• Primary IgA nephropathy: new insights and emerging therapies

  Selvaskandan, Haresh (2024-05)

  Primary IgA nephropathy (IgAN) is a common glomerular disorder defined by predominant mesangial IgA deposition. Once thought to follow a progressive course in 10-20% of those diagnosed, emerging evidence now suggests most will progress to kidney failure over their lifetimes. Although the lack of safe and effective treatments to impede disease progression continues to present a challenge, the landscape of IgAN has dramatically evolved over the last 2 years. Driven by fundamental changes to accepted end points for IgAN clinical trials as well as fascinating new insights into the pathophysiology of IgAN, a swathe of novel and repurposed therapies are currently being evaluated. Already, two novel drugs, targeted-release formulation budesonide and sparsentan, have received conditional approvals for the treatment of IgAN, with sodium glucose co-transporter 2 inhibitors establishing themselves as further options. Soon to join this ensemble are likely to be treatments that modulate the complement system and B-cell activity; several are currently undergoing clinical trials in IgAN with promising interim results. In this review, we provide an overview of evolving epidemiological insights, disease mechanisms, emerging therapies, and contemporary challenges surrounding the management of IgAN.
• Management of a patient with an unusual trajectory of a temporary trans-venous pacing lead

  Acharya, Metesh; Davorin, Sef; Kavanagh, Ethan (2024-06-26)

  Perforation of the right ventricle during placement of pacing wires is a well-documented complication and can be potentially fatal. Use of temporary pacemaker, helical screw leads and steroids use prior to implant are recognised as risk factors for development of post-permanent pacemaker effusion. We reported an unusual case of pacing wire perforating interventricular septum into the left ventricle that occurred during the implant procedure performed in another institution. After the preoperative work-up and transfer to our tertiary cardiothoracic centre, the patient underwent successful surgical management. In conclusion, early recognition and timely diagnosis using advanced multimodality imaging can guide surgical intervention and prevent unfavourable consequences of device-related complications.
• Editorial: Overcoming challenges in microbial immunology: 2022

  Ondondo, Beatrice (2024-06-17)
• The use of albuminuria or proteinuria for risk prediction in IgAN

  Barratt, Jonathan (2024-07-01)
• Association between socioeconomic deprivation, ethnicity and health outcomes in preschool children with recurrent wheeze in England: a retrospective cohort study

  Gaillard, Erol; Lo, David (2024-07-02)

  Background: Preschool-aged children have among the highest burden of acute wheeze. We investigated differences in healthcare use, treatment and outcomes for recurrent wheeze/asthma in preschoolers from different ethno-socioeconomic backgrounds. Methods: Retrospective cohort study using data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics in England. We reported number of acute presentations and hospitalisations stratified by index of multiple deprivation (IMD) and ethnicity; and factors associated with treatment non-escalation, and hospitalisation rates using multivariable logistic and Poisson regression models. Results: 194 291 preschool children were included. In children not trialled on asthma preventer medications, children from the most deprived IMD quintile (adjusted OR 1.67; 95% CI 1.53 to 1.83) and South Asian (1.77; 1.64 to 1.91) children were more likely to have high reliever usage and where specialist referral had not occurred, the odds of referral being indicated was higher in the most deprived quintile (1.39; 1.28 to 1.52) and South Asian (1.86; 1.72 to 2.01) children compared with the least deprived quintile and white children, respectively.Hospitalisation rates for wheeze/asthma were significantly higher in children from the most deprived quintile (adjusted IRR 1.20; 95% CI 1.13 to 1.27) compared with the least, and in South Asian (1.57; 1.44 to 1.70) and black (1.32; 1.22 to 1.42) compared with white children. Conclusions: We identified inequalities in wheeze/asthma treatment and morbidity in preschool children from more deprived, and non-white backgrounds. A multifaceted approach to tackle health inequality at both the national and local levels, which includes a more integrated and standardised approach to treatment, is needed to improve health outcomes in children with preschool wheeze/asthma.
• Phenogrouping heart failure with preserved or mildly reduced ejection fraction using electronic health record data

  Squire, Iain (2024-07-05)

  Background: Heart failure (HF) with preserved or mildly reduced ejection fraction includes a heterogenous group of patients. Reclassification into distinct phenogroups to enable targeted interventions is a priority. This study aimed to identify distinct phenogroups, and compare phenogroup characteristics and outcomes, from electronic health record data. Methods: 2,187 patients admitted to five UK hospitals with a diagnosis of HF and a left ventricular ejection fraction ≥ 40% were identified from the NIHR Health Informatics Collaborative database. Partition-based, model-based, and density-based machine learning clustering techniques were applied. Cox Proportional Hazards and Fine-Gray competing risks models were used to compare outcomes (all-cause mortality and hospitalisation for HF) across phenogroups. Results: Three phenogroups were identified: (1) Younger, predominantly female patients with high prevalence of cardiometabolic and coronary disease; (2) More frail patients, with higher rates of lung disease and atrial fibrillation; (3) Patients characterised by systemic inflammation and high rates of diabetes and renal dysfunction. Survival profiles were distinct, with an increasing risk of all-cause mortality from phenogroups 1 to 3 (p < 0.001). Phenogroup membership significantly improved survival prediction compared to conventional factors. Phenogroups were not predictive of hospitalisation for HF. Conclusions: Applying unsupervised machine learning to routinely collected electronic health record data identified phenogroups with distinct clinical characteristics and unique survival profiles.
• The effects of inhaled corticosteroids on healthy airways

  Bradding, Peter (2024-07)

  Background: The effects of inhaled corticosteroids (ICS) on healthy airways are poorly defined. Objectives: To delineate the effects of ICS on gene expression in healthy airways, without confounding caused by changes in disease-related genes and disease-related alterations in ICS responsiveness. Methods: Randomized open-label bronchoscopy study of high-dose ICS therapy in 30 healthy adult volunteers randomized 2:1 to (i) fluticasone propionate 500 mcg bd daily or (ii) no treatment, for 4 weeks. Laboratory staff were blinded to allocation. Biopsies and brushings were analysed by immunohistochemistry, bulk RNA sequencing, DNA methylation array and metagenomics. Results: ICS induced small between-group differences in blood and lamina propria eosinophil numbers, but not in other immunopathological features, blood neutrophils, FeNO, FEV1, microbiome or DNA methylation. ICS treatment upregulated 72 genes in brushings and 53 genes in biopsies, and downregulated 82 genes in brushings and 416 genes in biopsies. The most downregulated genes in both tissues were canonical markers of type-2 inflammation (FCER1A, CPA3, IL33, CLEC10A, SERPINB10 and CCR5), T cell-mediated adaptive immunity (TARP, TRBC1, TRBC2, PTPN22, TRAC, CD2, CD8A, HLA-DQB2, CD96, PTPN7), B-cell immunity (CD20, immunoglobulin heavy and light chains) and innate immunity, including CD48, Hobit, RANTES, Langerin and GFI1. An IL-17-dependent gene signature was not upregulated by ICS. Conclusions: In healthy airways, 4-week ICS exposure reduces gene expression related to both innate and adaptive immunity, and reduces markers of type-2 inflammation. This implies that homeostasis in health involves tonic type-2 signalling in the airway mucosa, which is exquisitely sensitive to ICS. Trial registration: ClinicalTrials.gov NCT02476825.
• Quantifying the effect of vaccination on transmission in modelling studies

  Nazareth, Joshua; Pan, Daniel; Pareek, Manish (2024-06-06)
• Role of gender in short and long-term outcomes after surgery for type a aortic dissection: analysis of a multicentre european registry

  Acharya, Metesh; Mariscalco, Giovanni (2024-07-01)

  Objectives: Gender difference in the outcome after type A aortic dissection (TAAD) surgery remains an issue of ongoing debate. In this study, we aimed to evaluate the impact of gender on the short- and long-term outcome after surgery for TAAD. Methods: A multicentre European registry retrospectively included all consecutive TAAD surgery patients between 2005 and 2021 from 18 hospitals across 8 European countries. Early and late mortality, and cumulative incidence of aortic reoperation were compared between genders. Results: A total of 3902 patients underwent TAAD surgery, with 1185 (30.4%) being females. After propensity score matching, 766 pairs of males and females were compared. No statistical differences were detected in the early postoperative outcome between genders. Ten-year survival was comparable between genders (47.8% vs 47.1%; log-rank test, P = 0.679), as well as cumulative incidences of distal or proximal aortic reoperations. Ten-year relative survival compared to country-, year-, age- and sex-matched general population was higher among males (0.65) compared to females (0.58). The time-period subanalysis revealed advancements in surgical techniques in both genders over the years. However, an increase in stroke was observed over time for both populations, particularly among females. Conclusions: The past 16 years have witnessed marked advancements in surgical techniques for TAAD in both males and females, achieving comparable early and late mortality rates. Despite these findings, late relative survival was still in favour of males.
• Can compassionate leadership of senior hospital leaders help retain trainee doctors?

  McCarthy, Mark (2024-07-02)

  Background: High burnout and low retention rates among trainee doctors threaten the future viability of the UK medical workforce. This study empirically examined factors that can sustain trainee doctors. Method: A total of 323 trainee doctors from 25 National Health Service (NHS) Trusts in England and Wales completed an online survey on their training and employment experiences. A mixed method approach was employed. Results: Structural equation modelling revealed that perceived compassionate leadership of hospital senior leaders (CLSL) (i.e., doctors in senior clinical and management positions, and senior managers) is directly and negatively associated with trainee doctors' burnout and intention to quit. We propose the associations may be indirectly strengthened through two mediating pathways: increased psychological contract fulfilment (PCF) of training/organisational support and reduced worry about the state of the NHS; however, only the former is supported. The model can explain a substantial 37% of the variance in reported burnout and 28% of intention to quit among trainee doctors. Being a Foundation Year (FY) trainee was significantly associated with poor PCF and burnout. Rich qualitative data further elaborated on their experiences in terms of senior leaders' awareness of their training/working experiences, listening to and acting on. Conclusions: Active and demonstrable CLSL plays a vital role in trainee doctors' retention. It has both direct (through support) and indirect effects through improving trainee doctors' PCF to reduce burnout and intention to quit. This seems particularly valuable among FY doctors. Implications for the development and management of the medical workforce are discussed.
• Obesity enhances Non-Th2 airway inflammation in a murine model of allergic asthma

  Mohamed, Marwa M E (2024-06-04)

  Obese patients with asthma present with aggravated symptoms that are also harder to treat. Here, we used a mouse model of allergic asthma sensitised and challenged to house dust mite (HDM) extracts to determine whether high-fat-diet consumption would exacerbate the key features of allergic airway inflammation. C57BL/6 mice were intranasally sensitised and challenged with HDM extracts over a duration of 3 weeks. The impact of high-fat-diet (HFD) vs. normal diet (ND) chow was studied on HDM-induced lung inflammation and inflammatory cell infiltration as well as cytokine production. HFD-fed mice had greater inflammatory cell infiltration around airways and blood vessels, and an overall more severe degree of inflammation than in the ND-fed mice (semiquantitative blinded evaluation). Quantitative assessment of HDM-associated Th2 responses (numbers of lung CD4+ T cells, eosinophils, serum levels of allergen-specific IgE as well as the expression of Th2 cytokines (Il5 and Il13)) did not show significant changes between the HFD and ND groups. Interestingly, the HFD group exhibited a more pronounced neutrophilic infiltration within their lung tissues and an increase in non-Th2 cytokines (Il17, Tnfa, Tgf-b, Il-1b). These findings provide additional evidence that obesity triggered by a high-fat-diet regimen may exacerbate asthma by involving non-Th2 and neutrophilic pathways.
• Best practice for the selection, design and implementation of UK Kidney Association guidelines: a modified Delphi consensus approach

  Burton, James (2024-06-18)

  Background: Despite research into how to effectively implement evidence-based recommendations into clinical practice, a lack of standardisation in the commissioning and development of clinical practice guidelines can lead to inconsistencies and gaps in implementation. This research aimed to ascertain how topics in kidney care worthy of guideline development within the UK should be chosen, prioritised, designed and implemented. Methods: Following a modified Delphi methodology, a multi-disciplinary panel of experts in kidney healthcare from across the UK developed 35 statements on the issues surrounding the selection, development and implementation of nephrology guidelines. Consensus with these statements was determined by agreement using an online survey; the consensus threshold was defined as 75% agreement. Results: 419 responses were received. Of the 364 healthcare practitioners (HCPs), the majority had over 20 years of experience in their role (n=123) and most respondents were nephrologists (n=95). Of the 55 non-clinical respondents, the majority were people with kidney disease (n=41) and the rest were their carers or family. Participants were from across England, Northern Ireland, Scotland and Wales. Consensus between HCPs was achieved in 32/35 statements, with 28 statements reaching ≥90% agreement. Consensus between patients and patient representatives was achieved across all 20 statements, with 13/20 reaching ≥90% agreement. Conclusions: The current results have provided the basis for six recommendations to improve the selection, design and implementation of guidelines. Actioning these recommendations will help improve the accessibility of, and engagement with, clinical guidelines, contributing to the continuing development of best practice in UK kidney care.
• Management of common femoral artery occlusive disease: the current gap in the evidence and future perspectives

  Messeder, Sarah; Musto, Liam; Saratzis, Athanasios (2024-06-18)

  The common femoral artery (CFA) is the most common site affected by peripheral artery disease. Due its various anatomical and morphological features, common femoral endarterectomy has long since been the preferred treatment option. However, there are complications associated with common femoral endarterectomy including, but not limited to, surgical site infections, hematoma formation, bleeding, and nerve injury. Unfortunately, this has been further complicated by the ageing population and increasing epidemic of obesity and diabetes mellitus. Within vascular surgery, there has been a rise in use of endovascular techniques for peripheral artery disease. Endovascular repair of the CFA is safe and feasible. One clear advantage is that they can be performed under local or regional anesthesia, thus reducing morbidity. This narrative review seeks to describe the current gap in the evidence and future perspectives in the management of common femoral artery occlusive disease.
• The training to improve dyspnoea study- patient experiences of using a High Frequency Airway Oscillating device

  Barradell, Amy; Daynes, Enya; Greening, Neil; Singh, Sally (2024-06-13)

  Introduction: The High Frequency Airway Oscillating device (HFAO) was developed to help patients with COPD feel less breathless through flow resistive respiratory muscle training and fixed rate oscillations. Previous work has demonstrated that this device can improve inspiratory muscle strength over and above a sham device. Both groups improved their breathlessness and preserved clinical benefits though there were no statistically significant differences seen over and above the sham device. It is important to understand patient perceptions of using a device and how this may influence their treatment and therefore a qualitative analysis was conducted to understand participant experiences of a HFAO device. Methods: This was an exploratory qualitative analysis involving participants recruited to the Training to Improve Dyspnoea (TIDe) study. Participants completed a satisfaction survey and were invited to take part in a focus group. Focus groups were conducted by a researcher independent to the randomised controlled trial. Data was analysed independently by two researchers using inductive thematic analysis, and themes/sub-themes were agreed jointly. Data is presented in themes and sub themes and triangulated with survey response data. Results: Fourteen participants were recruited to two focus groups (71% male, mean [SD] age 64[9] years). The key themes were patient selection, device use, and investment. Patient selection explores the disease characteristics, emotional impact and management of care. Device use explores the device prescription and usage, routine and lifestyle and effectiveness. Investment covers accessibility, understanding, benefits vs participation and overall perceptions of the device. Conclusion: This research demonstrates the complexity of device interventions and that key considerations should be given to patient selection, the device use itself and, the time and cost investment required for participants to successfully implement the device into daily life.
• Clinical outcomes of the type II hybrid procedure for the repair of extensive aortic arch pathology

  Mariscalco, Giovanni (2024-05-31)

  Background: Type II hybrid arch repair (HAR) has been used for the repair of extensive aortic arch pathology. The aim of this study was to retrospectively analyze single-stage hybrid treatment involving replacement of the ascending aorta, arch debranching, and zone 0 stent graft deployment. Methods: We retrospectively analyzed clinical data from 41 patients with acute and chronic aortic disease who underwent a type II hybrid arch procedure at Beijing Anzhen Hospital and Beijing Chaoyang Hospital from January 2020 to August 2022. The femoral arteries and right axillary arteries were used as cannulation sites to decrease the risk of malperfusion. During surgery, the nasopharyngeal temperature was lowered to 30 ℃. Demographic, perioperative, and late results data were retrieved and analyzed. Results: The mean age of the patients was 54.9±11.1 years, and 31 patients (75.6%) were men. In all cases, zone 0 stent graft deployment was successful, with no in-hospital mortality. The median follow-up time was 10.5 [interquartile range (IQR), 4.8-17.6] months, and the survival rate was 94.9% during follow-up. Complications included cerebral infarction (3 patients, 7.3%) and renal failure requiring dialysis (3 patients, 7.3%). There were no occurrences of paraplegia, and no stent-related complications occurred during the follow-up period. Conclusions: The single-stage hybrid arch procedure achieved satisfactory early results and represents a less invasive approach for treating complex diffuse aortic disease that affects the arch. This strategy is an important technical advance in the treatment of high-risk patients with extensive aortic arch pathology.
• Sodium zirconium cyclosilicate in HFrEF and hyperkalemia: REALIZE-K design and baseline characteristics

  Squire, Iain (2024-05-13)

  Background: Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF). However, MRAs are often underused because of hyperkalemia concerns. Objectives: The purpose of this study was to assess whether sodium zirconium cyclosilicate (SZC), a nonabsorbed crystal that traps and rapidly lowers potassium, enables MRA use in patients with HFrEF and prevalent hyperkalemia (or at high risk). Methods: REALIZE-K is a prospective, double-blind, placebo-controlled trial in patients with HFrEF (NYHA functional class II-IV; left ventricular ejection fraction ≤40%), optimal therapy (except MRA), and prevalent hyperkalemia (or at high risk). During the open-label run-in, all participants underwent protocol-mandated spironolactone titration (target: 50 mg daily); those with prevalent (cohort 1) or incident (cohort 2) hyperkalemia during titration started SZC. Participants achieving normokalemia while on spironolactone ≥25 mg daily were randomized to continuing SZC or matching placebo for 6 months. The primary composite endpoint was proportion of participants with optimal response (normokalemia, on spironolactone ≥25 mg daily, no rescue for hyperkalemia [months 1-6]). Results: Of 365 patients (run-in), 202 were randomized. Baseline characteristics included mean age 70 years, prevalent comorbidities (78% estimated glomerular filtration rate <60 mL/min/1.73 m2, 38% atrial fibrillation/flutter), high N-terminal pro B-type natriuretic peptide (median 1,136 pg/mL), and high HFrEF therapy use (64% sacubitril/valsartan, 96% beta-blocker, 42% sodium glucose co-transporter 2 inhibitor). At randomization, 78% were receiving spironolactone 50 mg daily. Conclusions: REALIZE-K is the first trial to evaluate whether SZC can enable rapid and safe MRA optimization and long-term continuation in patients with HFrEF and prevalent/high risk of hyperkalemia. (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients with Symptomatic HFrEF Receiving Spironolactone; NCT04676646).
• New horizons in peripheral artery disease

  Houghton, John; Saratzis, Athanasios; Sayers, Rob D (2024-06-01)

  Peripheral artery disease (PAD) is the lower limb manifestation of systemic atherosclerotic disease. PAD may initially present with symptoms of intermittent claudication, whilst chronic limb-threatening ischaemia (CLTI), the end stage of PAD, presents with rest pain and/or tissue loss. PAD is an age-related condition present in over 10% of those aged ≥65 in high-income countries. Guidelines regarding definition, diagnosis and staging of PAD and CLTI have been updated to reflect the changing patterns and presentations of disease given the increasing prevalence of diabetes. Recent research has changed guidelines on optimal medical therapy, with low-dose anticoagulant plus aspirin recommended in some patients. Recently published randomised trials highlight where bypass-first or endovascular-first approaches may be optimal in infra-inguinal disease. New techniques in endovascular surgery have increased minimally invasive options for ever more complex disease. Increasing recognition has been given to the complexity of patients with CLTI where a high prevalence of both frailty and cognitive impairment are present and a significant burden of multi-morbidity and polypharmacy. Despite advances in minimally invasive revascularisation techniques and reduction in amputation incidence, survival remains poor for many with CLTI. Shared decision-making is essential, and conservative management is often appropriate for older patients. There is emerging evidence of the benefit of specialist geriatric team input in the perioperative management of older patients undergoing surgery for CLTI. Recent UK guidelines now recommend screening for frailty, cognitive impairment and delirium in older vascular surgery patients as well as recommending all vascular surgery services have support and input from specialist geriatrics teams.
• Platelet membrane biomimetic nanoparticle-targeted delivery of TGF-β1 siRNA attenuates renal inflammation and fibrosis

  Yang, Bin (2024-06-25)

  The progression of renal fibrosis to end-stage renal disease (ESRD) is significantly influenced by transforming growth factor-beta (TGF-beta) signal pathway. This study aimed to develop nanoparticles (PMVs@PLGA complexes) with platelet membrane camouflage, which can transport interfering RNA to target and regulate the TGF-β1 pathway in damaged renal tissues. The aim is to reduce the severity of acute kidney injury and to reduce fibrosis in chronic kidney disease. Hence, we formulated PMVs@TGF-β1-siRNA NP complexes and employed them for both in vitro and in vivo therapy. From the experimental findings we know that the PMVs@siRNA NPs could effectively target the kidneys in unilateral ureteral obstruction (UUO) mice and ischemia/reperfusion injury (I/R) mice. In animal models of treatment, PMVs@siRNA NP complexes effectively decreased the expression of TGF-β1 and mitigated inflammation and fibrosis in the kidneys by blocking the TGF-β1/Smad3 pathway. Therefore, these PMVs@siRNA NP complexes can serve as a promising biological delivery system for treating kidney diseases.
• Heteroresistance in tuberculosis: are we missing drug-resistant bacteria hiding in plain sight?

  Haldar, Pranabashis (2024-06-14)
• Atrial fibrillation inpatient management patterns and clinical outcomes during the conflict in Syria: An observational cohort study

  Aljabal, Majed; Antoun, Ibrahim; Kotb, Ahmed; Nasser, Muhammad; Ng, Andre; Somani, Riyaz; Zakkar, Mustafa (2024-06-03)

  Background: Atrial fibrillation (AF) is the most common sustained arrhythmia worldwide. However, there is no data on AF inpatient management strategies and clinical outcomes in Syria. Objectives: The study aims were to review the inpatient management of patients with AF and assess cardiovascular (CV) mortality in a tertiary cardiology centre in Latakia, Syria. Methods: A single-centre retrospective observational cohort study was conducted at Tishreen's University Hospital, Latakia, Syria, from June 2021 to June 2023. Patients ≥16 years of age presenting and being treated for AF as the primary diagnosis with or without a thromboembolic event were included. Medical records were examined for patients' demographics, laboratory results, treatment plans and inpatient details. Studied outcomes include inpatient all-cause and CV mortality, ischemic and bleeding events, and conversion to sinus rhythm (SR). Results: The study included 596 patients. The median age was 58, and 61% were males. 121 patients (20.3%) were known to have AF. A rhythm control strategy was pursued in 39% of patients. Ischemic and bleeding events occurred in 62 (11%) and 12 (2%), respectively. CV and all-cause mortality occurred in 28 (4.7%) and 31 patients (5%), respectively. The presence of valvular heart disease (VHD) (adjusted odds ratio (aOR) = 9.1, 95% confidence interval (CI): 1.7 to 55.1, p < .001), thyroid disease (aOR: 9.7, 95% CI = 1.2 to 91.6, p < .001) and chronic obstructive pulmonary disease (COPD) (aOR: 82, 95% CI: 12.7 to 71, p < .001) were independent risk factors of increased CV inpatient mortality. Conclusion: Syrian inpatients admitted with AF in Latakia are relatively younger than those in other countries. Active thyroid disease, COPD and VHD were independent risk factors of inpatient CV mortality with AF.

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