects meta-analyses were used to calculate pooled hazard ratios (HRs)/risk ratios (RRs) and 95% confidence intervals by cytokine levels (highest vs. lowest quartile). Results: Only IL-6 and IL-1β levels have evidence allowing for quantitative evaluation concerning the onset of hypertension. Six studies (10406 participants, 2932 incident cases) examined the association of IL-6 with incident hypertension. The highest versus lowest quartile of circulating IL-6 was associated with a significant HR/RR of hypertension (1.61, 95% CI: 1.00 to 2.60; I2 =87%). After adjusting for potential confounders, including body mass index (BMI), HR/RR was no longer significant (HR/RR: 1.24; 95% CI, 0.96 to 1.61; I2 = 56%). About IL-1β, neither the crude (HR/RR: 1.03; 95% CI, 0.60 to 1.76; n = 2) nor multivariate analysis (HR/RR: 0.97, 95% CI, 0.60 to 1.56; n = 2) suggested a significant association with the risk of developing hypertension. Conclusions: A limited number of studies suggest that higher IL-6, but not IL-1β, might be associated with the development of hypertension.

Background and aimsEpidemiology of atherosclerotic cardiovascular disease might be different in patients with polygenic hypercholesterolemia plus high levels (≥30 mg/dl) of Lp(a) (H-Lpa) than in those with polygenic hypercholesterolemia alone (H-LDL). We compared the incidence of peripheral artery disease (PAD), coronary artery disease (CAD), and cerebrovascular disease (CVD) in patients with H-Lpa and in those with H-LDL.MethodsRetrospective analysis of demographics, risk factors, vascular events, therapy, and lipid profile in outpatient clinical data. Inclusion criteria was adult age, diagnosis of polygenic hypercholesterolemia, and both indication and availability for Lp(a) measurement.ResultsMedical records of 258 patients with H-Lpa and 290 H-LDL were reviewed for occurrence of vascular events. The median duration of follow-up was 10 years (IQR 3–16). In spite of a similar reduction of LDL cholesterol, vascular events occurred more frequently, and approximately 7 years earlier (P = 0.024) in patients with H-Lpa than in H-LDL (HR 1.96 1.21–3.17, P = 0.006). The difference was around 10 years for acute events (TIA, Stroke, acute coronary events) and one year for chronic ones (P = 0.023 and 0.525, respectively). Occurrence of acute CAD was higher in H-Lpa men (HR 3.1, 95% CI 1.2–7.9, P = 0.007) while, among women, PAD was observed exclusively in H-Lpa subjects with smoking habits (P = 0.009).ConclusionsPatients with high Lp(a) levels suffer from a larger and earlier burden of the disease compared to those with polygenic hypercholesterolemia alone. These patients are at higher risk of CAD if they are men, and of PAD if they are women.

Abstract Background SERPINC1 is a glycoprotein that regulates blood coagulation. SERPINC1 congenital or acquired deficiencies represent a significant risk factor for thromboembolic disease. SERPINC1 acquired defects are observed in very few cases and can occur in many clinical conditions such as treatment with l-asparaginase or oral contraceptive (particularly estrogen derivatives), but these conditions are not routinely investigated. Case presentation A 50-year-old Caucasian woman who took gestodene 75 µg/ethinylestradiol 20 µg as oral contraceptive, was sent to our thrombophilia clinic because, on thrombophilia testing, a reduction of SERPINC1 (74%) and a slight increase in circulating D-dimer and homocysteine were found. We investigated triggers of such SERPINC1 reduction, and identified gestodene 75 µg/ethinylestradiol 20 µg use as the most likely candidate. Two months after the discontinuation of the oral contraceptive, SERPINC1 value returned to normal (92%) and D-dimer and homocysteine were normalized. Conclusion Each patient has a different sensitivity to contraceptive use. Genetic (or epigenetic) regulation of anticoagulant proteins might account for a different rate of consumption of anticoagulant proteins as oral contraceptives and probably determine the susceptibility to thrombotic events.

Abstract Aims In people at risk of heart failure (HF) enrolled in the Heart ‘OMics’ in AGEing (HOMAGE) trial, spironolactone reduced circulating markers of collagen synthesis, natriuretic peptides, and blood pressure and improved cardiac structure and function. In the present report, we explored factors associated with dyskalaemia. Methods and results The HOMAGE trial was an open‐label study comparing spironolactone (up to 50 mg/day) versus standard care in people at risk for HF. After randomization, serum potassium was assessed at 1 and 9 months and was defined as low when ≤3.5 mmol/L (hypokalaemia) and high when ≥5.5 mmol/L (hyperkalaemia). Multivariable logistic regression models were constructed to identify clinical predictors of dyskalaemia. A total of 513 participants (median age 74 years, 75% men, median estimated glomerular filtration rate 71 mL/min/1.73 m2) had serum potassium available and were included in this analysis. At randomization, 88 had potassium 5.0 mmol/L. During follow‐up, on at least one occasion, a serum potassium 5.0 mmol/L was observed in 38 (8%) and >5.5 mmol/L in 5 (1.0%) participants. The median (percentile25−75) increase in serum potassium with spironolactone during the study was 0.23 (0.16; 0.29) mmol/L. Because of the low incidence of dyskalaemia, for regression analysis, hypokalaemia and hyperkalaemia thresholds were set at 5.0 mmol/L, respectively. The occurrence of a serum potassium > 5.0 mmol/L during follow‐up was positively associated with the presence of diabetes mellitus {odds ratio [OR]: 1.21 [95% confidence interval (CI) 2.14; 3.79]} and randomization to spironolactone (OR: 2.83 [95% CI 1.49; 5.37]). Conversely, the occurrence of a potassium concentration

Abstract Aims Risk changes with the progression of disease and the impact of treatment. We developed a dynamic risk stratification Markov chain model using artificial intelligence in patients with chronic heart failure (CHF). Methods and results We described the pattern of behaviour among 7496 consecutive patients assessed for suspected HF. The following mutually exclusive health states were defined and assessed every 4 months: death, hospitalization, outpatient visit, no event, and leaving the service altogether (defined as no event at any point following assessment). The observed figures at the first transition (4 months) weres 427 (6%), 1559 (21%), 2254 (30%), 1414 (19%), and 1842 (25%), respectively. The probabilities derived from the first two transitions (i.e. from baseline to 4 months and from 4 to 8 months) were used to construct the model. An example of the model's prediction is that at cycle 4, the cumulative probability of death was 14%; leaving the system, 37%; being hospitalized between 12 and 16 months, 10%; having an outpatient visit, 8%; and having no event, 31%. The corresponding observed figures were 14%, 41%, 10%, 15%, and 21%, respectively. The model predicted that during the first 2 years, a patient had a probability of dying of 0.19, and the observed value was 0.18. Conclusions A model derived from the first 8 months of follow‐up is strongly predictive of future events in a population of patients with chronic heart failure. The course of CHF is more linear than is commonly supposed, and thus more predictable.

Joseph J Cuthbert,1,2 Pierpaolo Pellicori,3 Andrew L Clark2 1Centre for Clinical Sciences, Hull York Medical School, Kingston Upon Hull, East Riding of Yorkshire, UK; 2Department of Cardiology, Hull University Teaching Hospital Trust, Kingston Upon Hull, East Riding of Yorkshire, UK; 3Robertson Centre for Biostatistics and Glasgow Clinical Trials Unit, University of Glasgow, Glasgow, UKCorrespondence: Joseph J Cuthbert, Department of Cardiorespiratory Medicine, Centre for Clinical Sciences, Hull York Medical School, Hull and East Yorkshire Medical Research and Teaching Centre, Castle Hill Hospital, Cottingham, Kingston Upon Hull, HU16 5JQ, UK, Tel +44 1482 461776, Fax +44 1482 461779, Email joe.cuthbert@hyms.ac.ukAbstract: Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are common causes of breathlessness which frequently co-exist; one potentially exacerbating the other. Distinguishing between the two can be challenging due to their similar symptomatology and overlapping risk factors, but a timely and correct diagnosis is potentially lifesaving. Modern treatment for HF can substantially improve symptoms and prognosis for many patients and may have beneficial effects for patients with COPD. Conversely, while many inhaled treatments for COPD can improve symptoms and reduce exacerbations, there is conflicting evidence regarding the safety of some inhaled treatments for COPD in patients with HF. Here we explore the overlap between HF and COPD, examine the effect of one condition on the other, and address the challenges of managing patients with both conditions.Keywords: chronic obstructive pulmonary disease, heart failure, management, outcomes, comorbidities

Water and salt retention, in other words congestion, are fundamental to the pathophysiology of heart failure and are important therapeutic targets. Echocardiography is the key tool with which to assess cardiac structure and function in the initial diagnostic workup of patients with suspected heart failure and is essential for guiding treatment and stratifying risk. Ultrasound can also be used to identify and quantify congestion in the great veins, kidneys and lungs. More advanced imaging methods might further clarify the aetiology of heart failure and its consequences for the heart and periphery, thereby improving the efficiency and quality of care tailored with greater precision to individual patient need.

Abstract Background Cachexia is common in patients with chronic heart failure and is associated with poor prognosis. How best to measure body composition is not clear. Methods and results We characterized body composition in 120 patients with chronic heart failure: mean (SD) age 70 (10) years, left ventricular ejection fraction 44 (10) %, and median (Q1–Q3) N‐terminal pro B‐type natriuretic peptide 845 (355–1368) ng/L. We measured body composition using dual‐energy X‐ray absorptiometry (DEXA) and a multi‐frequency bioelectrical impedance analysis (BIA) device (Tanita BIA MC‐180MA). Mean (SD) fat mass (FM) was 27.2 (11.7) kg by BIA and 32.3 (12.2) kg by DEXA (mean difference −5.1 kg, 95% limits of agreement: −11.7, 1.5; 4% of values outside limit of agreement); mean (SD) lean mass (LM) was 56.6 (10.9) kg by BIA and 51.1 (9.9) kg by DEXA (mean difference 5.5 kg, 95% limits of agreement: −1.3, 12.3; 6% of values outside limit of agreement); and mean (SD) bone mass (BM) was 3.0 (0.5) kg by BIA and 2.8 (0.6) kg by DEXA (mean difference 0.2 kg, 95% limits of agreement: −0.5, 0.8; 5% of values outside limit of agreement). There was a close correlation between DEXA and BIA for both LM and FM (LM: r = 0.95, P

Abstract Introduction Digoxin is used in patients with chronic heart failure (CHF) who remain symptomatic despite optimal medical treatment. Impaired renal function is commonly associated with CHF. We investigated the relation between digoxin use and change in renal function over time in patients with CHF. Methods One thousand two hundred forty-one patients with symptoms and signs of CHF (average age 72 years (64% male), and median NTproBNP 1426 ng/l (interquartile range 632–2897) were divided into four groups: never on digoxin (N = 394); digoxin throughout (N = 449); started digoxin at some point after baseline (N = 367); and stopped digoxin at some point after baseline (N = 31). The rate of change of estimated glomerular filtration rate (eGFR) was calculated using linear regression. Results Patients on digoxin throughout had a significantly greater rate of decline in eGFR per year than patients not on digoxin throughout (mean (± standard deviation); − 5 (14) ml/min/1.73m2 per year v − 2 (11) ml/min/1.73m2 per year, P = 0.02). In those patients who started digoxin during follow up, there was no significant difference in the rate of decline in eGFR before and after starting digoxin. There was no correlation between baseline eGFR (or rate of decline in eGFR) and age, haemoglobin or NTproBNP. Compared to patients taking both angiotensin-converting-enzyme inhibitor (ACEi) or angiotensin receptor blockers (ARB) and beta-blocker (BB), patients who were not taking an ACEi/ARB or BB had a numerically faster rate of decline in eGFR, although this was not statistically significant. Conclusion The rate of decline in renal function is greater in patients with CHF who are taking digoxin.

Abstract Background Patients with diabetes mellitus (DM) are at increased risk of developing heart failure (HF). The “Heart OMics in AGEing” (HOMAGE) trial suggested that spironolactone had beneficial effect on fibrosis and cardiac remodelling in an at risk population, potentially slowing the progression towards HF. We compared the proteomic profile of patients with and without diabetes among patients at risk for HF in the HOMAGE trial. Methods Protein biomarkers (n = 276) from the Olink®Proseek-Multiplex cardiovascular and inflammation panels were measured in plasma collected at baseline and 9 months (or last visit) from HOMAGE trial participants including 217 patients with, and 310 without, diabetes. Results Twenty-one biomarkers were increased and five decreased in patients with diabetes compared to non-diabetics at baseline. The markers clustered mainly within inflammatory and proteolytic pathways, with granulin as the key-hub, as revealed by knowledge-induced network and subsequent gene enrichment analysis. Treatment with spironolactone in diabetic patients did not lead to large changes in biomarkers. The effects of spironolactone on NTproBNP, fibrosis biomarkers and echocardiographic measures of diastolic function were similar in patients with and without diabetes (all interaction analyses p > 0.05). Conclusions Amongst patients at risk for HF, those with diabetes have higher plasma concentrations of proteins involved in inflammation and proteolysis. Diabetes does not influence the effects of spironolactone on the proteomic profile, and spironolactone produced anti-fibrotic, anti-remodelling, blood pressure and natriuretic peptide lowering effects regardless of diabetes status. Trial registration NCT02556450.

Abstract To assess the usefulness of lung ultrasound (LUS) for identifying community-acquired pneumonia (CAP) among adult patients with suspected lower respiratory tract infection (LRTI) and for discriminating between CAP with different cultural statuses, etiologies, and outcomes. LUS was performed at internal medicine ward admission. The performance of chest X-ray (CXR) and LUS in diagnosing CAP in 410 patients with suspected LRTI was determined. All possible positive results for pneumonia on LUS were condensed into pattern 1 (consolidation + / − alveolar-interstitial syndrome) and pattern 2 (alveolar-interstitial syndrome). The performance of LUS in predicting culture-positive status, bacterial etiology, and adverse outcomes of CAP was assessed in 315 patients. The area under the receiver operating characteristic curve for diagnosing CAP by LUS was significantly higher than for diagnosis CAP by CXR (0.93 and 0.71, respectively; p

Abstract Background Muscle wasting and unintentional weight loss (cachexia) have been associated with worse outcomes in heart failure (HF), but timely identification of these adverse phenomena is difficult. Spot urinary creatinine may be an easily accessible marker to assess muscle loss and cachexia. This study investigated the association of urinary creatinine with body composition changes and outcomes in patients with new‐onset or worsening HF (WHF). Methods In BIOSTAT‐CHF, baseline spot urinary creatinine measurements were available in 2315 patients with new‐onset or WHF in an international cohort (index cohort) and a validation cohort of 1431 similar patients from Scotland. Results Median spot urinary creatinine concentrations were 5.2 [2.7–9.6] mmol/L in the index cohort. Median age was 69 ± 12 years and 73% were men. Lower spot urinary creatinine was associated with older age, lower height and weight, worse renal function, more severe HF, and a higher risk of >5% weight loss from baseline to 9 months (odds ratio = 1.23, 95% CI = 1.09–1.39 per log decrease; P = 0.001). Spot urinary creatinine was associated with Evans criteria of cachexia (OR = 1.26 per log decrease, 95% CI = 1.04–1.49; P = 0.016) and clustered with markers of heart failure severity in hierarchical cluster analyses. Lower urinary creatinine was associated with poorer exercise capacity and quality of life (both P

Abstract Aims The EMPA‐REG OUTCOME trial demonstrated reductions in cardiovascular (CV) death and heart failure (HF) outcomes with empagliflozin, a sodium–glucose co‐transporter 2 inhibitor, in patients with type 2 diabetes and established CV disease over a study period of 3 years. We aimed to investigate the early benefit–risk profile of empagliflozin in patients enrolled in the EMPA‐REG OUTCOME trial according to HF status at baseline. Methods and results The effects of treatments on glycated haemoglobin, systolic blood pressure and body weight, and on the HF endpoints of hospitalization for HF (HHF), HHF or CV death, and HHF or all‐cause mortality were evaluated at 12 weeks, 6 months, and 1 year after randomization. Occurrence of adverse events (AEs) during these time points was also evaluated. Compared with placebo, empagliflozin lowered glycated haemoglobin, systolic blood pressure, and body weight and rates of all the HF endpoints, as early as at 12 weeks, regardless of HF status at baseline. Favourable clinical and metabolic effects were maintained over time. AEs were generally higher in those with HF than without HF; however, compared with placebo, empagliflozin did not increase risk of developing AEs over the first year of treatment. Conclusions In the EMPA‐REG OUTCOME trial, the use of empagliflozin led to early and beneficial effects on clinical, metabolic, and HF outcomes in patients with type 2 diabetes with or without HF at baseline, which were already apparent within 12 weeks from initiation of treatment. Over the first year of treatment, no safety concern was detected with the use of empagliflozin.

Joseph J Cuthbert,1 Pierpaolo Pellicori,2 Andrew L Clark1 1Department of Academic Cardiology, Hull York Medical School, Hull and East Yorkshire Medical Research and Teaching Centre, Castle Hill Hospital, Kingston upon Hull HU16 5JQ, UK; 2Robertson Institute of Biostatistics and Clinical Trials Unit, University of Glasgow, University Avenue, Glasgow G12 8QQ, UKCorrespondence: Joseph J CuthbertDepartment of Academic Cardiology, Hull York Medical School, Hull and East Yorkshire Medical Research and Teaching Centre, Castle Hill Hospital, Cottingham, Kingston upon Hull HU16 5JQ, UKTel + 44 (0)1482 461776Fax + 44 (0)1482 461779Email joe.cuthbert@hey.nhs.ukAbstract: One of the defining features of heart failure (HF) is neurohormonal activation. The renin-angiotensin-aldosterone-system (RAAS) and sympathetic nervous system (SNS) cause vasoconstriction and fluid retention and, in response, the secretion of natriuretic peptides (NPs) from volume and pressure-overloaded myocardium promotes vasodilation and diuresis. Inhibition of the RAAS with either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) has been the cornerstone of medical treatment for HF with a reduced ejection fraction (HFrEF) but, until recently, it was unclear how the beneficial effects of NPs may be augmented in patients with HF. Neprilysin, a metalloproteinase widely distributed throughout the body, plays a role in degrading the gross excess of circulating NPs in patients with HF. Early studies of neprilysin inhibition suggested possible physiological benefits. In 2014, the PARADIGM-HF trial found that sacubitril-valsartan, a combination of the ARB valsartan, and the neprilysin inhibitor sacubitril, was superior to enalapril in patients with HFrEF, reducing the relative risk of cardiovascular (CV) death or first hospitalisation with HF by 20%. Almost half of the patients with HF symptoms have a “preserved” ejection fraction (HFpEF); however, the PARAGON-HF study found that sacubitril-valsartan in patients with LVEF ≥ 45% had no effect on CV death or first and recurrent hospitalisations with HF compared to valsartan. Guidelines across the world have changed to include sacubitril-valsartan for patients with HFrEF yet, nearly 6 years after PARADIGM-HF, there is still uncertainty as to when and in whom sacubitril-valsartan should be started. Furthermore, there may yet be subsets of patients with HFpEF who might benefit from treatment with sacubitril-valsartan. This review will describe the mechanisms behind the outcome benefit of sacubitril-valsartan in patients with HFrEF and to consider its future role in the management of patients with HF.Keywords: sacubitril-valsartan, heart failure, PARADIGM-HF, PARAGON-HF, natriuretic peptide, angiotensin receptor neprilysin inhibitor

Assessment of vascular size and of its phasic changes by ultrasound is important for the management of many clinical conditions. For example, a dilated and stiff inferior vena cava reflects increased intravascular volume and identifies patients with heart failure at greater risk of an early death. However, lack of standardization and sub-optimal intra- and inter- operator reproducibility limit the use of these techniques. To overcome these limitations, we developed two image-processing algorithms that quantify phasic vascular deformation by tracking wall movements, either in long or in short axis. Prospective studies will verify the clinical applicability and utility of these methods in different settings, vessels and medical conditions.

The coronavirus disease-19 (COVID-19) pandemic dramatically impacted oncological patients’ care. Since the introduction of vaccines and the demonstration of their benefit on frail patients, COVID-19 vaccinations were indicated to also be beneficial to oncological population. However, data about the impact of anticancer-treatments and the timing between vaccinations and systemic therapy delivery were not available. We aimed to evaluate potential factors influencing the outcome of the COVID-19 vaccination in cancer patients. We prospectively collected data of patients undergoing the COVID-19 vaccination with gastro-entero-pancreatic and neuroendocrine neoplasms, treated at our institute, between 03/2021 and 12/2021. We enrolled 46 patients, 63.1% males; at the time of data collection, 86.9% had received two-doses of Pfizer-BioNTech and the rest had received the Moderna vaccine. All patients obtained a subsequent immune-response. Chemotherapy seems to determinate a significantly lower antibody response after vaccination compared to the other anti-cancer agents (p = 0.004). No significant effect on immune-response was reported for both vaccinations performed ≤7 vs. >7 days from the last systemic treatment (p = 0.77) and lymphocytes count (p = 0.11). The findings suggest that the optimal timing for COVID-19 vaccination and lymphocytes count are not the issue, but rather that the quality of the subset of lymphocytes before the vaccination determine the efficacy level of immune-response in this population.

Neoadjuvant chemotherapy (NAC) significantly improved the prognosis of patients with locally advanced resectable gastric cancer but, despite important progresses, relapse-related death remains a major challenge. Therefore, it appears crucial to understand which patients will benefit from peri-operative treatment. Biomarkers such as human epidermal growth factor receptor-2 (HER2), microsatellite instability (MSI), and Epstein-Barr Virus (EBV) have been widely studied; however, they do not yet guide the choice of perioperative treatment in clinical practice. We performed a narrative review, including 23 studies, addressing the value of tissue- or blood-based biomarkers in the neoadjuvant setting. Ten studies (43.5%) were prospective, and more than half were conducted in East-Asia. Biomarkers were evaluated only post-NAC (on surgical samples or blood) in seven studies (30.4%), only pre-NAC (on endoscopic specimens or blood) in 10 studies (43.5%), and both pre- and post-NAC (26.1%) in six studies. Among the high variety of investigated biomarkers, some of these including MSI-H or enzymatic profile (as TS, UGT1A1, MTHFR, ERCC or XRCC) showed promising results and deserve to be assessed in methodologically sound clinical trials. The identification of molecular biomarkers in patients treated with NAC for locally advanced resectable gastric or EGJ cancer remains crucial.

Introduction Early detection and treatment of diabetes as well as its prevention help lessen longer-term complications. We determined the prevalence of pre-diabetes and undiagnosed diabetes in the UK Biobank and standardized the results to the UK general population.Research design and methods This cross-sectional study analyzed baseline UK Biobank data on plasma glycated hemoglobin (HbA1c) to compare the prevalence of pre-diabetes and undiagnosed diabetes mellitus in white, South Asian, black, and Chinese participants. The overall and ethnic-specific results were standardized to the UK general population aged 40–70 years of age.Results Within the UK Biobank, the overall crude prevalence was 3.6% for pre-diabetes, 0.8% for undiagnosed diabetes, and 4.4% for either. Following standardization to the UK general population, the results were similar at 3.8%, 0.8%, and 4.7%, respectively. Crude prevalence was much higher in South Asian (11.0% pre-diabetes; 3.6% undiagnosed diabetes; 14.6% either) or black (13.8% pre-diabetes; 3.0% undiagnosed diabetes; 16.8% either) participants. Only six middle-aged or old-aged South Asian individuals or seven black would need to be tested to identify an HbA1c result that merits action.Conclusions Single-stage population screening for pre-diabetes or undiagnosed diabetes in middle-old or old-aged South Asian and black individuals using HbA1c could be efficient and should be considered.