Surgical or percutaneous coronary revascularization for heart failure: an in silico model using routinely collected health data to emulate a clinical trial.

AIMS: The choice of revascularization with coronary artery bypass grafting (CABG) vs. percutaneous coronary intervention (PCI) in people with ischaemic left ventricular dysfunction is not guided by high-quality evidence. METHODS AND RESULTS: A trial of CABG vs. PCI in people with heart failure (HF) was modelled in silico using routinely collected healthcare data. The in silico trial cohort was selected by matching the target trial cohort, identified from Hospital Episode Statistics in England, with individual patient data from the Surgical Treatment for Ischemic Heart Failure (STICH) trial. Allocation to CABG vs. complex PCI demonstrated random variation across administrative regions in England and was a valid statistical instrument. The primary outcome was 5-year all-cause mortality or cardiovascular hospitalization. Instrumental variable analysis (IVA) was used for the primary analysis. Results were expressed as average treatment effects (ATEs) with 95 confidence intervals (CIs). The target population included 13 519 HF patients undergoing CABG or complex PCI between April 2009 and March 2015. After matching, the emulated trial cohort included 2046 patients. The unadjusted primary outcome rate was 51.1 in the CABG group and 70.0 in the PCI group. IVA of the emulated cohort showed that CABG was associated with a lower risk of the primary outcome (ATE 16.2, 95 CI 20.6 to 11.8), with comparable estimates in the unmatched target population (ATE 15.5, 95 CI 17.5 to 13.5). CONCLUSION: In people with HF, in silico modelling suggests that CABG is associated with fewer deaths or cardiovascular hospitalizations at 5 years vs. complex PCI. A pragmatic clinical trial is needed to test this hypothesis and this trial would be feasible.

Effects of late, repetitive remote ischaemic conditioning on myocardial strain in patients with acute myocardial infarction.

Late, repetitive or chronic remote ischaemic conditioning (CRIC) is a potential cardioprotective strategy against adverse remodelling following ST-segment elevation myocardial infarction (STEMI). In the randomised Daily Remote Ischaemic Conditioning Following Acute Myocardial Infarction (DREAM) trial, CRIC following primary percutaneous coronary intervention (P-PCI) did not improve global left ventricular (LV) systolic function. A post-hoc analysis was performed to determine whether CRIC improved regional strain. All 73 patients completing the original trial were studied (38 receiving 4 weeks' daily CRIC, 35 controls receiving sham conditioning). Patients underwent cardiovascular magnetic resonance at baseline (5-7 days post-STEMI) and after 4 months, with assessment of LV systolic function, infarct size and strain (longitudinal/circumferential, in infarct-related and remote territories). At both timepoints, there were no significant between-group differences in global indices (LV ejection fraction, infarct size, longitudinal/circumferential strain). However, regional analysis revealed a significant improvement in longitudinal strain in the infarcted segments of the CRIC group (from - 16.2 ± 5.2 at baseline to - 18.7 ± 6.3 at follow up, p = 0.0006) but not in corresponding segments of the control group (from - 15.5 ± 4.0 to - 15.2 ± 4.7, p = 0.81; for change: - 2.5 ± 3.6 versus + 0.3 ± 5.6, respectively, p = 0.027). In remote territories, there was a lower increment in subendocardial circumferential strain in the CRIC group than in controls (- 1.2 ± 4.4 versus - 2.5 ± 4.0, p = 0.038). In summary, CRIC following P-PCI for STEMI is associated with improved longitudinal strain in infarct-related segments, and an attenuated increase in circumferential strain in remote segments. Further work is needed to establish whether these changes may translate into a reduced incidence of adverse remodelling and clinical events. Clinical Trial Registration: http://clinicaltrials.gov/show/NCT01664611 .

An outbreak of adenovirus D8 keratoconjunctivitis in Leicester, United Kingdom, from March to August 2019.

We report a large epidemic (n = 126) of keratoconjunctivitis predominantly with two lineages of adenovirus (AdV) type D8 in patients seen in eye casualty between march and August 2019. Other AdV species identified by viral sequencing included B, C, and E. Despite various features of more severe eye disease being present, these were not significantly different between the different AdV species, with similar rates of pseudomembrane formation and keratitis observed in patients with AdV species B as for those with AdV species D.

Patient blood management interventions do not lead to important clinical benefits or cost-effectiveness for major surgery: a network meta-analysis.

BACKGROUND: Patient blood management (PBM) interventions aim to improve clinical outcomes by reducing bleeding and transfusion. We assessed whether existing evidence supports the routine use of combinations of these interventions during and after major surgery. METHODS: Five systematic reviews and a National Institute of Health and Care Excellence health economic review of trials of common PBM interventions enrolling participants of any age undergoing surgery were updated. The last search was on June 1, 2019. Studies in trauma, burns, gastrointestinal haemorrhage, gynaecology, dentistry, or critical care were excluded. The co-primary outcomes were: risk of receiving red cell transfusion and 30-day or hospital all-cause mortality. Treatment effects were estimated using random-effects models and risk ratios (RR) with 95% confidence intervals (CIs). Heterogeneity assessments used I2. Network meta-analyses used a frequentist approach. The protocol was registered prospectively (PROSPERO CRD42018085730). RESULTS: Searches identified 393 eligible randomised controlled trials enrolling 54 917 participants. PBM interventions resulted in a reduction in exposure to red cell transfusion (RR=0.60; 95% CI 0.57, 0.63; I2=77%), but had no statistically significant treatment effect on 30-day or hospital mortality (RR=0.93; 95% CI 0.81, 1.07; I2=0%). Treatment effects were consistent across multiple secondary outcomes, sub-groups and sensitivity analyses that considered clinical setting, type of intervention, and trial quality. Network meta-analysis did not demonstrate additive benefits from the use of multiple interventions. No trial demonstrated that PBM was cost-effective. CONCLUSIONS: In randomised trials, PBM interventions do not have important clinical benefits beyond reducing bleeding and transfusion in people undergoing major surgery.

Activation of the innate immune response and organ injury after cardiac surgery: a systematic review and meta-analysis of randomised trials and analysis of individual patient data from randomised and non-randomised studies.

BACKGROUND: It is unclear whether the innate immune response represents a therapeutic target for organ protection strategies in cardiac surgery. METHODS: A systematic review of trials of interventions targeting the inflammatory response to cardiac surgery reporting treatment effects on both innate immune system cytokines and organ injury was performed. The protocol was registered at the International Prospective Register of Systematic Reviews: CRD42020187239. Searches of the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase were performed. Random-effects meta-analyses were used for the primary analysis. A separate analysis of individual patient data from six studies (n=785) explored sources of heterogeneity for treatment effects on cytokine levels. RESULTS: Searches to May 2020 identified 251 trials evaluating 24 interventions with 20 582 participants for inclusion. Most trials had important limitations. Methodological limitations of the included trials and heterogeneity of the treatment effects on cytokine levels between trials limited interpretation. The primary analysis demonstrated inconsistency in the direction of the treatment effects on innate immunity and organ failure or death between interventions. Analyses restricted to important subgroups or trials with fewer limitations showed similar results. Meta-regression, pooling available data from all trials, demonstrated no association between the direction of the treatment effects on inflammatory cytokines and organ injury or death. The analysis of individual patient data demonstrated heterogeneity in the association between the cytokine response and organ injury after cardiac surgery for people >75 yr old and those with some chronic diseases. CONCLUSIONS: The certainty of the evidence for a causal relationship between innate immune system activation and organ injury after cardiac surgery is low.

Biomarkers of Inflammation and Lung Recovery in Extracorporeal Membrane Oxygenation Patients With Persistent Pulmonary Hypertension of the Newborn: A Feasibility Study.

OBJECTIVES: Extracorporeal membrane oxygenation is a treatment for Persistent Pulmonary Hypertension of the Newborn with high mortality. HYPOTHESIS: the extracorporeal membrane oxygenation circuit results in inflammatory responses that mitigate against successful weaning. DESIGN: Single-center prospective observational feasibility study. SETTING: PICU. PATIENTS: Twenty-four neonates requiring extracorporeal membrane oxygenation support for Persistent Pulmonary Hypertension of the Newborn. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The reference outcome was death or more than 7 days of extracorporeal membrane oxygenation support. Other outcomes included serial measures of plasma-free hemoglobin and markers of its metabolism, leucocyte, platelet and endothelial activation, and biomarkers of inflammation. Of 24 participants recruited between February 2016 and June 2017, 10 died or required prolonged extracorporeal membrane oxygenation support. These patients were sicker at baseline with higher levels of plasma-free hemoglobin within 12 hours of cannulation (geometric mean ratio, 1.92; 95% CIs, 1.00-3.67; p = 0.050) but not thereafter, versus those requiring less than 7 days extracorporeal membrane oxygenation. Serum haptoglobin concentrations were significantly elevated in both groups. Patients who died or required prolonged extracorporeal membrane oxygenation support demonstrated elevated levels of platelet-leucocyte aggregation, but decreased concentrations of mediators of the inflammatory response: interleukin-8, C-reactive protein, and tumor necrosis factor α. CONCLUSIONS: Clinical status at baseline and not levels of plasma-free hemoglobin or the systemic inflammatory response may determine the requirement for prolonged extracorporeal membrane oxygenation support in neonates.

Correction to: does stress perfusion imaging improve the diagnostic accuracy of late gadolinium enhanced cardiac magnetic resonance for establishing the etiology of heart failure?

Following publication of the original article [1], the author reported his name has erroneously spelled as Abishek Shetye. The correct name is Abhishek Shetye.

Adult height and risk of 50 diseases: a combined epidemiological and genetic analysis.

BACKGROUND: Adult height is associated with risk of several diseases, but the breadth of such associations and whether these associations are primary or due to confounding are unclear. We examined the association of adult height with 50 diseases spanning multiple body systems using both epidemiological and genetic approaches, the latter to identify un-confounded associations and possible underlying mechanisms. METHODS: We examined the associations for adult height (using logistic regression adjusted for potential confounders) and genetically determined height (using a two-sample Mendelian randomisation approach with height-associated genetic variants as instrumental variables) in 417,434 individuals of white ethnic background participating in the UK Biobank. We undertook pathway analysis of height-associated genes to identify biological processes that could link height and specific diseases. RESULTS: Height was associated with 32 diseases and genetically determined height associated with 12 diseases. Of these, 11 diseases showed a concordant association in both analyses, with taller height associated with reduced risks of coronary artery disease (odds ratio per standard deviation (SD) increase in height ORepi = 0.80, 95% CI 0.78-0.81; OR per SD increase in genetically determined height ORgen = 0.86, 95% CI 0.82-0.90), hypertension (ORepi = 0.83, 95% CI 0.82-0.84; ORgen = 0.88, 95% CI 0.85-0.91), gastro-oesophageal reflux disease (ORepi = 0.85, 95% CI 0.84-0.86; ORgen = 0.94, 95% CI 0.92-0.97), diaphragmatic hernia (ORepi = 0.81, 95% CI 0.79-0.82; ORgen = 0.91, 95% CI 0.88-0.94), but increased risks of atrial fibrillation (ORepi = 1.42, 95% CI 1.38-1.45; ORgen = 1.33, 95% CI 1.26-1.40), venous thromboembolism (ORepi = 1.18, 95% CI 1.16-1.21; ORgen = 1.15, 95% CI 1.11-1.19), intervertebral disc disorder (ORepi = 1.15, 95% CI 1.13-1.18; ORgen = 1.14, 95% CI 1.09-1.20), hip fracture (ORepi = 1.19, 95% CI 1.12-1.26; ORgen = 1.27, 95% CI 1.17-1.39), vasculitis (ORepi = 1.15, 95% CI 1.11-1.19; ORgen = 1.20, 95% CI 1.14-1.28), cancer overall (ORepi = 1.09, 95% CI 1.08-1.11; ORgen = 1.06, 95% CI 1.04-1.08) and breast cancer (ORepi = 1.08, 95% CI 1.06-1.10; ORgen = 1.07, 95% CI 1.03-1.11). Pathway analysis showed multiple height-associated pathways associating with individual diseases. CONCLUSIONS: Adult height is associated with risk of a range of diseases. We confirmed previously reported height associations for coronary artery disease, atrial fibrillation, venous thromboembolism, intervertebral disc disorder, hip fracture and cancer and identified potential novel associations for gastro-oesophageal reflux disease, diaphragmatic hernia and vasculitis. Multiple biological mechanisms affecting height may affect the risks of these diseases.

Does stress perfusion imaging improve the diagnostic accuracy of late gadolinium enhanced cardiac magnetic resonance for establishing the etiology of heart failure?

BACKGROUND: Late gadolinium enhanced cardiovascular magnetic resonance (LGE-CMR) has excellent specificity, sensitivity and diagnostic accuracy for differentiating between ischemic cardiomyopathy (ICM) and non-ischemic dilated cardiomyopathy (NICM). CMR first-pass myocardial perfusion imaging (perfusion-CMR) may also play role in distinguishing heart failure of ischemic and non-ischemic origins, although the utility of additional of stress perfusion imaging in such patients is unclear. The aim of this retrospective study was to assess whether the addition of adenosine stress perfusion imaging to LGE-CMR is of incremental value for differentiating ICM and NICM in patients with severe left ventricular systolic dysfunction (LVSD) of uncertain etiology. METHODS: We retrospectively identified 100 consecutive adult patients (median age 69 years (IQR 59-73)) with severe LVSD (mean LV EF 26.6 ± 7.0%) referred for perfusion-CMR to establish the underlying etiology of heart failure. The cause of heart failure was first determined on examination of CMR cine and LGE images in isolation. Subsequent examination of complete adenosine stress perfusion-CMR studies (cine, LGE and perfusion images) was performed to identify whether this altered the initial diagnosis. RESULTS: On LGE-CMR, 38 patients were diagnosed with ICM, 46 with NICM and 16 with dual pathology. With perfusion-CMR, there were 39 ICM, 44 NICM and 17 dual pathology diagnoses. There was excellent agreement in diagnoses between LGE-CMR and perfusion-CMR (κ 0.968, p<0.001). The addition of adenosine stress perfusion images to LGE-CMR altered the diagnosis in only two of the 100 patients. CONCLUSION: The addition of adenosine stress perfusion-CMR to cine and LGE-CMR provides minimal incremental diagnostic yield for determining the etiology of heart failure in patients with severe LVSD.

Comparison of global myocardial strain assessed by cardiovascular magnetic resonance tagging and feature tracking to infarct size at predicting remodelling following STEMI.

BACKGROUND: To determine if global strain parameters measured by cardiovascular magnetic resonance (CMR) acutely following ST-segment Elevation Myocardial Infarction (STEMI) predict adverse left ventricular (LV) remodelling independent of infarct size (IS). METHODS: Sixty-five patients with acute STEMI (mean age 60 ± 11 years) underwent CMR at 1-3 days post-reperfusion (baseline) and at 4 months. Global peak systolic circumferential strain (GCS), measured by tagging and Feature Tracking (FT), and global peak systolic longitudinal strain (GLS), measured by FT, were calculated at baseline, along with IS. On follow up scans, volumetric analysis was performed to determine the development of adverse remodelling - a composite score based on development of either end-diastolic volume index [EDVI] ≥20% or end-systolic volume index [ESVI] ≥15% at follow-up compared to baseline. RESULTS: The magnitude of GCS was higher when measured using FT (-21.1 ± 6.3%) than with tagging (-12.1 ± 4.3; p < 0.001 for difference). There was good correlation of strain with baseline LVEF (r 0.64-to 0.71) and IS (ρ -0.62 to-0.72). Baseline strain parameters were unable to predict development of adverse LV remodelling. Only baseline IS predicted adverse remodelling - Odds Ratio 1.05 (95% CI 1.01-1.10, p = 0.03), area under the ROC curve 0.70 (95% CI 0.52-0.87, p = 0.04). CONCLUSION: Baseline global strain by CMR does not predict the development of adverse LV remodelling following STEMI.

Inequalities in access to and outcomes of cardiac surgery in England: retrospective analysis of Hospital Episode Statistics (2010-2019).

BACKGROUND: We aimed to characterise the variation in access to and outcomes of cardiac surgery for people in England. METHODS: We included people >18 years of age with hospital admission for ischaemic heart disease (IHD) and heart valve disease (HVD) between 2010 and 2019. Within these populations, we identified people who had coronary artery bypass graft (CABG) and/or valve surgery, respectively. We fitted logistic regression models to examine the effects of age, sex, ethnicity and socioeconomic deprivation on having access to surgery and in-hospital mortality, 1-year mortality and hospital readmission. RESULTS: We included 292 140 people, of whom 28% were women, 11% were from an ethnic minority and 17% were from the most deprived areas. Across all types of surgery, one in five people are readmitted to hospital within 1 year, rising to almost one in four for valve surgery. Women, black people and people living in the most deprived areas were less likely to have access to surgery (CABG: 59%, 32% and 35% less likely; valve: 31%, 33% and 39% less likely, respectively) and more likely to die within 1 year of surgery (CABG: 24%, 85% and 18% more likely, respectively; valve: 19% (women) and 10% (people from most deprived areas) more likely). CONCLUSIONS: Female sex, black ethnicity and economic deprivation are independently associated with limited access to cardiac surgery and higher post-surgery mortality. Actions are required to address these inequalities.

Urinary extracellular vesicles and micro-RNA as markers of acute kidney injury after cardiac surgery.

We hypothesised that measuring changes in urinary levels of EV and miR will predict the onset of acute kidney injury in cardiac surgery patients. The study was performed in the cohort of the REVAKI-2 trial. Urine samples were collected before and 24 h after the procedure from 94 cardiac surgery patients. Urinary particle concentrations and size distribution were assessed using NanoSight. EV derivation and levels were measured using flow cytometry. Samples from 10 selected patients were sequenced, and verification was performed with advanced TaqMan assays in samples from all patients. Urinary particle concentrations significantly increased in patients with AKI after surgery, with the percentage of EV positive for CD105 and ß1-integrin also increasing. Pre-surgery podocalyxin-positive EV were significantly lower in patients with AKI. Their levels correlated with the severity of the injury. Pre-operative miR-125a-5p was expressed at lower levels in urine from patients with AKI when adjusted for urinary creatinine. Levels of miR-10a-5p were lower after surgery in AKI patients and its levels correlated with the severity of the injury. Pre-operative levels of podocalyxin EVs, urinary particle concentrations and miR-125a-5p had moderate AKI predictive value and, in a logistic model together with ICU lactate levels, offered good (AUC = 82%) AKI prediction.

Gene and metabolite expression dependence on body mass index in human myocardium.

We hypothesized that body mass index (BMI) dependent changes in myocardial gene expression and energy-related metabolites underlie the biphasic association between BMI and mortality (the obesity paradox) in cardiac surgery. We performed transcriptome profiling and measured a panel of 144 metabolites in 53 and 55, respectively, myocardial biopsies from a cohort of sixty-six adult patients undergoing coronary artery bypass grafting (registration: NCT02908009). The initial analysis identified 239 transcripts with biphasic BMI dependence. 120 displayed u-shape and 119 n-shape expression patterns. The identified local minima or maxima peaked at BMI 28-29. Based on these results and to best fit the WHO classification, we grouped the patients into three groups: BMI < 25, 25 ≤ BMI ≤ 32, and BMI > 32. The analysis indicated that protein translation-related pathways were downregulated in 25 ≤ BMI ≤ 32 compared with BMI < 25 patients. Muscle contraction transcripts were upregulated in 25 ≤ BMI ≤ 32 patients, and cholesterol synthesis and innate immunity transcripts were upregulated in the BMI > 32 group. Transcripts involved in translation, muscle contraction and lipid metabolism also formed distinct correlation networks with biphasic dependence on BMI. Metabolite analysis identified acylcarnitines and ribose-5-phosphate increasing in the BMI > 32 group and α-ketoglutarate increasing in the BMI < 25 group. Molecular differences in the myocardium mirror the biphasic relationship between BMI and mortality.

Comparison of pandemic (H1N1) 2009 and seasonal influenza viral loads, Singapore.

Mean viral loads for patients with pandemic (H1N1) 2009 were ≈1 log10 times lower than those for patients with seasonal influenza within the first week after symptom onset. Neither pandemic nor seasonal influenza viral loads correlated with clinical severity of illness. No correlation was found between viral loads and concurrent illness.

Systematic Review and Meta-Analysis of Diagnostic Test Accuracy Studies Evaluating Point-of-Care Tests of Coagulopathy in Cardiac Surgery.

Treatment guidelines recommend the routine use of point-of-care diagnostic tests for coagulopathy in the management of cardiac surgery patients at risk of severe bleeding despite uncertainty as to their diagnostic accuracy. We performed a systematic review and meta-analysis of studies that evaluated the diagnostic accuracy of viscoelastometry, platelet function tests, and modified thromboelastography (TEG) tests, for coagulopathy in cardiac surgery patients. The reference standard included resternotomy for bleeding, transfusion of non-red cell components, or massive transfusion. We searched MEDLINE, EMBASE, CINAHL, and Clinical Trials.gov, from inception to June 2019. Study quality was assessed using QUADAS-2. Bivariate models were used to estimate summary sensitivity and specificity with (95% confidence intervals). All 29 studies (7440 participants) included in the data synthesis evaluated the tests as predictors of bleeding. No study evaluated their role in the management of bleeding. None was at low risk of bias. Four were judged as low concern regarding applicability. Pooled estimates of diagnostic accuracy were; Viscoelastic tests, 12 studies, sensitivity 0.61 (0.44, 0.76), specificity 0.83 (0.70, 0.91) with significant heterogeneity. Platelet function tests, 12 studies, sensitivity 0.63 (0.53, 0.72), specificity 0.75 (0.64, 0.84) with significant heterogeneity. TEG modification tests, 3 studies, sensitivity 0.80 (0.67, 0.89), specificity 0.76 (0.69, 0.82) with no evidence of heterogeneity. Studies reporting the highest values for sensitivity and specificity had important methodological limitations. In conclusion, we did not demonstrate predictive accuracy for commonly used point-of-care devices for coagulopathic bleeding in cardiac surgery. However, the certainty of the evidence was low.

Comparison of the incidence of influenza in relation to climate factors during 2000-2007 in five countries.

Relatively few international comparisons of the incidence of influenza related to climate parameters have been performed, particularly in the Eastern hemisphere. In this study, the incidence of influenza and climate data such as temperature, relative humidity, and rainfall, from cities at different latitudes with contrasting climates: Singapore, Hong Kong (China), Ulaanbaatar (Mongolia), Vancouver (Canada), and three Australian cities (Brisbane, Melbourne and Sydney) were examined to determine whether there was any overall relationship between the incidence of influenza and climate. Applying time-series analyses to the more comprehensive datasets, it was found that relative humidity was associated with the incidence of influenza A in Singapore, Hong Kong, Brisbane, and Vancouver. In the case of influenza B, the mean temperature was the key climate variable associated with the incidence of influenza in Hong Kong, Brisbane, Melbourne, and Vancouver. Rainfall was not significantly correlated with the incidence of influenza A or B in any of these cities.

The Metastatic Early Prognostic (MEP) score.

AIMS: The early mortality in patients with hip fractures from bony metastases is unknown. The objectives of this study were to quantify 30- and 90-day mortality in patients with proximal femoral metastases, and to create a mortality prediction tool based on biomarkers associated with early death. METHODS: This was a retrospective cohort study of consecutive patients referred to the orthopaedic department at a UK trauma centre with a proximal femoral metastasis (PFM) over a seven-year period (2010 to 2016). The study group were compared to a matched control group of non-metastatic hip fractures. Minimum follow-up was one year. RESULTS: There was a 90-day mortality of 46% in patients with metastatic hip fractures versus 12% in controls (89/195 and 24/192, respectively; p < 0.001). Mean time to surgery was longer in symptomatic metastases versus complete fractures (9.5 days (SD 19.8) and 3.4 days (SD 11.4), respectively; p < 0.05). Albumin, urea, and corrected calcium were all independent predictors of early mortality and were used to generate a simple tool for predicting 90-day mortality, titled the Metastatic Early Prognostic (MEP) score. An MEP score of 0 was associated with the lowest risk of death at 30 days (14%, 3/21), 90 days (19%, 4/21), and one year (62%, 13/21). MEP scores of 3/4 were associated with the highest risk of death at 30 days (56%, 5/9), 90 days (100%, 9/9), and one year (100%, 9/9). Neither age nor primary cancer diagnosis was an independent predictor of mortality at 30 and 90 days. CONCLUSION: This score could be used to predict early mortality and guide perioperative counselling. The delay to surgery identifies a potential window to intervene and correct these abnormalities with the aim of improving survival. Cite this article: Bone Joint J. 2020;102-B(1):72-81.

Identifying research priorities in cardiac surgery: a report from the James Lind Alliance Priority Setting Partnership in adult heart surgery.

OBJECTIVE: To identify research priorities that address the needs of people affected by cardiac surgery and those who support and care for them. DESIGN: James Lind Alliance (JLA) process-two surveys and a consensus workshop guided by an independent JLA adviser. SETTING: The UK with international participation. PARTICIPANTS: Three stakeholder groups-heart surgery patients, carers and healthcare professionals involved in care delivery. METHODS: The initial survey was set to collect potential research questions in cardiac surgery as identified by stakeholders. Submitted questions were summarised into indicative questions. The existing evidence was searched to verify that these indicative questions had not been answered. In the second survey, stakeholders then voted for their top 10 from the list of unanswered questions. The top voted questions were taken forward for final ranking in a workshop. RESULTS: In the initial survey, 629 respondents (28% patients/carers, 62% healthcare professionals) submitted 1082 potential questions. Of these, 797 in-scope questions were summarised into 49 indicative questions and of which 45 had not been answered by existing research. In the second survey, 492 respondents (43% patients/carers, 49% healthcare professionals) cast their votes with the top 12 from each of the three stakeholder groups totalling 21 questions advancing to the final priority setting workshop. The workshop attended by 25 delegates (10 patients/carers and 15 healthcare professionals) agreed on the top 10 research questions including long-term outcomes (quality of life), and aspects from preoperative personalised care (prehabilitation, frailty, comorbidities), intraoperative management (minimally invasive techniques), to prevention and management of postoperative complications (organ injury, atrial fibrillation, infection). CONCLUSIONS: This Priority Setting Partnership (PSP) identified the priorities and unmet needs of patients and clinicians in cardiac surgery. The next step is to disseminate and implement the PSP results to ensure that these priorities shape future research and improve clinical services.

Systematic review and meta-analysis of experimental studies evaluating the organ protective effects of histone deacetylase inhibitors.

The clinical efficacy of organ protection interventions are limited by the redundancy of cellular activation mechanisms. Interventions that target epigenetic mechanisms overcome this by eliciting genome wide changes in transcription and signaling. We aimed to review preclinical studies evaluating the organ protection effects of histone deacetylase inhibitors (HDACi) with a view to informing the design of early phase clinical trials. A systematic literature search was performed. Methodological quality was assessed against prespecified criteria. The primary outcome was mortality, with secondary outcomes assessing mechanisms. Prespecified analyses evaluated the effects of likely moderators on heterogeneity. The analysis included 101 experimental studies in rodents (n = 92) and swine (n = 9), exposed to diverse injuries, including: ischemia (n = 72), infection (n = 7), and trauma (n = 22). There were a total of 448 comparisons due to the evaluation of multiple independent interventions within single studies. Sodium valproate (VPA) was the most commonly evaluated HDACi (50 studies, 203 comparisons). All of the studies were judged to have significant methodological limitations. HDACi reduced mortality in experimental models of organ injury (risk ratio = 0.52, 95% confidence interval 0.40-0.68, p < 0.001) without heterogeneity. HDACi administration resulted in myocardial, brain and kidney protection across diverse species and injuries that was attributable to increases in prosurvival cell signaling, and reductions in inflammation and programmed cell death. Heterogeneity in the analyses of secondary outcomes was explained by differences in species, type of injury, HDACi class (Class I better), drug (trichostatin better), and time of administration (at least 6 hours prior to injury better). These findings highlight a potential novel application for HDACi in clinical settings characterized by acute organ injury.