Aflibercept monotherapy versus aflibercept with targeted retinal laser to peripheral retinal ischemia for diabetic macular oedema (LADAMO).

OBJECTIVE: We tested the hypothesis that targeted retinal laser photocoagulation (TPRP) to peripheral retinal ischaemia reduces the overall burden of aflibercept injections when treating diabetic macular oedema (DMO) over a 24-month period. METHODS: Prospective, double-masked, multicentre, randomised controlled trial in Australia comparing aflibercept monotherapy, following a treat-and-extend protocol, or combination therapy of aflibercept and TPRP for DMO. The aflibercept monotherapy group received placebo laser. The primary outcome measure was the mean number of intravitreal aflibercept injections for each group at 24 months. Secondary outcome included: mean change in central macular thickness (CMT) and vision at trial completion, the proportion of eyes whose DMO resolved and the mean injection treatment interval. Ocular and systemic adverse events were recorded. RESULTS: We enrolled 48 eyes of 47 patients; 27 eyes were randomised to combination therapy (aflibercept and TPRP) and 21 to aflibercept monotherapy. Thirty-two eyes (67%) completed the 2-year study. The number of intravitreal treatments given were similar for combination therapy (10.5 (SD 5.8) and monotherapy (11.8 (SD5.6)) (P = 0.44). The mean visual improvement (+4.0 (-1.8, 9.8) and +7.8 (2.6, 12.9) letters, P = 0.32), mean decrease in CMT (-154 (-222,-87) µm and -152 (-218,-86) µm, P = 0.96), proportion of eyes with CMT < 300 µm (48% and 67%; P = 0.50) and safety outcomes were similar in both the combination and monotherapy treatment groups (respectively). CONCLUSIONS: Laser to areas of ischaemic peripheral retina does not reduce the burden of intravitreal aflibercept injections when treating diabetic macular oedema.

Thalamic deep brain stimulation for post-traumatic neuropathic limb pain: Efficacy at five years' follow-up and effective volume of activated brain tissue.

Chronic neuropathic pain affects 7%-10% of the population. Deep brain stimulation (DBS) has shown variable but promising results in its treatment. This study prospectively assessed the long-term effectiveness of DBS in a series of patients with chronic neuropathic pain, correlating clinical results with neuroimaging. Sixteen patients received 5 years' post-surgical follow-up in a single center. Six had phantom limb pain after amputation and 10 had deafferentation pain after traumatic brachial plexus injury. Patient-reported outcome measures were completed before and after surgery, using VAS, UWNPS, BPI and SF-36 scores. Neuroimaging evaluated electrode location and effective volumes of activated tissue (VAT). Two subgroups were created based on the percentage of VAT superimposed upon the ventroposterolateral thalamic nucleus (eVAT), and clinical outcomes were compared. Analgesic effect was assessed at 5 years and compared to preoperative pain, with an improvement on VAS of 76.4% (p=0.0001), on UW-NPS of 35.2% (p=0.3582), on BPI of 65.1% (p=0.0505) and on SF-36 of 5% (p=0.7406). Eight patients with higher eVAT showed improvement on VAS of 67.5% (p=0.0017) while the remaining patients, with lower eVAT, improved by 50.6% (p=0.03607). DBS remained effective in improving chronic neuropathic pain after 5 years. While VPL-targeting contributes to success, analgesia is also obtained by stimulating surrounding posterior ventrobasal thalamic structures and related spinothalamocortical tracts.

Population Data Centre Profiles: Centre for Data Linkage.

The Centre for Data Linkage (CDL) was established at Curtin University, Western Australia, to develop infrastructure to enable cross-jurisdictional record linkage in Australia. The CDL's operating model makes use of the 'separation principle', with content data typically provided to researchers directly by the data custodian; jurisdictional linkage where available are used within the linkage process. Along with conducting record linkage, the team has also invested in establishing a research programme in record linkage methodology and in developing modern record linkage software which can handle the size and complexity of today's workloads. The Centre has been instrumental in the development of practical methods for privacy-preserving record linkage, with this methodology now regularly used for real-world linkages. While the promise of a nation-wide linkage system in Australia has yet to be met, distributed models provide a potential solution.

Optogenetic approaches to vision restoration.

Inherited retinal disease (IRD) affects about 1 in 3000 to 1 in 5000 individuals and is now believed to be the most common cause of blindness registration in developed countries. Until recently, the management of such conditions had been exclusively supportive. However, advances in molecular biology and medical engineering have now seen the rise of a variety of approaches to restore vision in patients with IRDs. Optogenetic approaches are primarily aimed at rendering secondary and tertiary neurons of the retina light-sensitive in order to replace degenerate or dysfunctional photoreceptors. Such approaches are attractive because they provide a "causative gene-independent" strategy, which may prove suitable for a variety of patients with IRD. We discuss theoretical and practical considerations in the selection of optogenetic molecules, vectors, surgical approaches and review previous trials of optogenetics for vision restoration. Optogenetic approaches to vision restoration have yielded promising results in pre-clinical trials and a phase I/II clinical trial is currently underway (ClinicalTrials.gov NCT02556736). Despite the significant inroads made in recent years, the ideal optogenetic molecule, vector and surgical approach have yet to be established.

The surgical safety checklist and patient outcomes after surgery: a prospective observational cohort study, systematic review and meta-analysis.

BACKGROUND: The surgical safety checklist is widely used to improve the quality of perioperative care. However, clinicians continue to debate the clinical effectiveness of this tool. METHODS: Prospective analysis of data from the International Surgical Outcomes Study (ISOS), an international observational study of elective in-patient surgery, accompanied by a systematic review and meta-analysis of published literature. The exposure was surgical safety checklist use. The primary outcome was in-hospital mortality and the secondary outcome was postoperative complications. In the ISOS cohort, a multivariable multi-level generalized linear model was used to test associations. To further contextualise these findings, we included the results from the ISOS cohort in a meta-analysis. Results are reported as odds ratios (OR) with 95% confidence intervals. RESULTS: We included 44 814 patients from 497 hospitals in 27 countries in the ISOS analysis. There were 40 245 (89.8%) patients exposed to the checklist, whilst 7508 (16.8%) sustained ≥1 postoperative complications and 207 (0.5%) died before hospital discharge. Checklist exposure was associated with reduced mortality [odds ratio (OR) 0.49 (0.32-0.77); P<0.01], but no difference in complication rates [OR 1.02 (0.88-1.19); P=0.75]. In a systematic review, we screened 3732 records and identified 11 eligible studies of 453 292 patients including the ISOS cohort. Checklist exposure was associated with both reduced postoperative mortality [OR 0.75 (0.62-0.92); P<0.01; I2=87%] and reduced complication rates [OR 0.73 (0.61-0.88); P<0.01; I2=89%). CONCLUSIONS: Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine.

pRotective vEntilation with veno-venouS lung assisT in respiratory failure: A protocol for a multicentre randomised controlled trial of extracorporeal carbon dioxide removal in patients with acute hypoxaemic respiratory failure.

One of the few interventions to demonstrate improved outcomes for acute hypoxaemic respiratory failure is reducing tidal volumes when using mechanical ventilation, often termed lung protective ventilation. Veno-venous extracorporeal carbon dioxide removal (vv-ECCO2R) can facilitate reducing tidal volumes. pRotective vEntilation with veno-venouS lung assisT (REST) is a randomised, allocation concealed, controlled, open, multicentre pragmatic trial to determine the clinical and cost-effectiveness of lower tidal volume mechanical ventilation facilitated by vv-ECCO2R in patients with acute hypoxaemic respiratory failure. Patients requiring intubation and mechanical ventilation for acute hypoxaemic respiratory failure will be randomly allocated to receive either vv-ECCO2R and lower tidal volume mechanical ventilation or standard care with stratification by recruitment centre. There is a need for a large randomised controlled trial to establish whether vv-ECCO2R in acute hypoxaemic respiratory failure can allow the use of a more protective lung ventilation strategy and is associated with improved patient outcomes.

Effect of nicotine replacement therapy on mortality, delirium, and duration of therapy in critically ill smokers: a systematic review and meta-analysis.

Nicotine replacement therapy is widely used in critically ill smokers and its effect on delirium, mortality and duration of intensive care unit (ICU) admission is unknown. The aims of this review were to determine whether the management of nicotine withdrawal with nicotine replacement therapy reduces delirium, mortality or length of stay in critically ill smokers in ICU. The primary outcome was incidence of author-defined ICU delirium. Secondary outcomes were ICU or hospital mortality, ICU-free days at day 28, and ICU or hospital length of stay. We conducted a systematic review and meta-analysis of the data sources MEDLINE, EMBASE, CINAHL, and the Cochrane Database of Systematic Reviews for randomised controlled trials and observational studies. Clinical trials, observational studies and systematic reviews comparing nicotine replacement therapy with placebo or no treatment were included. Case reports, case series, non-systematic reviews and studies that involved children were excluded. Eight studies were eligible (n=2,636) for inclusion in the data synthesis. In a meta-analysis of observational studies, nicotine replacement therapy was associated with increased delirium (three studies; n=908; I2=0%; finite element method: odds ratio 4.03 [95% confidence interval 2.64, 6.15]; P <0.001). There was no difference in ICU mortality (three studies; n=1,309; P=0.10, I2=44%; finite element method: odds ratio 0.58; 95% confidence intervals 0.31-1.10) and hospital mortality or 28-day ICU-free days. In the absence of high-quality data, nicotine replacement therapy cannot currently be recommended for routine use to prevent delirium or to reduce hospital or ICU mortality in critically ill smokers.

Frequency of surgical treatment and related hospital procedures in the UK: a national ecological study using hospital episode statistics.

BACKGROUND: Despite evidence of high activity, the number of surgical procedures performed in UK hospitals, their cost and subsequent mortality remain unclear. METHODS: Time-trend ecological study using hospital episode data from England, Scotland, Wales and Northern Ireland. The primary outcome was the number of in-hospital procedures, grouped using three increasingly specific categories of surgery. Secondary outcomes were all-cause mortality, length of hospital stay and healthcare costs according to standard National Health Service tariffs. RESULTS: Between April 1, 2009 and March 31, 2014, 39 631 801 surgical patient episodes were recorded. There was an annual average of 7 926 360 procedures (inclusive category), 5 104 165 procedures (intermediate category) and 1 526 421 procedures (restrictive category). This equates to 12 537, 8073 and 2414 procedures per 100 000 population per year, respectively. On average there were 85 181 deaths (1.1%) within 30 days of a procedure each year, rising to 178 040 deaths (2.3%) after 90 days. Approximately 62.8% of all procedures were day cases. Median length of stay for in-patient procedures was 1.7 (1.3-2.0) days. The total cost of surgery over the 5 yr period was £54.6 billion ($104.4 billion), representing an average annual cost of £10.9 billion (inclusive), £9.5 billion (intermediate) and £5.6 billion (restrictive). For each category, the number of procedures increased each year, while mortality decreased. One-third of all mortalities in national death registers occurred within 90 days of a procedure (inclusive category). CONCLUSIONS: The number of surgical procedures in the UK varies widely according to definition. The number of procedures is slowly increasing whilst the number of deaths is decreasing.

The Cognitive Role of the Globus Pallidus interna; Insights from Disease States.

The motor symptoms of both Parkinson's disease and focal dystonia arise from dysfunction of the basal ganglia, and are improved by pallidotomy or deep brain stimulation of the Globus Pallidus interna (GPi). However, Parkinson's disease is associated with a greater degree of basal ganglia-dependent learning impairment than dystonia. We attempt to understand this observation in terms of a comparison of the electrophysiology of the output of the basal ganglia between the two conditions. We use the natural experiment offered by Deep Brain Stimulation to compare GPi local field potential responses in subjects with Parkinson's disease compared to subjects with dystonia performing a forced-choice decision-making task with sensory feedback. In dystonic subjects, we found that auditory feedback was associated with the presence of high gamma oscillations nestled on a negative deflection, morphologically similar to sharp wave ripple complexes described in human rhinal cortex. These were not present in Parkinson's disease subjects. The temporal properties of the high gamma burst were modified by incorrect trial performance compared to correct trial performance. Both groups exhibited a robust low frequency response to 'incorrect' trial performance in dominant GPi but not non-dominant GPi at theta frequency. Our results suggest that cellular processes associated with striatum-dependent memory function may be selectively impaired in Parkinson's disease even if dopaminergic drugs are administered, but that error detection mechanisms are preserved.

Effect of day of the week on short- and long-term mortality after emergency general surgery.

BACKGROUND: The effect of day of the week on outcome after surgery is the subject of debate. The aim was to determine whether day of the week of emergency general surgery alters short- and long-term mortality. METHODS: This was an observational study of all patients undergoing emergency general surgery in Scotland between 1 January 2005 and 31 December 2007, followed to 2012. Multilevel logistic and Cox proportional hazards regression were used to assess the effect of day of the week of surgery on outcome after adjustment for case mix and risk factors. The primary outcome was perioperative mortality; the secondary outcome was overall survival. RESULTS: A total of 50 844 patients were identified, of whom 31 499 had an emergency procedure on Monday to Thursday and 19 345 on Friday to Sunday. Patients undergoing surgery at the weekend were younger (mean 45·9 versus 47·5 years; P < 0·001) and had fewer co-morbidities, but underwent riskier and/or more complex procedures (P < 0·001). Patients who had surgery at the weekend were more likely to have been operated on sooner than those who had weekday surgery (mean time from admission to operation 1·2 versus 1·6 days; P < 0·001). No difference in perioperative mortality (odds ratio 1·00, 95 per cent c.i. 0·89 to 1·13; P = 0·989) or overall survival (hazard ratio 1·01, 0·97 to 1·06; P = 0·583) was observed when surgery was performed at the weekend. There was no difference in overall survival after surgery undertaken on any particular day compared with Wednesday; a borderline reduction in perioperative mortality was seen on Tuesday. CONCLUSION: There was no difference in short- or long-term mortality following emergency general surgery at the weekend, compared with mid-week.

Intensive care utilization and outcomes after high-risk surgery in Scotland: a population-based cohort study.

BACKGROUND: The optimal perioperative use of intensive care unit (ICU) resources is not yet defined. We sought to determine the effect of ICU admission on perioperative (30 day) and long-term mortality. METHODS: This was an observational study of all surgical patients in Scotland during 2005-7 followed up until 2012. Patient, operative, and care process factors were extracted. The primary outcome was perioperative mortality; secondary outcomes were 1 and 4 yr mortality. Multivariable regression was used to construct a risk prediction model to allow standard-risk and high-risk groups to be defined based on deciles of predicted perioperative mortality risk, and to determine the effect of ICU admission (direct from theatre; indirect after initial care on ward; no ICU admission) on outcome adjusted for confounders. RESULTS: There were 572 598 patients included. The risk model performed well (c-index 0.92). Perioperative mortality occurred in 1125 (0.2%) in the standard-risk group (n=510 979) and in 3636 (6.4%) in the high-risk group (n=56 785). Patients with no ICU admission within 7 days of surgery had the lowest perioperative mortality (whole cohort 0.7%; high-risk cohort 5.3%). Indirect ICU admission was associated with a higher risk of perioperative mortality when compared with direct admission for the whole cohort (20.9 vs 12.1%; adjusted odds ratio 2.39, 95% confidence interval 2.01-2.84; P<0.01) and for high-risk patients (26.2 vs 17.8%; adjusted odds ratio 1.64, 95% confidence interval 1.37-1.96; P<0.01). Compared with direct ICU admission, indirectly admitted patients had higher severity of illness on admission, required more organ support, and had an increased duration of ICU stay. CONCLUSIONS: Indirect ICU admission was associated with increased mortality and increased requirement for organ support. TRIAL REGISTRATION: UKCRN registry no. 15761.

Meta-analysis of the association between preoperative anaemia and mortality after surgery.

BACKGROUND: Numerous published studies have explored associations between anaemia and adverse outcomes after surgery. However, there are no evidence syntheses describing the impact of preoperative anaemia on postoperative outcomes. METHODS: A systematic review and meta-analysis of observational studies exploring associations between preoperative anaemia and postoperative outcomes was performed. Studies investigating trauma, burns, transplant, paediatric and obstetric populations were excluded. The primary outcome was 30-day or in-hospital mortality. Secondary outcomes were acute kidney injury, stroke and myocardial infarction. Predefined analyses were performed for the cardiac and non-cardiac surgery subgroups. A post hoc analysis was undertaken to evaluate the relationship between anaemia and infection. Data are presented as odds ratios (ORs) with 95 per cent c.i. RESULTS: From 8973 records, 24 eligible studies including 949 445 patients were identified. Some 371 594 patients (39·1 per cent) were anaemic. Anaemia was associated with increased mortality (OR 2·90, 2·30 to 3·68; I(2) = 97 per cent; P < 0·001), acute kidney injury (OR 3·75, 2·95 to 4·76; I(2) = 60 per cent; P < 0·001) and infection (OR 1·93, 1·17 to 3·18; I(2) = 99 per cent; P = 0·01). Among cardiac surgical patients, anaemia was associated with stroke (OR 1·28, 1·06 to 1·55; I(2) = 0 per cent; P = 0·009) but not myocardial infarction (OR 1·11, 0·68 to 1·82; I(2) = 13 per cent; P = 0·67). Anaemia was associated with an increased incidence of red cell transfusion (OR 5·04, 4·12 to 6·17; I(2) = 96 per cent; P < 0·001). Similar findings were observed in the cardiac and non-cardiac subgroups. CONCLUSION: Preoperative anaemia is associated with poor outcomes after surgery, although heterogeneity between studies was significant. It remains unclear whether anaemia is an independent risk factor for poor outcome or simply a marker of underlying chronic disease. However, red cell transfusion is much more frequent amongst anaemic patients.

Dose Estimation for a Study of Nuclear Workers in France, the United Kingdom and the United States of America: Methods for the International Nuclear Workers Study (INWORKS).

In the framework of the International Nuclear Workers Study conducted in France, the UK and the U.S. (INWORKS), updated and expanded methods were developed to convert recorded doses of ionizing radiation to estimates of organ doses or individual personal dose equivalent [H(p)(10)] for a total number of 308,297 workers, including 40,035 women. This approach accounts for differences in dosimeter response to predominant workplace energy and geometry of exposure and for the recently published ICRP report on dose coefficients for men and women separately. The overall mean annual individual personal dose equivalent, including zero doses, is 1.73 mSv [median = 0.42; interquartile range (IQR): 0.07, 1.59]. Associated individual organ doses were estimated. INWORKS includes workers who had potential for exposure to neutrons. Therefore, we analyzed neutron dosimetry data to identify workers potentially exposed to neutrons. We created a time-varying indicator for each worker, classifying them according to whether they had a positive recorded neutron dose and if so, whether their neutron dose ever exceeded 10% of their total external penetrating radiation dose. The number of workers flagged as being exposed to neutrons was 13% for the full cohort, with 15% of the cohort in France, 12% of the cohort in the UK and 14% in the U.S. We also used available information on in vivo and bioassay monitoring to identify workers with known depositions or suspected internal contaminations. As a result of this work, information is now available that will allow various types of sensitivity analyses.

Perioperative myocardial injury in patients receiving cardiac output-guided haemodynamic therapy: a substudy of the OPTIMISE Trial.

BACKGROUND: Evidence suggests that cardiac output-guided haemodynamic therapy algorithms improve outcomes after high-risk surgery, but there is some concern that this could promote acute myocardial injury. We evaluated the incidence of myocardial injury in a perioperative goal-directed therapy trial. METHODS: Patients undergoing major gastrointestinal surgery (n=723) were randomly assigned to cardiac output-guided haemodynamic therapy (intervention group) or usual care as part of the OPTIMISE trial. At four participating sites, 288 patients were enrolled in a biomarker substudy. Serum high-sensitivity cardiac troponin I (TnI) concentration and N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration were measured before and at 24 and 72 h after surgery. RESULTS: Median preoperative TnI and NT-ProBNP concentrations were 4.3 ng litre(-1) and 144 pg ml(-1), respectively. After surgery, 67 (46%) patients in the intervention group and 68 (48%) patients receiving usual care had TnI concentrations above the 99th centile upper reference limit (P=0.82). Peak serum TnI concentration was similar in the intervention and usual care groups (median [interquartile range]: 10.0 [5.3-21.5] vs 7.8 [5.0-21.8] ng litre(-1); P=0.85), and no differences were observed in serum TnI concentrations over 72 h (repeated-measures anova, P=0.51). Likewise, there were no differences in peak NT-proBNP concentration between intervention and usual care groups (645 [362-1169] vs 659 [381-1028] pg ml(-1); P=0.86) or in serial NT-proBNP concentrations over 72 h (P=0.20). CONCLUSIONS: Myocardial injury is common among patients undergoing major gastrointestinal surgery. In this study, the frequency was not affected by cardiac output-guided fluid and low-dose inotropic therapy.

Glucocorticoids: structure, signaling and molecular mechanisms in the treatment of diabetic retinopathy and diabetic macular edema.

Diabetic retinopathy (DR) is one of the leading causes of blindness in the working population worldwide. Vascular leakage, angiogenesis and neuronal degeneration are key features of DR. Current effective interventions for DR include treatment of systemic risk factors such as elevated blood glucose, blood pressure and dyslipidemia. Ocular treatments include vascular endothelial growth factor A (VEGF-A) inhibitors, laser photocoagulation and surgery. While anti-VEGF therapy has become as first-line treatment for diabetic macular edema (DME) that causes reduced vision, intravitreal glucocorticoids also have been shown to be efficacious in this situation. It has been reported that all the major pathological processes of DR are susceptible to glucocorticoid treatment. The effects of glucocorticoids on vascular leakage and angiogenesis may be mediated through their well established anti-inflammatory role. Alternatively, glucocorticoids may affect other mechanisms known to be activated in DR. Potential mechanisms for the anti-inflammatory effects of glucocorticoids include blockage of cytokine production and inhibition of leukocyte adhesion induced by VEGF-A. Glucocorticoids decrease the expression of VEGF-A directly, and increase the production, or decrease phosphorylation, of tight junction-associated proteins. Glucocorticoids have also been shown to be neuroprotective, in contrast to VEGF-A inhibitors which animal studies suggest may be neurotoxic. This review outlines the biological properties of synthetic glucocorticoids, with particular emphasis on the potential beneficial effect of combining glucocorticoids with anti-VEGF treatment for DME and DR.