IntroductionAcute kidney injury (AKI) is a common and severe complication of cardiac surgery. The administration of pharmacological renoprotective agents during the perioperative period could prevent ...or reduce the severity of AKI and improve clinical outcomes. Experimental studies suggest that sildenafil may have therapeutic potential for the prevention of AKI. This trial will test the hypothesis that postoperative AKI will be reduced in cardiac surgery patients if they receive sildenafil compared with placebo.Methods and analysisAdult cardiac surgery patients 18 years of age or above undergoing cardiac surgery with cardiopulmonary bypass and cardioplegic arrest at a single tertiary cardiac centre in the UK will be randomised in a 1:1 ratio to receive either sildenafil or placebo. The primary outcome is serum creatinine concentration measured at preoperation and daily for up to 7 days postoperatively. Secondary outcomes will include measures of inflammation, organ injury, volumes of blood transfused and resource use. Allocation concealment, internet-based randomisation stratified by operation type, and blinding of outcome assessors will reduce the risk of bias. A sample size of 112 patients will have a 90% power to detect a mean difference of 10 μmol/L for serum creatinine values between treatment and placebo control groups with an alpha value of 0.05.Ethics and disseminationThe trial protocol was approved by a UK ethics committee (reference 15/YH/0489). The trial findings will be disseminated in scientific journals and meetings.Trial registration number ISRCTN18386427.
Risk assessment tools quantify the risk of an outcome using multiple covariates (risk factors). Risk assessment tools are recommended by diabetes prevention guidelines to allow blood tests to be ...targeted at individuals with an increased risk of currently having non-diabetic hyperglycaemia or undiagnosed diabetes. This thesis presents work on the identification, development and validation of such risk assessment tools. Key Findings: - A systematic review of risk assessment tools for prevalent non-diabetic hyperglycaemia was undertaken. This is the first systematic review to focus on risk assessment tools for prevalent non-diabetic hyperglycaemia. Eighteen risk assessment tools for prevalent non-diabetic hyperglycaemia, and prevalent non-diabetic hyperglycaemia or undiagnosed Type 2 diabetes are summarised. - An empirical comparison of logistic regression, decision trees, support vector machines and the novel application of chain event graphs for developing risk assessment tools found logistic regression and linear support machine vectors had the best external performance. This is the first empirical comparison for a binary medical outcome in cross-sectional data to include an external validation. - Risk groups for the Leicester Practice risk score were established, allowing consistent advice to be given across general practices when utilising the tool. - The Leicester Self-Assessment and Leicester Practice risk scores were externally validated using a nationally representative longitudinal dataset. Both gave comparable performance for identifying prevalent non-diabetic hyperglycaemia or undiagnosed diabetes to the dataset on which they were developed. Furthermore, both identified a small proportion of the population with a substantially increased risk of developing diabetes when utilised in the recommended two-stage screening programme and thus are advocated for use across England. This thesis aids those wishing to use a risk assessment tool for non-diabetic hyperglycaemia in their selection or development of an appropriate tool, as well as addressing some of the previous limitations of the Leicester Self-Assessment and Leicester Practice risk scores.
Risk assessment tools quantify the risk of an outcome using multiple covariates (risk factors). Risk assessment tools are recommended by diabetes prevention guidelines to allow blood tests to be ...targeted at individuals with an increased risk of currently having non-diabetic hyperglycaemia or undiagnosed diabetes. This thesis presents work on the identification, development and validation of such risk assessment tools. Key Findings: - A systematic review of risk assessment tools for prevalent non-diabetic hyperglycaemia was undertaken. This is the first systematic review to focus on risk assessment tools for prevalent non-diabetic hyperglycaemia. Eighteen risk assessment tools for prevalent non-diabetic hyperglycaemia, and prevalent non-diabetic hyperglycaemia or undiagnosed Type 2 diabetes are summarised. - An empirical comparison of logistic regression, decision trees, support vector machines and the novel application of chain event graphs for developing risk assessment tools found logistic regression and linear support machine vectors had the best external performance. This is the first empirical comparison for a binary medical outcome in cross-sectional data to include an external validation. - Risk groups for the Leicester Practice risk score were established, allowing consistent advice to be given across general practices when utilising the tool. - The Leicester Self-Assessment and Leicester Practice risk scores were externally validated using a nationally representative longitudinal dataset. Both gave comparable performance for identifying prevalent non-diabetic hyperglycaemia or undiagnosed diabetes to the dataset on which they were developed. Furthermore, both identified a small proportion of the population with a substantially increased risk of developing diabetes when utilised in the recommended two-stage screening programme and thus are advocated for use across England. This thesis aids those wishing to use a risk assessment tool for non-diabetic hyperglycaemia in their selection or development of an appropriate tool, as well as addressing some of the previous limitations of the Leicester Self-Assessment and Leicester Practice risk scores.
Peripheral action of irisin improves glucose homeostasis and increases energy expenditure, with no data on a central role of irisin in metabolism. These studies sought to examine 1) presence of ...irisin in human cerebrospinal fluid (CSF) and banked human hypothalamic tissue, 2) serum irisin in maternal subjects across varying adiposities with or without gestational diabetes (GDM), and 3) their respective neonate offspring. CSF, serum, and neonatal cord serum were collected from 91 pregnant women with and without GDM attending for an elective cesarean section body mass index (BMI): 37.7 ± 7.6 kg/m(2); age: 32 ± 8.3 yr. Irisin was assessed by ELISA and correlated with biochemical and anthropometric data. Irisin expression was examined in human hypothalamus by immunohistochemical staining. Serum irisin in pregnant women was significantly lower in nonobese compared with obese and GDM subjects, after adjusting for BMI, lipids, and glucose. Irisin was present in neonatal cord serum (237 ± 8 ng/ml) and maternal CSF (32 ± 1.5 ng/ml). CSF irisin correlated positively with serum irisin levels from nonobese and obese pregnant women (P < 0.01), with CSF irisin significantly raised in GDM subjects (P < 0.05). Irisin was present in human hypothalamic sections in the paraventricular neurons, colocalized with neuropeptide Y. Irisin was detectable in CSF and in paraventricular neurons. Maternal serum irisin was lower in nonobese pregnant women after adjusting for BMI and a number of metabolic parameters. These studies indicate that irisin may have a central role in metabolism in addition to the known peripheral role. Further studies investigating the central action of irisin in human metabolic disease are required.
Complete surgical resection of pulmonary metastatic disease in patients with osteosarcoma is crucial to long‐term survival. Open thoracotomy allows palpation of nodules not identified on imaging but ...the impact on survival is unknown. The objective of this study was to compare overall survival (OS) and pulmonary disease‐free survival (DFS) in children who underwent thoracotomy vs thoracoscopic surgery for pulmonary metastasectomy. A multi‐institutional collaborative group retrospectively reviewed 202 pediatric patients with osteosarcoma who underwent pulmonary metastasectomy by thoracotomy (n = 154) or thoracoscopy (n = 48). Results were analyzed by Kaplan‐Meier survival estimates and multivariate Cox proportional hazard regression models. With median follow‐up of 45 months, 135 (67.5%) patients had a pulmonary relapse and 95 (47%) patients were deceased. Kaplan‐Meier analysis showed no significant difference in 5‐year pulmonary DFS (25% vs 38%; P = .18) or OS (49% vs 42%, P = .37) between the surgical approaches of thoracotomy and thoracoscopy. In Cox regression analysis controlling for other factors impacting outcome, there was a significantly increased risk of mortality (HR 2.11; P = .027; 95% CI 1.09‐4.09) but not pulmonary recurrence (HR 0.96; P = .90; 95% CI 0.52‐1.79) with a thoracoscopic approach. However, in the subset analysis limited to patients with oligometastatic disease, thoracoscopy had no increased risk of mortality (HR 1.16; P = .62; 0.64‐2.11). In conclusion, patients with metastatic osteosarcoma and limited pulmonary disease burden demonstrate comparable outcomes after thoracotomy and thoracoscopy for metastasectomy. While significant selection bias in these surgical cohorts limits the generalizability of the conclusions, clinical equipoise for a randomized clinical trial in patients with oligometastatic disease is supported.
What's new?
In patients with osteosarcoma that has metastasized to the lungs, complete surgical resection is crucial for long‐term survival. But is full thoracotomy necessary? In this study, the authors found that, in patients with limited metastases, both mortality and risk of pulmonary recurrence were similar for patients who had thoracoscopic surgery vs. those who underwent thoracotomy. Thoracotomy did improve survival for patients with more extensive disease, however. These results indicate that the less invasive, lower‐risk thoracoscopic approach may be preferable for a subset of patients.
Background: Anticoagulant-associated intracerebral hemorrhage (ICH) is a significant cause of morbidity and mortality. Despite approval of a specific reversal agent for factor Xa inhibitors, there is ...still much interest in nonspecific reversal agents, such as activated prothrombin complex concentrates (aPCCs). Objective: The objective of this study was to describe ICH expansion in a cohort of patients with factor Xa inhibitor-associated ICH who were treated with aPCC. Methods: This was a retrospective cohort study conducted at an academic medical center designated as a comprehensive stroke center. Consecutive patients admitted for ICH who reported use of apixaban or rivaroxaban prior to admission were considered for inclusion in the study. Patients were treated with 25 to 50 units/kg of aPCC. Intracerebral hemorrhage volume was measured before administration of aPCC and then again within 36 hours of aPCC administration. Results: A total of 40 patients were included in the final analysis. Overall, the cohort was predominantly male (24 60%), white (27 67.5%), and the mean age was 75.3 ± 10.5 years. Most patients reported taking apixaban prior to admission (31 77.5%) and a large proportion were also taking aspirin (13 32.5%). The mean change in ICH volume was 1.12 ± 6.03 mL (P = 0.2475). Conclusions and Relevance: There was a nonsignificant change in mean ICH volume and no reported cases of thromboembolism. Due to the relatively high proportion of patients with significant hematoma expansion, more studies are needed on which patient population would best benefit from treatment with aPCC.
Background
The surgical management of hiatal hernia remains controversial. We aimed to compare outcomes of mesh versus no mesh and fundoplication versus no fundoplication in symptomatic patients; ...surgery versus observation in asymptomatic patients; and redo hernia repair versus conversion to Roux-en-Y reconstruction in recurrent hiatal hernia.
Methods
We searched PubMed, Embase, CINAHL, Cochrane Library and the ClinicalTrials.gov databases between 2000 and 2022 for randomized controlled trials (RCTs), observational studies, and case series (asymptomatic and recurrent hernias). Screening was performed by two trained independent reviewers. Pooled analyses were performed on comparative data. Risk of bias was assessed using the Cochrane Risk of Bias tool and Newcastle Ottawa Scale for randomized and non-randomized studies, respectively.
Results
We included 45 studies from 5152 retrieved records. Only six RCTs had low risk of bias. Mesh was associated with a lower recurrence risk (RR = 0.50, 95%CI 0.28, 0.88;
I
2
= 57%) in observational studies but not RCTs (RR = 0.98, 95%CI 0.47, 2.02;
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= 34%), and higher total early dysphagia based on five observational studies (RR = 1.44, 95%CI 1.10, 1.89;
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= 40%) but was not statistically significant in RCTs (RR = 3.00, 95%CI 0.64, 14.16). There was no difference in complications, reintervention, heartburn, reflux, or quality of life. There were no appropriate studies comparing surgery to observation in asymptomatic patients. Fundoplication resulted in higher early dysphagia in both observational studies and RCTs (RR = 2.08, 95%CI 1.16, 3.76 and RR = 20.58, 95%CI 1.34, 316.69) but lower reflux in RCTs (RR = 0.31, 95%CI 0.17, 0.56,
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= 0%). Conversion to Roux-en-Y was associated with a lower reintervention risk after 30 days compared to redo surgery.
Conclusions
The evidence for optimal management of symptomatic and recurrent hiatal hernia remains controversial, underpinned by studies with a high risk of bias. Shared decision making between surgeon and patient is essential for optimal outcomes.
People with avascular necrosis of the hip have very limited treatment options currently available to stop the progression of this disease; this often results in the need for a hip replacement. There ...is some weak evidence that a class of drugs called bisphosphonates may delay the course of the disease, and this trial was commissioned and set up to provide robust evidence regarding the use of bisphosphonates in adults aged ≥ 18 years with this condition.
The aim of the Managing Avascular Necrosis Treatments: an Interventional Study ( MANTIS ) trial was to evaluate the clinical effectiveness and cost-effectiveness of a 12-month course of alendronate in the treatment of avascular necrosis.
This was a 66-month, definitive, multisite, two-arm, parallel-group, placebo-controlled, double-blind, randomised controlled trial, with an internal pilot phase.
Eight secondary care NHS hospitals across the UK.
Planned trial size - 280 adult patients with avascular necrosis.
Participants in the intervention group received 70 mg of alendronate (an oral bisphosphonate) weekly for 12 months.
The main outcomes were Oxford Hip Score at 12 months (short-term outcome) and the time to decision that a hip replacement is required at 36 months (long-term outcome).
Twenty-one patients were recruited and randomised to receive either the intervention drug, alendronate, or a placebo-matched tablet.
This trial was principally limited by low disease prevalence. Other limitations included the late disease stage at which participants were identified and the rapid progression of the disease.
This trial was limited by a low recruitment rate. Avascular necrosis of the hip should be treated as a rare disease. Future trials would need to recruit many more sites and recruit over a longer time period, and, for this reason, a registry may provide a more effective means of collecting data pertaining to this disease.
The MANTIS trial was terminated at the end of the pilot phase, because it did not meet its go/no-go criteria. The main issue was a poor recruitment rate, owing to a lower than expected disease prevalence and difficulties in identifying the condition at a sufficiently early stage. Those patients who were identified and screened either were too advanced in their disease progression or were already taking medication. We would not recommend that a short-term interventional study is conducted on this condition until its prevalence, geographic foci and natural history and better understood. The difficulty of acquiring this understanding is likely to be a barrier in most health-care markets. One means of developing this understanding would be the introduction of a database/registry for patients suffering from avascular necrosis of the hip.
The trial is registered as ISRCTN14015902.
This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in
; Vol. 26, No. 43. See the NIHR Journals Library website for further project information.
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