Heart of England: HEFT Repository
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The Effect of Ex Vivo Human Serum from Liver Disease Patients on Cellular Protein Synthesis and Growth.
No full textSarcopenia is a common complication affecting liver disease patients, yet the underlying mechanisms remain unclear. We aimed to elucidate the cellular mechanisms that drive sarcopenia progression using an in vitro model of liver disease. C2C12 myotubes were serum and amino acid starved for 1-h and subsequently conditioned with fasted ex vivo serum from four non-cirrhotic non-alcoholic fatty liver disease patients (NAFLD), four decompensated end-stage liver disease patients (ESLD) and four age-matched healthy controls (CON) for 4- or 24-h. After 4-h C2C12 myotubes were treated with an anabolic stimulus (5 mM leucine) for 30-min. Myotube diameter was reduced following treatment with serum from ESLD compared with CON (-45%) and NAFLD (-35%; < 0.001 for both). A reduction in maximal mitochondrial respiration (24% and 29%, respectively), coupling efficiency (~12%) and mitophagy (~13%) was identified in myotubes conditioned with NAFLD and ESLD serum compared with CON ( < 0.05 for both). Myostatin (43%, = 0.04) and MuRF-1 (41%, = 0.03) protein content was elevated in myotubes treated with ESLD serum compared with CON. Here we highlight a novel, experimental platform to further probe changes in circulating markers associated with liver disease that may drive sarcopenia and develop targeted therapeutic interventions
Developing a simulation-based learning model for acute medical education during COVID-19 pandemic with Simulation via Instant Messaging - Birmingham Advance (SIMBA).
No full textSimulation-based learning (SBL) is well-established in medical education and has gained popularity, particularly during the COVID-19 pandemic when in-person teaching is infeasible. SBL replicates real-life scenarios and provides a fully immersive yet safe learning environment to develop clinical competency. Simulation via Instant Messaging - Birmingham Advance (SIMBA) is an exemplar of SBL, which we previously showed to be effective in endocrinology and diabetes. Previous studies reported the efficacy of SBL in acute medicine. We studied SIMBA as a learning intervention for healthcare professionals interested in acute medicine and defined our aims using the Kirkpatrick model: (i) develop an SBL tool to improve case management; (ii) evaluate experiences and confidence before and after; and (iii) compare efficacy across training levels.Three sessions were conducted, each representing a PDSA cycle (Plan-Do-Study-Act), consisting of four cases and advertised to healthcare professionals at our hospital and social media. Moderators facilitated progression through 25 min simulations and adopted patient and clinical roles as appropriate. Consultants chaired discussion sessions using relevant guidelines. Presimulation and postsimulation questionnaires evaluated self-reported confidence, feedback and intended changes to clinical practice.Improvements were observed in self-reported confidence managing simulated cases across all sessions. Of participants, 93.3% found SIMBA applicable to clinical practice, while 89.3% and 88.0% felt SIMBA aided personal and professional development, respectively. Interestingly, 68.0% preferred SIMBA to traditional teaching methods. Following participant feedback, more challenging cases were included, and we extended the time for simulation and discussion. The transcripts were amended to facilitate more participant-moderator interaction representing clinical practice. In addition, we refined participant recruitment over the three sessions. In cycle 1, we advertised incentives: participation counted towards teaching requirements, certificates and feedback. To rectify the reduction in participants in cycle 2, we implemented new advertisement methods in cycle 3, including on-site posters, reminder emails and recruitment of the defence deanery cohort
SARS-CoV-2 Vaccine Responses in Individuals with Antibody Deficiency: Findings from the COV-AD Study.
No full textBACKGROUND
Vaccination prevents severe morbidity and mortality from COVID-19 in the general population. The immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with antibody deficiency is poorly understood.
OBJECTIVES
COVID-19 in patients with antibody deficiency (COV-AD) is a multi-site UK study that aims to determine the immune response to SARS-CoV-2 infection and vaccination in patients with primary or secondary antibody deficiency, a population that suffers from severe and recurrent infection and does not respond well to vaccination.
METHODS
Individuals on immunoglobulin replacement therapy or with an IgG less than 4 g/L receiving antibiotic prophylaxis were recruited from April 2021. Serological and cellular responses were determined using ELISA, live-virus neutralisation and interferon gamma release assays. SARS-CoV-2 infection and clearance were determined by PCR from serial nasopharyngeal swabs.
RESULTS
A total of 5.6% (n = 320) of the cohort reported prior SARS-CoV-2 infection, but only 0.3% remained PCR positive on study entry. Seropositivity, following two doses of SARS-CoV-2 vaccination, was 54.8% (n = 168) compared with 100% of healthy controls (n = 205). The magnitude of the antibody response and its neutralising capacity were both significantly reduced compared to controls. Participants vaccinated with the Pfizer/BioNTech vaccine were more likely to be seropositive (65.7% vs. 48.0%, p = 0.03) and have higher antibody levels compared with the AstraZeneca vaccine (IgGAM ratio 3.73 vs. 2.39, p = 0.0003). T cell responses post vaccination was demonstrable in 46.2% of participants and were associated with better antibody responses but there was no difference between the two vaccines. Eleven vaccine-breakthrough infections have occurred to date, 10 of them in recipients of the AstraZeneca vaccine.
CONCLUSION
SARS-CoV-2 vaccines demonstrate reduced immunogenicity in patients with antibody deficiency with evidence of vaccine breakthrough infection
The value of ultrasound-defined tenosynovitis and synovitis in the prediction of persistent arthritis.
No full textOBJECTIVES
The value of ultrasound-defined tenosynovitis in predicting the persistence of inflammatory arthritis is not well described. In particular, the predictive utility of ultrasound-defined tenosynovitis of larger tendons is yet to be reported. We assessed the value of ultrasound-defined tenosynovitis alongside ultrasound-defined synovitis and clinical and serological variables in predicting persistent arthritis in an inception cohort of disease-modifying antirheumatic drug (DMARD)-naïve patients with early arthritis.
METHODS
One hundred and fifty DMARD-naïve patients with clinically apparent synovitis of one or more joints and a symptom duration ⩽3 months underwent baseline clinical, laboratory and ultrasound (of 19 bilateral joints and 16 bilateral tendon compartments) assessments. Outcomes were classified as persistent or resolving arthritis after 18 months follow-up. The predictive value of ultrasound-defined tenosynovitis for persistent arthritis was compared with those of ultrasound-defined synovitis, clinical and serological variables.
RESULTS
At 18 months, 99 patients (66%) had developed persistent arthritis and 51 patients (34%) had resolving disease. Multivariate logistic regression analysis showed that ultrasound-detected digit flexor tenosynovitis (OR: 6.6, 95% CI: 2.0 - 22.1, p = 0.002) provided independent predictive data for persistence over and above the presence of ultrasound-detected joint synovitis and rheumatoid factor antibodies. In the RF/ACPA-negative sub-cohort, ultrasound-defined digit flexor tenosynovitis remained a significant predictive variable (OR: 4.7, 95% CI: 1.4 - 15.8, p = 0.012), even after adjusting for ultrasound-defined joint synovitis.
CONCLUSION
Ultrasound-defined tenosynovitis provided independent predictive data for the development of persistent arthritis. The predictive role of ultrasound-defined digit flexor tenosynovitis should be further assessed; investigators should consider including this tendon site as a candidate variable when designing imaging-based predictive algorithms for persistent inflammatory arthritis development
Highly Sensitive and Specific Detection of Bladder Cancer via Targeted Ultra-deep Sequencing of Urinary DNA.
No full textBACKGROUND
There is an unmet need for an accurate, validated, noninvasive test for diagnosing and monitoring bladder cancer (BC). Detection of BC-associated mutations in urinary DNA via targeted deep sequencing could meet this need.
OBJECTIVE
To test the ability of mutational analysis of urinary DNA to noninvasively detect BC within the context of haematuria investigations and non-muscle-invasive BC (NMIBC) surveillance.
DESIGN, SETTING, AND PARTICIPANTS
Capture-based ultra-deep sequencing was performed for 443 somatic mutations in 23 genes in 591 urine cell-pellet DNAs from haematuria clinic patients and 293 from NMIBC surveillance patients. Variant calling was optimised to minimise false positives using urine samples from 162 haematuria clinic patients without BC.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
The sensitivity and specificity for BC diagnosis were determined.
RESULTS AND LIMITATIONS
Mutational analysis of urinary DNA detected 144 of the 165 haematuria patients diagnosed with incident BC from two independent cohorts, yielding overall sensitivity of 87.3% (95% confidence interval [CI] 81.2-92.0%) at specificity of 84.8% (95% CI 79.9-89.0%). The sensitivity was 97.4% for grade 3, 86.5% for grade 2, and 70.8% for grade 1 BC. Among NMIBC surveillance patients, 25 out of 29 recurrent BCs were detected, yielding sensitivity of 86.2% (95% CI 70.8-97.7%) at specificity of 62.5% (95% CI 56.1-68.0%); a positive urine mutation test in the absence of clinically detectable disease was associated with a 2.6-fold increase in the risk of future recurrence. The low number of recurrences in the NMIBC surveillance cohort and the lower sensitivity for detecting grade 1 pTa BC are limitations.
CONCLUSIONS
Detection of mutations in a small panel of BC-associated genes could facilitate noninvasive BC testing and expedite haematuria investigations. Following further validation, the test could also play a role in NMIBC surveillance.
PATIENT SUMMARY
Identification of alterations in genes that are frequently mutated in bladder cancer appears to be a promising strategy for detecting disease from urine samples and reducing reliance on examination of the bladder via a telescopic camera inserted through the urethra
Use of the oral beta blocker bisoprolol to reduce the rate of exacerbation in people with chronic obstructive pulmonary disease (COPD): a randomised controlled trial (BICS).
No full textBACKGROUND
Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity, mortality and healthcare costs. Beta blockers are well-established drugs widely used to treat cardiovascular conditions. Observational studies consistently report that beta blocker use in people with COPD is associated with a reduced risk of COPD exacerbations. The bisoprolol in COPD study (BICS) investigates whether adding bisoprolol to routine COPD treatment has clinical and cost-effective benefits. A sub-study will risk stratify participants for heart failure to investigate whether any beneficial effect of bisoprolol is restricted to those with unrecognised heart disease.
METHODS
BICS is a pragmatic randomised parallel group double-blind placebo-controlled trial conducted in UK primary and secondary care sites. The major inclusion criteria are an established predominant respiratory diagnosis of COPD (post-bronchodilator FEV < 80% predicted, FEV/FVC < 0.7), a self-reported history of ≥ 2 exacerbations requiring treatment with antibiotics and/or oral corticosteroids in a 12-month period since March 2019, age ≥ 40 years and a smoking history ≥ 10 pack years. A computerised randomisation system will allocate 1574 participants with equal probability to intervention or control groups, stratified by centre and recruitment in primary/secondary care. The intervention is bisoprolol (1.25 mg tablets) or identical placebo. The dose of bisoprolol/placebo is titrated up to a maximum of 4 tablets a day (5 mg bisoprolol) over 4-7 weeks depending on tolerance to up-dosing of bisoprolol/placebo-these titration assessments are completed by telephone or video call. Participants complete the remainder of the 52-week treatment period on the final titrated dose (1, 2, 3, 4 tablets) and during that time are followed up at 26 and 52 weeks by telephone or video call. The primary outcome is the total number of participant reported COPD exacerbations requiring oral corticosteroids and/or antibiotics during the 52-week treatment period. A sub-study will risk stratify participants for heart failure by echocardiography and measurement of blood biomarkers.
DISCUSSION
The demonstration that bisoprolol reduces the incidence of exacerbations would be relevant not only to patients and clinicians but also to healthcare providers, in the UK and globally.
TRIAL REGISTRATION
Current controlled trials ISRCTN10497306 . Registered on 16 August 2018
Risk Aversion, Organ Utilization and Changing Behavior.
No full textImproving organ acceptance and utilization rates is critical to ensure we maximize usage of donated organs as a scarce resource. Many factors underlie unnecessary discard of viable organs. Declined transplantation opportunities for candidates is associated with increased wait-list mortality. Technological advancements in organ preservation may help bridge the gap between donation and utilization, but an overlooked obstacle is the practice of risk aversion by transplant professionals when decision-making under risk. Lessons from behavioral economics, where experimental work has outlined the impact of loss or risk aversion on decision-making, have not been translated to transplantation. Many external factors can influence decision-making when accepting or utilizing organs, which are potentially amendable if external conditions are improved. However, attitudes and perceptions to risk for transplant professionals can pervade decision-making and influence behaviour. If we wish to change this behavior, then the underlying nature of decision-making under risk when accepting or utilizing organs must be studied to facilitate the design of targeted behavior change interventions to convert risk aversion to risk tolerance. To ensure optimal use of donated organs, we need more research into decision-making under risk
A Phase II trial of Higher RadiOtherapy Dose In The Eradication of early rectal cancer (APHRODITE): protocol for a multicentre, open-label randomised controlled trial.
No full textINTRODUCTION
The standard of care for patients with localised rectal cancer is radical surgery, often combined with preoperative neoadjuvant (chemo)radiotherapy. While oncologically effective, this treatment strategy is associated with operative mortality risks, significant morbidity and stoma formation. An alternative approach is chemoradiotherapy to try to achieve a sustained clinical complete response (cCR). This non-surgical management can be attractive, particularly for patients at high risk of surgical complications. Modern radiotherapy techniques allow increased treatment conformality, enabling increased radiation dose to the tumour while reducing dose to normal tissue. The objective of this trial is to assess if radiotherapy dose escalation increases the cCR rate, with acceptable toxicity, for treatment of patients with early rectal cancer unsuitable for radical surgery.
METHODS AND ANALYSIS
APHRODITE (A Phase II trial of Higher RadiOtherapy Dose In The Eradication of early rectal cancer) is a multicentre, open-label randomised controlled phase II trial aiming to recruit 104 participants from 10 to 12 UK sites. Participants will be allocated with a 2:1 ratio of intervention:control. The intervention is escalated dose radiotherapy (62 Gy to primary tumour, 50.4 Gy to surrounding mesorectum in 28 fractions) using simultaneous integrated boost. The control arm will receive 50.4 Gy to the primary tumour and surrounding mesorectum. Both arms will use intensity-modulated radiotherapy and daily image guidance, combined with concurrent chemotherapy (capecitabine, 5-fluorouracil/leucovorin or omitted). The primary endpoint is the proportion of participants with cCR at 6 months after start of treatment. Secondary outcomes include early and late toxicities, time to stoma formation, overall survival and patient-reported outcomes (European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires QLQ-C30 and QLQ-CR29, low anterior resection syndrome (LARS) questionnaire).
ETHICS AND DISSEMINATION
The trial obtained ethical approval from North West Greater Manchester East Research Ethics Committee (reference number 19/NW/0565) and is funded by Yorkshire Cancer Research. The final trial results will be published in peer-reviewed journals and adhere to International Committee of Medical Journal Editors guidelines.
TRIAL REGISTRATION NUMBER
ISRCTN16158514
