• Identifying dimensions of fatigue in haemodialysis important to patients,caregivers, and health professionals: an international survey.

      Fluck, Richard (2019-07)
      BACKGROUND: Patient-reported outcome measures of fatigue used in research in haemodialysis vary widely in the dimensions assessed; and the importance of these dimensions to patients and health professionals is unknown. This study aimed to identify the most important dimensions of fatigue to assess in patients on haemodialysis participating in trials. METHODS: In an international survey, patients/caregivers and health professionals rated the absolute and relative importance of content and measurement dimensions to include in a core outcome measure of fatigue. A 9-point Likert scale (7-9 indicating critical importance) was used to assess absolute importance and best-worst scale (BWS) was used to assess importance of each dimension compared to others RESULTS: In total, 169 patients/caregivers and 336 health professionals from 60 countries completed the survey. Both groups (patients/caregivers and health professionals) rated life participation (7.55), tiredness (7.40), level of energy (7.37), ability to think clearly (7.15), post-dialysis fatigue (7.13), motivation (7.03) and ability to concentrate (7.03) as critically important (mean Likert score greater than 7) content dimensions to include in a core outcome measure. Compared to patients and caregivers, health professionals rated post-dialysis fatigue, memory and verbal abilities more highly. Based on the relative importance scores, life participation was ranked most highly above all content dimensions. Severity was rated and ranked the most important measurement dimension by all stakeholders. CONCLUSION: A core outcome measure of fatigue should assess impact of fatigue on life participation, tiredness and level of energy, using a severity scale. A consistent and valid measurement of fatigue will improve the value of trials in supporting decision-making based on this important outcome.
    • Imaging the kidney using magnetic resonance techniques: structure to function

      Selby, Nicholas; Mahmoud, Hudu (2016-09)
      PURPOSE OF REVIEW: MRI can noninvasively assess the structure and function of the kidney in a single MRI scan session. This review summarizes recent advancements in functional renal MRI techniques, with a particular focus on clinical applications. RECENT FINDINGS: A number of MRI techniques now provide measures of relevance to the pathophysiology of kidney disease. Diffusion-weighted imaging, used in chronic kidney disease and renal transplantation, shows promise as a measure of renal fibrosis. Longitudinal relaxation time (T1) mapping has been utilized in cardiac MRI to measure fibrosis and oedema; recent work shows its potential in the kidney. Blood oxygen-level-dependent MRI to measure renal oxygenation has been extensively studied, but a number of other factors affect results making it hard to draw definite conclusions as to its utility as an independent measure. Phase contrast and arterial spin labelling can measure renal artery blood flow and renal perfusion without exogenous contrast, as opposed to dynamic contrast-enhanced studies. In general, current data on clinical use of functional renal MRI are restricted to cross-sectional studies. SUMMARY: Renal MRI has seen significant recent advances. Current evidence demonstrates its potential, and next steps include wider evaluation of its clinical application.
    • Imaging the kidney using magnetic resonance techniques: structure to function.

      Selby, Nicholas (2016-11)
      PURPOSE OF REVIEW: MRI can noninvasively assess the structure and function of the kidney in a single MRI scan session. This review summarizes recent advancements in functional renal MRI techniques, with a particular focus on clinical applications. RECENT FINDINGS: A number of MRI techniques now provide measures of relevance to the pathophysiology of kidney disease. Diffusion-weighted imaging, used in chronic kidney disease and renal transplantation, shows promise as a measure of renal fibrosis. Longitudinal relaxation time (T1) mapping has been utilized in cardiac MRI to measure fibrosis and oedema; recent work shows its potential in the kidney. Blood oxygen-level-dependent MRI to measure renal oxygenation has been extensively studied, but a number of other factors affect results making it hard to draw definite conclusions as to its utility as an independent measure. Phase contrast and arterial spin labelling can measure renal artery blood flow and renal perfusion without exogenous contrast, as opposed to dynamic contrast-enhanced studies. In general, current data on clinical use of functional renal MRI are restricted to cross-sectional studies. SUMMARY: Renal MRI has seen significant recent advances. Current evidence demonstrates its potential, and next steps include wider evaluation of its clinical application.
    • The impact of acute beta-hydroxy-beta-methylbutyrate (HMB) ingestion on glucose and insulin kinetics in young and older men

      Herrod, Philip; Phillips, Hannah; Ranat, Reesha; Hardy, EJO (2020-10)
      Insulin resistance (IR) is a key feature in the development of numerous metabolic diseases. The cornerstone for treatment for IR remains diet and exercise, however these have poor rates of adherence. Beta-hydroxy-beta-methylbutyrate (HMB) is a nutraceutical with contentious effects on IR in animal models. The aim of this study was to evaluate the impact of acute HMB on IR in humans during an oral glucose tolerance test (OGTT). Young and older male volunteers underwent two 75 g OGTT with or without 3 g HMB. In young men, HMB significantly reduced the insulin area-under-the-curve (AUC), with no difference in glucose AUC, resulting in a numerical increase in the Cederholm index of insulin sensitivity. In older men, HMB had no effect on insulin or glucose responses. In conclusion, acute HMB may improve IR following a glucose load in young men; however, this does not appear to be sustained into older age.
    • Impact of Compliance with a Care Bundle on Acute Kidney Injury Outcomes: A Prospective Observational Study.

      Kolhe, Nitin; Staples, David; Reilly, Timothy; Merrison, Daniel; McIntyre, Christopher; Fluck, Richard; Selby, Nicholas; Taal, Maarten (2015-07)
      BACKGROUND: A recent report has highlighted suboptimal standards of care for acute kidney injury (AKI) patients in England. The objective of this study was to ascertain if improvement in basic standard of care by implementing a care bundle (CB) with interruptive alert improved outcomes in patients with AKI. METHODS: An AKI CB linked to electronic recognition of AKI, coupled with an interruptive alert, was introduced to improve basic care delivered to patients with AKI. Outcomes were compared in patients who had the CB completed within 24 hours (early CB group) versus those who didn't have the CB completed or had it completed after 24 hours. RESULTS: In the 11-month period, 2297 patients had 2500 AKI episodes, with 1209 and 1291 episodes occurring before and after implementation of the AKI CB with interruptive alert, respectively. The CB was completed within 24 hours in 306 (12.2%) of AKI episodes. In-hospital case-fatality was significantly lower in the early CB group (18% versus 23.1%, p 0.046). Progression to higher AKI stages was lower in the early CB group (3.9% vs. 8.1%, p 0.01). In multivariate analysis, patients in the early CB group had lower odds of death at discharge (0.641; 95% CI 0.46, 0.891), 30 days (0.707; 95% CI 0.527, 0.950), 60 days (0.704; 95% CI 0.526, 0.941) and after a median of 134 days (0.771; 95% CI 0.62, 0.958). CONCLUSIONS: Compliance with AKI CB was associated with a decrease in case-fatality and reduced progression to higher AKI stage. Further interventions are required to improve utilization of the CB.
    • Impact of Dietetic Intervention on Skin Autofluorescence and Nutritional Status in Persons Receiving Dialysis: A Proof of Principle Study

      Willingham, Fiona; Selby, Nicholas; Taal, Maarten (2020-02)
      OBJECTIVE: Advanced glycation end-products (AGEs) are uremic toxins that result from oxidative stress and food consumption. It has been reported that markers of malnutrition are more important determinants of increased skin autofluorescence (SAF), a measure of AGE accumulation and risk factor for mortality, than high dietary AGE intake in a hemodialysis (HD) population, suggesting that correcting malnutrition may decrease SAF. DESIGN AND METHODS: We investigated this hypothesis in a single-center, nonrandomized proof-of-principle study. We enrolled 27 patients on HD and one on peritoneal dialysis with malnutrition who received individualized nutritional advice and support over 6 months. SAF was measured at baseline, 3 months, and 6 months. Dietary intake and nutritional status were assessed at baseline and 6 months. Results were compared with a control group of malnourished patients on dialysis (n = 41 HD and 8 peritoneal dialysis) from a previous observational study. RESULTS: The intervention group showed a significant increase in dietary intake, including AGEs, Subjective Global Assessment score, and serum albumin, while SAF levels remained stable for over 6 months (3.8 ± 0.7 arbitrary units [AU] vs. 3.7 ± 0.7 AU; P = .3). Conversely, in the control group, SAF increased significantly during the observation period (3.5 ± 0.9 AU vs. 3.8 ± 1.2 AU; P = .03) during which there was no improvement in nutritional intake and other markers of nutrition, although dietary AGE intake and Subjective Global Assessment score did increase. CONCLUSION: Dietetic support was associated with stable SAF levels in this proof-of-principal study despite an increase in dietary AGE intake, suggesting that interventions to improve nutrition may be important in preventing the rise in SAF observed in malnourished dialysis populations. Further long-term studies are needed to test this hypothesis and evaluate the impact on survival.
    • Impact of gut hormone FGF-19 on type-2 diabetes and mitochondrial recovery in a prospective study of obese diabetic women undergoing bariatric surgery

      Piya, Milan (2017-02)
      BACKGROUND: The ileal-derived hormone, fibroblast growth factor 19 (FGF-19), may promote weight loss and facilitate type-2 diabetes mellitus remission in bariatric surgical patients. We investigated the effect of different bariatric procedures on circulating FGF-19 levels and the resulting impact on mitochondrial health in white adipose tissue (AT). METHODS: Obese and type-2 diabetic women (n = 39, BMI > 35 kg/m(2)) undergoing either biliopancreatic diversion (BPD), laparoscopic greater curvature plication (LGCP), or laparoscopic adjustable gastric banding (LAGB) participated in this ethics approved study. Anthropometry, biochemical, clinical data, serum, and AT biopsies were collected before and 6 months after surgery. Mitochondrial gene expression in adipose biopsies and serum FGF-19 levels were then assessed. RESULTS: All surgeries led to metabolic improvements with BPD producing the greatest benefits on weight loss (↓30%), HbA1c (↓28%), and cholesterol (↓25%) reduction, whilst LGCP resulted in similar HbA1c improvements (adjusted for BMI). Circulating FGF-19 increased in both BPD and LGCP (χ(2)(2) = 8.088; P = 0.018), whilst, in LAGB, FGF-19 serum levels decreased (P = 0.028). Interestingly, circulating FGF-19 was inversely correlated with mitochondrial number in AT across all surgeries (n = 39). In contrast to LGCP and LAGB, mitochondrial number in BPD patients corresponded directly with changes in 12 of 14 mitochondrial genes assayed (P < 0.01). CONCLUSIONS: Elevated serum FGF-19 levels post-surgery were associated with improved mitochondrial health in AT and overall diabetic remission. Changes in circulating FGF-19 levels were surgery-specific, with BPD producing the best metabolic outcomes among the study procedures (BPD > LGCP > LAGB), and highlighting mitochondria in AT as a potential target of FGF-19 during diabetes remission.
    • Impact of malnutrition on health-related quality of life in persons receiving dialysis: a prospective study.

      Pittman, Zoe; Selby, Nicholas; Taal, Maarten
      Health-related quality of life (HRQoL) is severely impaired in persons receiving dialysis. Malnutrition has been associated with some measures of poor HRQoL in cross-sectional analyses in dialysis populations, but no studies have assessed the impact of malnutrition and dietary intake on change in multiple measures of HRQoL over time. We investigated the most important determinants of poor HRQoL and the predictors of change in HRQoL over time using several measures of HRQoL. We enrolled 119 haemodialysis and 31 peritoneal dialysis patients in this prospective study. Nutritional assessments (Subjective Global Assessment [SGA], anthropometry and 24-hour dietary recalls) and HRQoL questionnaires (Short Form-36 [SF-36] mental [MCS] and physical component scores [PCS] and European QoL-5 Dimensions [EQ5D] health state [HSS] and visual analogue scores [VAS]) were performed at baseline, 6 and 12 months. Mean age was 64(14) years. Malnutrition was present in 37% of the population. At baseline, malnutrition assessed by SGA was the only factor independently (and negatively) associated with all four measures of HRQoL. No single factor was independently associated with decrease in all measures of HRQoL over 1 year. However, prevalence/development of malnutrition over one year was an independent predictor of 1-year decrease in EQ5D HSS and 1-year decrease in fat intake independently predicted the 1-year decline in SF-36 MCS and PCS, and EQ5D VAS. These findings strengthen the importance of monitoring for malnutrition and providing nutritional advice to all persons on dialysis. Future studies are needed to evaluate the impact of nutritional interventions on HRQoL and other long-term outcomes.
    • Improving Clinical Prediction Rules In Acute Kidney Injury With The Use of Biomarkers of Cell Cycle Arrest: A Pilot Study.

      Selby, Nicholas (2018-06)
      INTRODUCTION: Early recognition of patients developing acute kidney injury is of considerable interest, we report the first use of a combination of a clinical prediction rule with a biomarker in emergent adult medical patients to improve AKI recognition. METHODS: Single-centre prospective pilot study of medical admissions without AKI identified as high risk by a clinical prediction rule. Urine samples were obtained and tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) - biomarkers associated with cell cycle arrest, were measured. OUTCOME: Creatinine based KDIGO hospital-acquired AKI (HA-AKI). RESULTS: Of 69 patients recruited, HA-AKI developed in 13% (n = 9), in whom biomarker values were higher (median 0.43 [interquartile range 0.21-1.25] vs. 0.07 [0.03-0.16] in cases without (P = 0.008). Peak rise in creatinine was higher in biomarker positive cases (median 30 μmol/l (7-72) vs 1 μmol/l (0-16), P = 0.002). AUROC was 0.78 (95% CI 0.57-0.98). At the suggested cut-off (0.3) sensitivity for predicting AKI was 78% (95% CI 40-97%), specificity 89% (78-95%), positive predictive value 50% (31-69%) and negative predictive value 96% (89-99%). DISCUSSION: Addition of a urinary biomarker allows exclusion of a significant number of patients identified to be at higher risk of AKI by a clinical prediction rule.
    • Improving readiness for recruitment through simulated trial activation: the Adjuvant Steroids in Adults with Pandemic influenza (ASAP) trial.

      Bewick, Tom (2017-11)
      BACKGROUND: Research in public health emergencies requires trials to be set up in readiness for activation at short notice and in anticipation of limited timelines for patient recruitment. We conducted a simulated activation of a hibernating pandemic influenza clinical trial in order to test trial processes and to determine the value of such simulation in maintaining trial readiness. METHODS: The simulation involved the Nottingham Clinical Trials Unit, one participating hospital, one manufacturing unit and the Investigational Medicinal Product (IMP) supplier. During the exercise, from 15 September 2015 to 2 December 2015, clinical staff at the participating site completed the trial training package, a volunteer acting as a patient was recruited to the study, 'dummy' IMP was prescribed and follow-up completed. RESULTS: Successful activation of the hibernating trial with patient recruitment within 4 weeks of 'arousal' as planned was demonstrated. A need for greater resilience in anticipation of staff absenteeism was identified, particularly in relation to key trial procedures where the potential for delay is high. A specific issue relating to the IMP Stock Control System was highlighted as a potential source of error that could compromise the randomisation sequence. The simulation exercise was well received by site investigators and increased their confidence in being able to meet the likely demands of the trial when activated. The estimated cost of the exercise was £1995; 90% of this being staff costs. CONCLUSIONS: Simulated activation is useful as a means to test, and prepare for, the rapid activation of 'hibernating' research studies. Whether simulation exercises can also help reduce waste in complex clinical trial research deserves further exploration. TRIAL REGISTRATION: EudraCT Number 2013-001051-12, ISRCTN72331452 . Registered on 6 March 2013.
    • In Patients With Severe Alcoholic Hepatitis, Prednisolone Increases Susceptibility to Infection and Infection-Related Mortality, and Is Associated With High Circulating Levels of Bacterial DNA.

      Austin, Andrew (2017-04)
      BACKGROUND & AIMS: Infections are common in patients with severe alcoholic hepatitis (SAH), but little information is available on how to predict their development or their effects on patients. Prednisolone is advocated for treatment of SAH, but can increase susceptibility to infection. We compared the effects of infection on clinical outcomes of patients treated with and without prednisolone, and identified risk factors for development of infection in SAH. METHODS: We analyzed data from 1092 patients enrolled in a double-blind placebo-controlled trial to evaluate the efficacy of treatment with prednisolone (40 mg daily) or pentoxifylline (400 mg 3 times each day) in patients with SAH. The 2 × 2 factorial design led to 547 patients receiving prednisolone; 546 were treated with pentoxifylline. The trial was conducted in the United Kingdom from January 2011 through February 2014. Data on development of infection were collected at evaluations performed at screening, baseline, weekly during admission, on discharge, and after 90 days. Patients were diagnosed with infection based on published clinical and microbiologic criteria. Risk factors for development of infection and effects on 90-day mortality were evaluated separately in patients treated with prednisolone (n = 547) and patients not treated with prednisolone (n = 545) using logistic regression. Pre treatment blood levels of bacterial DNA (bDNA) were measured in 731 patients. RESULTS: Of the 1092 patients in the study, 135 had an infection at baseline, 251developed infections during treatment, and 89 patients developed an infection after treatment. There was no association between pentoxifylline therapy and the risk of serious infection (P = .084), infection during treatment (P = .20), or infection after treatment (P = .27). Infections classified as serious were more frequent in patients treated with prednisolone (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.27-2.92; P = .002). There was no association between prednisolone therapy and infection during treatment (OR, 1.04; 95% CI, 0.78-1.37; P = .80). However, a higher proportion (10%) of patients receiving prednisolone developed an infection after treatment than of patients not given prednisolone (6%) (OR, 1.70; 95% CI, 1.07-2.69; P = .024). Development of infection was associated with increased 90-day mortality in patients with SAH treated with prednisolone, independent of model for end-stage liver disease or Lille score (OR, 2.46; 95% CI, 1.41-4.30; P = .002). High circulating bDNA predicted infection that developed within 7 days of prednisolone therapy, independent of Model for End-Stage Liver Disease and white blood cell count (OR, 4.68; 95% CI, 1.80-12.17; P = .001). In patients who did not receive prednisolone, infection was not independently associated with 90-day mortality (OR, 0.94; 95% CI, 0.54-1.62; P = .82) or levels of bDNA (OR, 0.83; 95% CI, 0.39-1.75; P = .62). CONCLUSIONS: Patients with SAH given prednisolone are at greater risk for developing serious infections and infections after treatment than patients not given prednisolone, which may offset its therapeutic benefit. Level of circulating bDNA before treatment could identify patients at high risk of infection if given prednisolone; these data could be used to select therapies for patients with SAH. EudraCT no: 2009-013897-42; Current Controlled Trials no: ISRCTN88782125.
    • Incidence of metachronous visible lesions in patients referred for radiofrequency ablation (RFA) therapy for early Barrett's neoplasia: a single-centre experience.

      Cole, Andrew (2016-01)
      OBJECTIVE: Evaluate the incidence of metachronous visible lesions (VLs) in patients referred for radiofrequency ablation (RFA) for early Barrett's neoplasia. DESIGN: This study was conducted as part of the service evaluation audit. SETTING: Tertiary referral centre. PATIENTS: All patients with dysplastic Barrett's oesophagus referred for RFA were included for analysis. White light high-resolution endoscopy (HRE), autofluorescence imaging and narrow band imaging were sequentially performed. Endoscopic mucosal resection (EMR) was performed for all VL. Three to six months after EMR, all patients underwent initial RFA and then repeat RFA procedures at three monthly intervals. INTERVENTIONS: All endoscopy reports and final staging by EMR/surgery were evaluated and included for analysis. RESULTS: Fifty patients were analysed; median age 73 years, 84% men. 38/50 patients (76%) had a previous EMR due to the presence of VL before referred for ablation; twelve patients had no previous treatment. In total, 151 ablation procedures were performed, median per patient 2.68. Twenty metachronous VL were identified in 14 patients before the first ablation or during the RFA protocol; incidence was 28%. All metachronous lesions were successfully resected by EMR. Upstaging after rescue EMR compared with the initial histology was observed in four patients (28%). CONCLUSIONS: In total, 28% of patients enrolled in the RFA programme were diagnosed to have metachronous lesions. This high-incidence rate highlights the importance of a meticulous examination to identify and resect any VL before every ablation session. RFA treatment for early Barrett's neoplasia should be performed in tertiary referral centres with HRE and EMR facilities and expertise.
    • Increased incidence of adult pneumococcal pneumonia during school holiday periods.

      Bewick, Tom (2017-03)
      Child contact is a recognised risk factor for adult pneumococcal disease. Peaks in invasive pneumococcal disease incidence observed during winter holidays may be related to changes in social dynamics. This analysis was conducted to examine adult pneumococcal community-acquired pneumonia (CAP) incidence during school holiday periods. Between September 2008 and 2013, consecutive adults admitted to hospitals covering the Greater Nottingham area with a diagnosis of CAP were studied. Pneumococcal pneumonia was detected using culture and antigen detection methods. Of 2221 adults studied, 575 (25.9%) were admitted during school holidays and 643 (29.0%) had pneumococcal CAP. CAP of pneumococcal aetiology was significantly more likely in adults admitted during school holidays compared to term time (35.3% versus 26.7%; adjusted OR 1.38, 95% CI 1.11-1.72, p=0.004). Over the 5-year period, the age-adjusted incidence of hospitalised pneumococcal CAP was higher during school holidays compared to term time (incident rate ratio 1.35, 95% CI 1.14-1.60, p<0.001); there was no difference in rates of all-cause CAP or non pneumococcal CAP. Reported child contact was higher in individuals with pneumococcal CAP admitted during school holidays compared to term time (42.0% versus 33.7%, OR 1.43, 95% CI 1.00-2.03, p=0.046). Further study of transmission dynamics in relation to these findings and to identify appropriate intervention strategies is warranted.
    • Individualised dialysate temperature improves intradialytic haemodynamics and abrogates haemodialysis-induced myocardial stunning, without compromising tolerability.

      Jefferies, Helen; Burton, James; McIntyre, Christopher (2011-01)
      BACKGROUND/AIMS: Haemodialysis-induced myocardial stunning is associated with intradialytic hypotension, increased likelihood of cardiovascular events and death. Dialysis at 35°C reduces stunning, but adverse thermal symptoms limit technique adoption. This study investigated whether individualised body temperature dialysis improves haemodynamic stability and abrogates stunning. METHODS: Randomised crossover study of 11 patients compared LV regional wall motion abnormalities (RWMAs) at 37°C (HD(37)) and body temperature ('individualised', HD(ind)). Regional systolic function was quantitatively assessed by echocardiography. Haemodynamics were assessed using continuous pulse wave analysis. Thermal symptoms were scored by questionnaire. RESULTS: Mean predialysis body temperature was 36.0 ± 0.1°C. Mean number of peak stress RWMAs per patient was lower with HD(ind) (3.9 ± 1.4 vs. 5.3 ± 1.5, p = 0.03). Intradialytic systolic BP was higher during HD(ind) versus HD(37) (p < 0.001). Individualised body temperature dialysis demonstrated symptomatic tolerability comparable to HD(37). CONCLUSIONS: Individualised-temperature haemodialysis abrogates stunning, providing effective haemodynamic stabilisation at no additional therapy cost.
    • Infarct size following complete revascularization in patients presenting with STEMI: a comparison of immediate and staged in-hospital non-infarct related artery PCI subgroups in the CvLPRIT study.

      Kelly, Damian (2016-11)
      BACKGROUND: The CvLPRIT study showed a trend for improved clinical outcomes in the complete revascularisation (CR) group in those treated with an immediate, as opposed to staged in-hospital approach in patients with multivessel coronary disease undergoing primary percutaneous intervention (PPCI). We aimed to assess infarct size and left ventricular function in patients undergoing immediate compared with staged CR for multivessel disease at PPCI. METHODS: The Cardiovascular Magnetic Resonance (CMR) substudy of CvLPRIT was a multicentre, prospective, randomized, open label, blinded endpoint trial in PPCI patients with multivessel disease. These data refer to a post-hoc analysis in 93 patients randomized to the CR arm (63 immediate, 30 staged) who completed a pre-discharge CMR scan (median 2 and 4 days respectively) after PPCI. The decision to stage non-IRA revascularization was at the discretion of the treating interventional cardiologist. RESULTS: Patients treated with a staged approach had more visible thrombus (26/30 vs. 31/62, p = 0.001), higher SYNTAX score in the IRA (9.5, 8-16 vs. 8.0, 5.5-11, p = 0.04) and a greater incidence of no-reflow (23.3 % vs. 1.6 % p < 0.001) than those treated with immediate CR. After adjustment for confounders, staged patients had larger infarct size (19.7 % [11.7-37.6] vs. 11.6 % [6.8-18.2] of LV Mass, p = 0.012) and lower ejection fraction (42.2 ± 10 % vs. 47.4 ± 9 %, p = 0.019) compared with immediate CR. CONCLUSIONS: Of patients randomized to CR in the CMR substudy of CvLPRIT, those in whom the operator chose to stage revascularization had larger infarct size and lower ejection fraction, which persisted after adjusting for important covariates than those who underwent immediate CR. Prospective randomized trials are needed to assess whether immediate CR results in better clinical outcomes than staged CR. TRIAL REGISTRATION: ISRCTN70913605 , Registered 24th February 2011. DOI: 10.1186/s12968-016-0298-2 PMID: 27842548 [PubMed - in process] 2. Mol Med Rep. 2016 Nov 8. doi: 10.3892/mmr.2016.5933. [Epub ahead of print] Selection of suitable reference genes for gene expression studies in normal human ovarian tissues, borderline ovarian tumours and ovarian cancer. Ofinran O(1), Bose U(1), Hay D(1), Abdul S(2), Tufatelli C(1), Khan R(1). Author information: (1)Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, The University of Nottingham, Royal Derby Hospital, Derby DE22 3DT, UK. (2)Department of Gynaecological Oncology, Royal Derby Hospital, Derby DE22 3NE, UK. The use of reference genes is the most common method of controlling the variation in mRNA expression during quantitative polymerase chain reaction, although the use of traditional reference genes, such as β actin, glyceraldehyde 3 phosphate dehydrogenase or 18S ribosomal RNA, without validation occasionally leads to unreliable results. Therefore, the present study aimed to evaluate a set of five commonly used reference genes to determine the most suitable for gene expression studies in normal ovarian tissues, borderline ovarian and ovarian cancer tissues. The expression stabilities of these genes were ranked using two gene stability algorithms, geNorm and NormFinder. Using geNorm, the two best reference genes in ovarian cancer were β glucuronidase and β actin. Hypoxanthine phosphoribosyltransferase 1 and β glucuronidase were the most stable in ovarian borderline tumours, and hypoxanthine phosphoribosyltransferase 1 and glyceraldehyde 3 phosphate dehydrogenase were the most stable in normal ovarian tissues. NormFinder ranked β actin the most stable in ovarian cancer, and the best combination of two genes was β glucuronidase and β actin. In borderline tumours, hypoxanthine phosphoribosyltransferase 1 was identified as the most stable, and the best combination was hypoxanthine phosphoribosyltransferase 1 and β glucuronidase. In normal ovarian tissues, β glucuronidase was recommended as the optimum reference gene, and the most optimum pair of reference genes was hypoxanthine phosphoribosyltransferase 1 and β actin. To the best of our knowledge, this is the first study to investigate the selection of a set of reference genes for normalisation in quantitative polymerase chain reactions in different ovarian tissues, and therefore it is recommended that β glucuronidase, β actin and hypoxanthine phosphoribosyltransferase 1 are the most suitable reference genes for such analyses.
    • Infarct Size Following Treatment With Second- Versus Third-Generation P2Y12 Antagonists in Patients With Multivessel Coronary Disease at ST-Segment Elevation Myocardial Infarction in the CvLPRIT Study.

      Kelly, Damian (2016-05)
      BACKGROUND: Third-generation P2Y12 antagonists (prasugrel and ticagrelor) are recommended in guidelines on ST-segment elevation myocardial infarction. Mechanisms translating their more potent antiplatelet activity into improved clinical outcomes versus the second-generation P2Y12 antagonist clopidogrel are unclear. The aim of this post hoc analysis of the Complete Versus Lesion-Only PRImary PCI Trial-CMR (CvLPRIT-CMR) substudy was to assess whether prasugrel and ticagrelor were associated with reduced infarct size compared with clopidogrel in patients undergoing primary percutaneous coronary intervention. METHODS AND RESULTS: CvLPRIT-CMR was a multicenter, prospective, randomized, open-label, blinded end point trial in 203 ST-segment elevation myocardial infarction patients with multivessel disease undergoing primary percutaneous coronary intervention with either infarct-related artery-only or complete revascularization. P2Y12 inhibitors were administered according to local guidelines. The primary end point of infarct size on cardiovascular magnetic resonance was not significantly different between the randomized groups. P2Y12 antagonist administration was not randomized. Patients receiving clopidogrel (n=70) compared with those treated with either prasugrel or ticagrelor (n=133) were older (67.8±12 versus 61.5±10 years, P<0.001), more frequently had hypertension (49% versus 29%, P=0.007), and tended to have longer symptom-to-revascularization time (234 versus 177 minutes, P=0.05). Infarct size (median 16.1% [quartiles 1-3, 10.5-27.7%] versus 12.1% [quartiles 1-3, 4.8-20.7%] of left ventricular mass, P=0.013) and microvascular obstruction incidence (65.7% versus 48.9%, P=0.022) were significantly greater in patients receiving clopidogrel. Infarct size remained significantly different after adjustment for important covariates using both generalized linear models (P=0.048) and propensity score matching (P=0.025). CONCLUSIONS: In this analysis of CvLPRIT-CMR, third-generation P2Y12 antagonists were associated with smaller infarct size and lower microvascular obstruction incidence versus the second-generation P2Y12 antagonist clopidogrel for ST-segment elevation myocardial infarction. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com/ISRCTN70913605.
    • Infections in relapsed myeloma patients treated with isatuximab plus pomalidomide and dexamethasone during the COVID-19 pandemic: Initial results of a UK-wide real-world study.

      Firas, AK
      OBJECTIVES: There are no real-world data describing infection morbidity in relapsed/refractory myeloma (RRMM) patients treated with anti-CD38 isatuximab in combination with pomalidomide and dexamethasone (IsaPomDex). In this UK-wide retrospective study, we set out to evaluate infections experienced by routine care patients who received this novel therapy across 24 cancer centres during the COVID-19 pandemic. METHODS: The primary endpoint was infection morbidity (incidence, grading, hospitalization) as well as infection-related deaths. Secondary outcomes were clinical predictors of increased incidence of any grade (G2-5) and high grade (≥G3) infections. RESULTS: In a total cohort of 107 patients who received a median (IQR) of 4 cycles (2-8), 23.4% of patients experienced ≥1 any grade (G2-5) infections (total of 31 episodes) and 18.7% of patients experienced ≥1 high grade (≥G3) infections (total of 22 episodes). Median time (IQR) from start of therapy to first episode was 29 days (16-75). Six patients experienced COVID-19 infection, of whom 5 were not vaccinated and 1 was fully vaccinated. The cumulative duration of infection-related hospitalizations was 159 days. The multivariate (MVA) Poisson Regression analysis demonstrated that a higher co-morbidity burden with Charlson Co-morbidity Index (CCI) score ≥4 (incidence rate ratio (IRR) = 3, p = 0.012) and sub-optimal myeloma response less than a partial response.
    • Influence of dialysis therapies in the development of cardiac disease in CKD.

      Odudu, Aghogho; McIntyre, Christopher (2012-05)
      It is well recognised that dialysis patients suffer excess morbidity and mortality and that this is mainly due to cardiac failure and sudden cardiac death rather than conventional risk factors. Dialysis patients are primed by a number of structural, functional and microcirculatory abnormalities to experience demand myocardial ischaemia. We have shown that haemodialysis induces repetitive myocardial ischaemia in the majority of patients. In this way, haemodialysis itself may contribute to the development of heart failure and the risk of sudden death. There is recent appreciation that peritoneal dialysis is also capable of exerting short-term effects on cardiovascular performance through mechanisms both mutual and exclusive to haemodialysis. The aim of this paper is to give an appreciation of the possibility that modification of the dialysis procedure is capable of improving treatment tolerability and has the potential to reduce the excessive rates of cardiovascular morbidity and mortality.
    • Inhaled corticosteroids and bone health.

      Sellahewa, Luckni (2014-01)
      Inhaled corticosteroids (ICS) are the cornerstones in the management of bronchial asthma and some cases of chronic obstructive pulmonary disease. Although ICS are claimed to have low side effect profiles, at high doses they can cause systemic adverse effects including bone diseases such as osteopenia, osteoporosis and osteonecrosis. Corticosteroids have detrimental effects on function and survival of osteoblasts and osteocytes, and with the prolongation of osteoclast survival, induce metabolic bone disease. Glucocorticoid-induced osteoporosis (GIO) can be associated with major complications such as vertebral and neck of femur fractures. The American College of Rheumatology (ACR) published criteria in 2010 for the management of GIO. ACR recommends bisphosphonates along with calcium and vitamin D supplements as the first-line agents for GIO management. ACR recommendations can be applied to manage patients on ICS with a high risk of developing metabolic bone disease. This review outlines the mechanisms and management of ICS-induced bone disease.