Effects of atidarsagene autotemcel gene therapy on peripheral nerves in late-infantile metachromatic leukodystrophy.

This study evaluates the efficacy of arsa-cel gene therapy (GT) in mitigating the severity and progression of peripheral neuropathy as assessed by nerve conduction velocity (NCV) in individuals affected by late-infantile metachromatic leukodystrophy (LI-MLD). This is a post-hoc analysis conducted on pre-symptomatic patients affected by LI-MLD treated with ex vivo autologous hematopoietic stem cell GT (atidarsagene autotemcel, "arsa-cel") in the context of prospective open-label, single-arm, interventional trials and expanded access programs. All patients were followed longitudinally with nerve conduction studies (NCSs) of peripheral motor (ulnar - UN, deep peroneal - DPN) and sensory (median - MN, sural - SN) nerves.

Long-Term Effects of Atidarsagene Autotemcel for Metachromatic Leukodystrophy.

Background: Metachromatic leukodystrophy (MLD) is an ultrarare, severe lysosomal storage disorder caused by a deficiency of arylsulfatase A (ARSA).

Methods: We treated patients who had MLD with atidarsagene autotemcel (arsa-cel), a hematopoietic stem-cell-based gene therapy, in two prospective open-label clinical studies and expanded-access programs. We compared their outcomes with those of untreated patients (natural history cohort).

Hypoglycemia and Cardiovascular Outcomes in the CARMELINA and CAROLINA Trials of Linagliptin: A Secondary Analysis of Randomized Clinical Trials.

Importance: Previous studies have reported an association between hypoglycemia and cardiovascular (CV) events in people with type 2 diabetes (T2D), but it is unclear if this association is causal or identifies a high-risk patient phenotype.

Objective: To evaluate the associations between hypoglycemia and CV outcomes.

Design, Setting, And Participants: This secondary analysis was a post hoc assessment of the multinational, double-blind CARMELINA (Cardiovascular and Renal Microvascular Outcome Study With Linagliptin; 2013-2016) and CAROLINA (Cardiovascular Outcome Trial of Linagliptin vs Glimepiride in Type 2 Diabetes; 2010-2018) randomized clinical trials of the antihyperglycemic drug, linagliptin, a dipeptidyl peptidase 4 inhibitor.

Resource utilisation and outcomes of people with heart failure in England: a descriptive analysis of linked primary and secondary care data - the PULSE study.

Background: Heart failure (HF) is associated with high levels of resource use and mortality, but prior UK studies have not compared outcomes by HF subtype (HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF)) in large patient populations. This study investigated healthcare resource utilisation and mortality in patients with HF in England, overall and by HF subtype.

Methods: This non-interventional cohort study linked data from the Clinical Practice Research Datalink database to Hospital Episode Statistics inpatient and UK Office for National Statistics mortality data.

Effects of empagliflozin on cardiovascular and renal outcomes in heart failure with reduced ejection fraction according to age: a secondary analysis of EMPEROR-Reduced.

Aims: Empagliflozin improves cardiovascular and renal outcomes in patients with heart failure (HF) and reduced ejection fraction (HFrEF), but its efficacy and safety across patient's age is not well established.

Methods And Results: We assessed the effects of empagliflozin (10 mg daily) versus placebo, on top of standard HF therapy, in symptomatic HFrEF patients with a left ventricular ejection fraction ≤40% and increased natriuretic peptides stratified by age (<65, 65-74, ≥75 years). The primary endpoint was a composite of cardiovascular death or HF hospitalization.

Empagliflozin Improves Outcomes in Patients With Heart Failure and Preserved Ejection Fraction Irrespective of Age.

Background: Empagliflozin reduces cardiovascular death (CVD) or heart failure (HF) hospitalization (HFH) in patients with HF and preserved ejection fraction. Treatment effects and safety in relation to age have not been studied.

Objectives: The purpose of this study was to evaluate the interplay of age and empagliflozin effects in EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction).

Erratum to: Effect of linagliptin versus placebo on cardiovascular and kidney outcomes in nephrotic-range proteinuria and type 2 diabetes (t2d): the carmelina randomised controlled trial.

[This corrects the article DOI: 10.1093/ckj/sfaa225.].

Novel biomarker-driven prognostic models to predict morbidity and mortality in chronic heart failure: the EMPEROR-Reduced trial.

Aims: The aim of this study was to generate a biomarker-driven prognostic tool for patients with chronic HFrEF. Circulating levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) each have a marked positive relationship with adverse outcomes in heart failure with reduced ejection fraction (HFrEF). A risk model incorporating biomarkers and clinical variables has not been validated in contemporary heart failure (HF) trials.

Prescribing in Type 2 Diabetes Patients With and Without Cardiovascular Disease History: A Descriptive Analysis in the UK CPRD.

Purpose: Some classes of glucose-lowering medications, including sodium-glucose co-transporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1-receptor agonists (GLP1-RAs) have cardio-protective benefit, but it is unclear whether this influences prescribing in the United Kingdom (UK). This study aims to describe class-level prescribing in adults with type 2 diabetes mellitus (T2DM) by cardiovascular disease (CVD) history using the Clinical Practice Research Datalink (CPRD).

Methods: Four cross-sections of people with T2DM aged 18-90 and registered with their general practice for >1 year on 1st January 2017 (n = 166,012), 1st January 2018 (n = 155,290), 1st January 2019 (n = 152,602) and 31st December 2019 (n = 143,373) were identified.

Effect of linagliptin versus placebo on cardiovascular and kidney outcomes in nephrotic-range proteinuria and type 2 diabetes: the CARMELINA randomized controlled trial.

Background: Nephrotic-range proteinuria (NRP) is associated with rapid kidney function loss and increased cardiovascular (CV) disease risk. We assessed the effects of linagliptin (LINA) on CV and kidney outcomes in people with Type 2 diabetes (T2D) with or without NRP.

Methods: Cardiovascular and renal microvascular outcome study with LINA randomized participants with T2D and CV disease and/or kidney disease to LINA 5 mg or placebo (PBO).

Long-lasting blood pressure lowering effects of nitrite are NO-independent and mediated by hydrogen peroxide, persulfides, and oxidation of protein kinase G1α redox signalling.

Aims: Under hypoxic conditions, nitrite (NO2-) can be reduced to nitric oxide (NO) eliciting vasorelaxation. However, nitrite also exerts vasorelaxant effects of potential therapeutic relevance under normal physiological conditions via undetermined mechanisms. We, therefore, sought to investigate the mechanism(s) by which nitrite regulates the vascular system in normoxia and, specifically, whether the biological effects are a result of NO generation (as in hypoxia) or mediated via alternative mechanisms involving classical downstream targets of NO [e.

DPP-4 Inhibitor Dose Selection According to Manufacturer Specifications: A Contemporary Experience From UK General Practice.

Recently, 2 dipeptidyl peptidase-4 (DPP-4) inhibitors, sitagliptin and saxagliptin, adjusted dosing specification from creatinine clearance to glomerular filtration rate, more typically reported in routine laboratory tests. This cross-sectional study examines all DPP-4 inhibitor initiations that require dose adjustment and the dose selection using data from UK general practice. Results indicate that 34% of patients taking a nonlinagliptin DPP-4 inhibitor were given a higher dose and 11% a lower dose than specified in the Summary of Product Characteristics.

Effect of Bruton's tyrosine kinase inhibitors on platelet aggregation in patients with acute myocardial infarction.

Aims: Despite widespread use of dual antiplatelet therapy in acute myocardial infarction, there remains a residual risk of morbidity and mortality. Bruton's Tyrosine Kinase inhibitors have been found to inhibit platelet aggregation through the Glycoprotein VI collagen-mediated pathway. The Bruton's Tyrosine Kinase inhibitor, Ibrutinib is used in the management of haematological malignancies and another Bruton's Tyrosine Kinase inhibitor, ONO-4059 (also known as tirabrutinib), is in clinical development.

Diastolic Ventricular Interaction in Heart Failure With Preserved Ejection Fraction.

Background Exercise-induced pulmonary hypertension is common in heart failure with preserved ejection fraction ( HF p EF ). We hypothesized that this could result in pericardial constraint and diastolic ventricular interaction in some patients during exercise. Methods and Results Contrast stress echocardiography was performed in 30 HF p EF patients, 17 hypertensive controls, and 17 normotensive controls (healthy).

Are patients in heart failure trials representative of primary care populations? A systematic review.

Background: Guidelines recommend drug treatment for patients with heart failure with a reduced ejection fraction (HFrEF), however the evidence for benefit in patients with mild disease, such as most in primary care, is uncertain. Importantly, drugs commonly used in heart failure account for one in seven of emergency admissions for adverse drug reactions.

Aim: To determine to what extent patients included in studies of heart failure treatment with beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and aldosterone antagonists were representative of a typical primary care population with HFrEF in England.

Determinants of Length of Stay Following Total Anterior Circulatory Stroke.

Identification of factors that determine length of stay (LOS) in total anterior circulatory stroke (TACS) has potential for targeted intervention to reduce the associated health care burden. This study aimed to determine which factors predict LOS following either ischaemic or haemorrhagic TACS. The study sample population was drawn from the Norfolk and Norwich Stroke and Transient Ischemic Attack (TIA) Register (1996⁻2012), a prospective registry.

Assessment of pulmonary artery pressure by echocardiography-A comprehensive review.

Pulmonary hypertension is a pathological haemodynamic condition defined as an increase in mean pulmonary arterial pressure ≥ 25 mmHg at rest, assessed using gold standard investigation by right heart catheterisation. Pulmonary hypertension could be a complication of cardiac or pulmonary disease, or a primary disorder of small pulmonary arteries. Elevated pulmonary pressure (PAP) is associated with increased mortality, irrespective of the aetiology.

A 6-Point TACS Score Predicts In-Hospital Mortality Following Total Anterior Circulation Stroke.

Background And Purpose: Little is known about the factors associated with in-hospital mortality following total anterior circulation stroke (TACS). We examined the characteristics and comorbidity data for TACS patients in relation to in-hospital mortality with the aim of developing a simple clinical rule for predicting the acute mortality outcome in TACS.

Methods: A routine data registry of one regional hospital in the UK was analyzed.

Implementation of a teaching programme to improve doctors' awareness of DVLA guidelines: a multicentre study.

Introduction: Over half of the UK population holds a driver's licence. Driver and Vehicle Licensing Authority (DVLA) guidelines are available for conditions from most specialties. Despite this, no focused training occurs in the undergraduate or postgraduate setting.

Present and future pharmacotherapeutic agents in heart failure: an evolving paradigm.

Many conditions culminate in heart failure (HF), a multi-organ systemic syndrome with an intrinsically poor prognosis. Pharmacotherapeutic agents that correct neurohormonal dysregulation and haemodynamic instability have occupied the forefront of developments within the treatment of HF in the past. Indeed, multiple trials aimed to validate these agents in the 1980s and early 1990s, resulting in a large and robust evidence-base supporting their use clinically.

Knowledge of Driving Vehicle Licensing Agency guidelines among NHS doctors: a multicentre observational study.

Objectives: Over half of the UK population holds a driver's licence. The DVLA have produced guidelines to ensure drivers with medical conditions drive safely. Doctors should ensure that patients are given appropriate information and advice if they have a medical condition affecting their driving.