Outcome monitoring and risk stratification after cardiac procedure in neonates, infants, children and young adults born with congenital heart disease: protocol for a multicentre prospective cohort study (Children OMACp).

INTRODUCTION: Congenital heart disease (CHD) represents the most common birth defect, affecting from 0.4% to 1.2% of children born in developed countries. The survival of these patients has increased significantly, but CHD remains one of the major causes of neonatal and childhood death. The aetiology of CHD is complex, with some evidence of both genetic and environmental causes. However, there is still lack of knowledge regarding modifiable risk factors and molecular and genetic mechanisms underlying the development of CHD. This study aims to develop a prospective cohort of patients undergoing cardiac procedures that will bring together routinely collected clinical data and biological samples from patients and their biological mothers, in order to investigate risk factors and predictors of postoperative-outcomes, as well as better understanding the effect of the surgical intervention on the early and long-term outcomes. METHODS AND ANALYSIS: Children OMACp (OMACp, outcome monitoring after cardiac procedure in congenital heart disease) is a multicentre, prospective cohort study recruiting children with CHD undergoing a cardiac procedure. The study aims to recruit 3000 participants over 5 years (2019-2024) across multiple UK sites. Routine clinical data will be collected, as well as participant questionnaires collecting sociodemographic, NHS resource use and quality of life data. Biological samples (blood, urine and surgical waste tissue from patients, and blood and urine samples from biological mothers) will be collected where consent has been obtained. Follow-up outcome and questionnaire data will be collected for 5 years. ETHICS AND DISSEMINATION: The study was approved by the London-Brent Research Ethics Committee on 30 July 2019 (19/SW/0113). Participants (or their parent/guardian if under 16 years of age) must provide informed consent prior to being recruited into the study. Mothers who wish to take part must also provide informed consent prior to being recruited. The study is sponsored by University Hospitals Bristol and Weston Foundation Trust and is managed by the University of Bristol. Children OMACp is adopted onto the National Institute for Health Research Clinical Research Network portfolio. Findings will be disseminated through peer-reviewed publications, presentation at conference, meetings and through patient organisations and newsletters. TRIAL REGISTRATION NUMBER: ISRCTN17650644.

Efficacy of propofol-supplemented cardioplegia on biomarkers of organ injury in patients having cardiac surgery using cardiopulmonary bypass: A protocol for a randomised controlled study (ProMPT2).

INTRODUCTION: Cardiac surgery with cardiopulmonary bypass and cardioplegic arrest is known to be responsible for ischaemia and reperfusion organ injury. In a previous study, ProMPT, in patients undergoing coronary artery bypass or aortic valve surgery we demonstrated improved cardiac protection when supplementing the cardioplegia solution with propofol (6 mcg/ml). The aim of the ProMPT2 study is to determine whether higher levels of propofol added to the cardioplegia could result in increased cardiac protection. METHODS AND ANALYSIS: The ProMPT2 study is a multi-centre, parallel, three-group, randomised controlled trial in adults undergoing non-emergency isolated coronary artery bypass graft surgery with cardiopulmonary bypass. A total of 240 patients will be randomised in a 1:1:1 ratio to receive either cardioplegia supplementation with high dose of propofol (12 mcg/ml), low dose of propofol (6 mcg/ml) or placebo (saline). The primary outcome is myocardial injury, assessed by serial measurements of myocardial troponin T up to 48 hours after surgery. Secondary outcomes include biomarkers of renal function (creatinine) and metabolism (lactate). ETHICS AND DISSEMINATION: The trial received research ethics approval from South Central - Berkshire B Research Ethics Committee and Medicines and Healthcare products Regulatory Agency in September 2018. Any findings will be shared though peer-reviewed publications and presented at international and national meetings. Participants will be informed of results through patient organisations and newsletters. TRIAL REGISTRATION: ISRCTN15255199. Registered in March 2019.

Surgical-PEARL protocol: a multicentre prospective cohort study exploring aetiology, management and outcomes for patients with congenital anomalies potentially requiring surgical intervention.

INTRODUCTION: Congenital anomalies affect over 2% of pregnancies. Surgical advances have reduced mortality and improved survival for patients with congenital anomalies potentially requiring surgical (CAPRS) intervention. However, our understanding of aetiology, diagnostic methods, optimal management, outcomes and prognostication is limited. Existing birth cohorts have low numbers of individual heterogenous CAPRS. The Surgical Paediatric congEnital Anomalies Registry with Long term follow-up (Surgical-PEARL) study aims to establish a multicentre prospective fetal, child and biological parent cohort of CAPRS. METHODS AND ANALYSIS: From 2022 to 2027, Surgical-PEARL aims to recruit 2500 patients with CAPRS alongside their biological mothers and fathers from up to 15 UK centres. Recruitment will be antenatal or postnatal dependent on diagnosis timing and presentation to a recruitment site. Routine clinical data including antenatal scans and records, neonatal intensive care unit (NICU) records, diagnostic and surgical data and hospital episode statistics will be collected. A detailed biobank of samples will include: parents' blood and urine samples; amniotic fluid if available; children's blood and urine samples on admission to NICU, perioperatively or if the child has care withdrawn or is transferred for extracorporeal membrane oxygenation; stool samples; and surplus surgical tissue. Parents will complete questionnaires including sociodemographic and health data. Follow-up outcome and questionnaire data will be collected for 5 years. Once established we will explore the potential of comparing findings in Surgical-PEARL to general population cohorts born in the same years and centres. ETHICS AND DISSEMINATION: Ethical and health research authority approvals have been granted (IRAS Project ID: 302251; REC reference number 22/SS/0004). Surgical-PEARL is adopted onto the National Institute for Health Research Clinical Research Network portfolio. Findings will be disseminated widely through peer-reviewed publication, conference presentations and through patient organisations and newsletters. TRIAL REGISTRATION NUMBER: ISRCTN12557586.

Effectiveness, cost-effectiveness and safety of gabapentin versus placebo as an adjunct to multimodal pain regimens in surgical patients: protocol of a placebo controlled randomised controlled trial with blinding (GAP study).

INTRODUCTION: Gabapentin is an antiepileptic drug currently licensed to treat epilepsy and neuropathic pain but has been used off-label to treat acute postoperative pain. The GAP study will compare the effectiveness, cost-effectiveness and safety of gabapentin as an adjunct to standard multimodal analgesia versus placebo for the management of pain after major surgery. METHODS AND ANALYSIS: The GAP study is a multicentre, double-blind, randomised controlled trial in patients aged 18 years and over, undergoing different types of major surgery (cardiac, thoracic or abdominal). Patients will be randomised in a 1:1 ratio to receive either gabapentin (600 mg just before surgery and 600 mg/day for 2 days after surgery) or placebo in addition to usual pain management for each type of surgery. Patients will be followed up daily until hospital discharge and then at 4 weeks and 4 months after surgery. The primary outcome is length of hospital stay following surgery. Secondary outcomes include pain, total opioid use, adverse health events, health related quality of life and costs. ETHICS AND DISSEMINATION: This study has been approved by the Research Ethics Committee . Findings will be shared with participating hospitals and disseminated to the academic community through peer-reviewed publications and presentation at national and international meetings. Patients will be informed of the results through patient organisations and participant newsletters. TRIAL REGISTRATION NUMBER: ISRCTN63614165.

DALBACEN cohort: dalbavancin as consolidation therapy in patients with endocarditis and/or bloodstream infection produced by gram-positive cocci.

OBJECTIVES: To analyse the effectiveness of dalbavancin (DBV) in clinical practice as consolidation therapy in patients with bloodstream infection (BSI) and/or infective endocarditis (IE) produced by gram-positive cocci (GPC), as well as its safety and pharmacoeconomic impact. METHODS: A multicentre, observational and retrospective study was conducted of hospitalised patients with IE and/or BSI produced by GPC who received at least one dose of DBV. Clinical response was assessed during hospitalization, at 3 months and at 1 year. RESULTS: Eighty-three patients with median age of 73 years were enrolled; 73.5% were male; 59.04% had BSI and 49.04% IE (44.04% prosthetic valve IE, 32.4% native IE, 23.5% pacemaker lead). The most frequently isolated microorganism was Staphylococcus aureus in BSI (49%) and coagulase-negative staphylococci in IE (44.1%). All patients with IE were clinically cured in hospital; at 12 months, there was 2.9% loss to follow-up, 8.8% mortality unrelated to IE, and 2.9% therapeutic failure rate. The percentage effectiveness of DBV to treat IE was 96.7%. The clinical cure rate for BSI was 100% during hospital stay and at 3 months; there were no recurrences or deaths during the follow-up. No patient discontinued treatment for adverse events. The saving in hospital stay was 636 days for BSI (315,424.20€) and 557 days for IE (283,187.45€). CONCLUSIONS: DBV is an effective consolidation antibiotic therapy in clinically stabilized patients with IE and/or BSI. It proved to be a cost-effective treatment, reducing the hospital stay, thanks to the pharmacokinetic/pharmacodynamic profile of this drug.

Effectiveness and safety of dual therapy with rilpivirine and boosted darunavir in treatment-experienced patients with advanced HIV infection: a preliminary 24 week analysis (RIDAR study).

BACKGROUND: The objective was to analyze the effectiveness and safety of dual therapy with rilpivirine plus boosted-darunavir (RPV + bDRV) in real-life patients. METHODS: Observational, retrospective, multi-center study in HIV+ patients who had received RPV + bDRV for 24 weeks to optimize/simplify their previous antiretroviral treatment. We determined the percentage of patients without virologic failure (2 consecutive viral loads > 50 copies/mL) at 24 weeks of treatment. RESULTS: The study included 161 patients from 15 hospitals with median age of 49 years; 29.3% had previous AIDS stage and median CD4+ lymphocyte nadir of 170 cells/uL. They had been diagnosed with HIV for a median of 17 years and had received 14 years of ART, with five previous treatment combinations, and 36.6% had a history of virological failure. The reasons for the switch were simplification/optimization (49.7%), toxicity/intolerance (17.4%), or inadequate effectiveness of previous ART (10.6%). Baseline VL of 50-1000 copies/mL was recorded in 25.5% of the patients. In the"intention-to-treat" analysis at 24 weeks, 87.6% of 161 patients continued the study treatment without virologic failure criteria. In the "on treatment" analysis (excluding patients who discontinued treatment with dual therapy for any reason other than virologic failure) the efficacy was 94.6% (141/149 patients). CONCLUSIONS: Dual therapy with RPV + DRVb proved to be effective and safe in patients with advanced HIV infection, long exposure to ART, low CD4 nadir, previous virologic failure, and/or history of ineffective ART.

High prevalence and incidence of HPV-related anal cancer precursor lesions in HIV-positive women in the late HAART era. / Alta prevalencia e incidencia de lesiones precursoras de cáncer anal asociada a la infección por VPH en mujeres VIH positivas en la era tardía del TAR.

INTRODUCTION: Anal cancer is one of the most common non-AIDS defining malignancies, especially in men who have sex with men and women living with HIV (WLHIV). OBJECTIVES: To evaluate the prevalence and incidence of precursor lesions (high-grade squamous intraepithelial lesions [HSIL]) and anal cancer in our cohort of women and to compare them to cervical lesions; to calculate the percentage of patients that acquire and clear oncogenic genotypes (HR-HPV) in the anal canal; and to determine predictive factors for anal HPV infection. PATIENTS AND METHODS: Prospective-longitudinal study (May 2012-December 2016). At baseline (V1) and follow up visits, anal mucosa samples were taken in liquid medium for cytology and HPV PCR. In cases of abnormal anal cytology and/or positive HR-HPV PCR results, a high resolution anoscopy was performed. Patients were also referred to the gynaecologist. RESULTS: Ninety five women with an average age of 43.7years were included. At baseline, 11.6% had cervical abnormalities (4.1% CIN1, 2.2% CIN2/3, 1.1% cervical cancer), 64.3% anal abnormalities (50% LSIL/AIN1, 9.5% HSIL/AIN2/3 and 2.4% anal cancer) and 49.4% had HR-HPV genotypes. During 36months of follow up, the incidence of anal HSIL was 16×1,000 person-years; 14.8% acquired HR-HPV genotypes and 51.2% cleared them, P=.007. No patients presented CIN1/2/3/ or cervical cancer. In the multivariate analysis we found the following predictive factors for HR-HPV infection: smoking (RR: 1.55, 95%CI: 0.99-2.42), number of sexual partners >3 (RR: 1.69; 95%CI: 1.09-2.62), cervical and anal dysplasia (RR: 1.83; 95%CI: 1.26-2.67) and (RR: 1.55; 95%CI: 1.021-2.35), respectively. CONCLUSIONS: Despite clearance rates of anal oncogenic genotypes being higher than acquisition rates, prevalence and incidence of HSIL were still high and greater than cervical HSIL. Therefore, screening for these lesions should perhaps be offered to all WLHIV.

Polyethyleneimine-Coated Gold Nanoparticles: Straightforward Preparation of Efficient DNA Delivery Nanocarriers.

A novel one-pot method for the synthesis of polyethyleneimine (PEI)-coated gold nanoparticles (AuPEI-NPs) that combines the reductant-stabilizer properties of PEI with microwave irradiation starting from hydrogen tetrachloroaurate acid (HAuCl4 ) and branched PEI 25 kDa (b25kPEI) was explored. The method was straightforward, green, and low costing, for which the Au/PEI ratio (1:1 to 1:128 w/w) was a key parameter to modulate their capabilities as DNA delivery nanocarriers. Transfection assays in CHO-k1 cells demonstrated that AuPEI-NPs with 1:16 and 1:32 w/w ratios behaved as effective DNA gene vectors with improved transfection efficiencies (twofold) and significantly lower toxicity than unmodified b25kPEI and Lipofectamine 2000. The transfection mediated by these AuPEI-NP-DNA polyplexes preferentially used the caveolae-mediated route for intracellular internalization, as shown by studies performed by using specific internalization inhibitors as well as colocalization with markers of clathrin- and caveolae-dependent pathways. The AuPEI-NP polyplexes preferentially used the more efficient caveolae internalization pathway to promote transfection, a fact that supports their higher transfection efficiency relative to that of Lipofectamine 2000. In addition, intracellular trafficking of the AuPEI-NPs was studied by transmission electron microscopy.