A randomized controlled trial of nebulized surfactant for the treatment of severe COVID-19 in adults (COVSurf trial).

SARS-CoV-2 directly targets alveolar epithelial cells and can lead to surfactant deficiency. Early reports suggested surfactant replacement may be effective in improving outcomes. The aim of the study to assess the feasibility and efficacy of nebulized surfactant in mechanically ventilated COVID-19 patients. Patients were randomly assigned to receive open-labelled bovine nebulized surfactant or control (ratio 3-surfactant: 2-control). This was an exploratory dose-response study starting with 1080 mg of surfactant delivered at 3 time points (0, 8 and 24 h). After completion of 10 patients, the dose was reduced to 540 mg, and the frequency of nebulization was increased to 5/6 time points (0, 12, 24, 36, 48, and an optional 72 h) on the advice of the Trial Steering Committee. The co-primary outcomes were improvement in oxygenation (change in PaO2/FiO2 ratio) and ventilation index at 48 h. 20 patients were recruited (12 surfactant and 8 controls). Demographic and clinical characteristics were similar between groups at presentation. Nebulized surfactant administration was feasible. There was no significant improvement in oxygenation at 48 h overall. There were also no differences in secondary outcomes or adverse events. Nebulized surfactant administration is feasible in mechanically ventilated patients with COVID-19 but did not improve measures of oxygenation or ventilation.

Clinical impact of syndromic molecular point-of-care testing for gastrointestinal pathogens in adults hospitalised with suspected gastroenteritis (GastroPOC): a pragmatic, open-label, randomised controlled trial.

BACKGROUND: Single-occupancy isolation rooms are a finite resource in UK hospitals but are crucial in preventing transmission of infection. Patients with suspected gastroenteritis are nursed in single-occupancy rooms, but delays in laboratory testing lead to non-infectious patients remaining isolated for prolonged periods unnecessarily. Rapid molecular test panels for gastrointestinal pathogens have a run time of around 1 h but their clinical impact is unknown. We aimed to evaluate the clinical impact of syndromic molecular point-of-care testing (mPOCT) for gastrointestinal pathogens in adult patients presenting to hospital with suspected gastroenteritis on single-occupancy room use and a range of other outcome measures. METHODS: In this pragmatic, open-label, randomised controlled trial, we enrolled adults hospitalised with suspected gastroenteritis in a large UK hospital. Patients were randomly allocated (1:1) to receive syndromic mPOCT of stool or rectal samples, or to routine clinical care (control) with laboratory testing. The primary outcome was the duration of time in single-occupancy rooms assessed on a modified intention-to-treat basis. Secondary outcomes included the time to results, time to de-isolation, antibiotic use, and safety outcomes. The study was registered with ISRCTN, ISRCTN88918395, and is complete. FINDINGS: Between March 20, 2017 and March 17, 2020, from 455 patients assessed for eligibility, we enrolled 278 patients, 138 assigned to mPOCT (one withdrawal) and 140 to the control group. The duration (geometric mean) of single-occupancy room isolation was 1·8 days (95% CI 1·5-2·2) in the mPOCT group compared with 2·6 days (2·2-3·0) in the control group (exponentiated coefficient 0·70 [95% CI 0·56 to 0·87]; p=0·0017). The median (IQR) time to results was 1·7 h (1·5-2·0) for mPOCT and 44·7 h (21·2-66·1) for the control group (p<0·0001). Time to de-isolation was 0·6 days (0·3-1·8) in the mPOCT group compared with 2·2 days (1·2-3·2) in the control group, (p<0·0001). Antibiotics were given in 89 (65%) of 137 in the mPOCT group and 66 (47%) of 140 in the control group (p=0·0028). There were no differences between groups in length of hospital stay, or in safety outcomes including mortality, intensive care unit admission, or readmission to hospital. INTERPRETATION: mPOCT for gastrointestinal pathogens in patients with suspected gastroenteritis returned results more rapidly than conventional testing and was associated with a reduction in single-occupancy room use. However, these benefits need to be balanced against a potential increase in antibiotic use. FUNDING: University Hospital Southampton NHS Foundation Trust.

Body mass index and clinical outcome of severe COVID-19 patients with acute hypoxic respiratory failure: Unravelling the "obesity paradox" phenomenon.

BACKGROUND AND AIMS: Although obesity have been generally shown to be an independent risk factor for poor outcomes in COVID-19 infection, some studies demonstrate a paradoxical protective effect ("obesity paradox"). This study examines the influence of obesity categories on clinical outcomes of severe COVID-19 patients admitted to an intensive care unit with acute hypoxic respiratory failure requiring either non-invasive or invasive mechanical ventilation. METHODS: This is a single centre, retrospective study of consecutive COVID-19 patients admitted to the intensive care unit between 03/2020 to 03/2021. Patients were grouped according to the NICE Body Mass Index (BMI) category. Admission variables including age, sex, comorbidities, and ICU severity indices (APACHE-II, SOFA and PaO2/FiO2) were collected. Data were compared between BMI groups for outcomes such as need for invasive mechanical ventilation (IMV), renal replacement therapy (RRT) and 28-day and overall hospital mortality. RESULTS: 340 patients were identified and of those 333 patients had their BMI documented. Just over half of patients (53%) had obesity. Those with extreme obesity (obesity groups II and III) were younger with fewer comorbidities, but were more hypoxaemic at presentation, than the healthy BMI group. Although non-significant, obesity groups II and III paradoxically showed a lower in-hospital mortality than the healthy weight group. However, adjusted (age, sex, APACHE-II and CCI) competing risk regression analysis showed three-times higher mortality in obese category I (sub-distribution hazard ratio = 3.32 (95% CI 1.30-8.46), p = 0.01) and a trend to higher mortality across all obesity groups compared to the healthy weight group. CONCLUSIONS: In this cohort, those with obesity were at higher risk of mortality after adjustment for confounders. We did not identify an "obesity paradox" in this cohort. The obesity paradox may be explained by confounding factors such as younger age, fewer comorbidities, and less severe organ failures. The impact of obesity on indicators of morbidity including likelihood of requirement for organ support measures was not conclusively demonstrated and requires further scrutiny.

Molecular point-of-care testing for lower respiratory tract pathogens improves safe antibiotic de-escalation in patients with pneumonia in the ICU: Results of a randomised controlled trial.

BACKGROUND: Effective treatment of pneumonia requires timely administration of appropriate antimicrobials but standard diagnostic tests take around 48 h to generate results. Highly accurate, rapid molecular tests have been developed for identifying organisms in lower respiratory tract samples, however their impact on antibiotic use is unknown. The aim of this study was to assess the impact of syndromic molecular point-of-care testing compared to conventional diagnostic testing, on antibiotic use. METHODS: In this pragmatic, randomised controlled trial, we enrolled critically ill adults with pneumonia. Patients were assigned (1:1) to molecular testing of samples at the point-of-care or routine clinical care. The primary outcome was the proportion of patients who received results-directed antimicrobial therapy. RESULTS: 200 patients were randomly assigned to point-of-care testing (n = 100) or the control group (n = 100). 85 patients had community acquired pneumonia (42 in the mPOCT group and 43 in the control group), 69 hospital acquired pneumonia (30 in mPOCT and 39 in control) and 46 ventilator associated pneumonia (28 in mPOCT and 18 in control). The median [IQR] time to results was 1.7 [1.6-1.9] hours for point-of-care testing and 66.7 [56.7-88.5] hours for standard diagnostics (difference of -65.0 h, 95%CI -68.0 to -62.0; p < 0.0001). 71 (71%) patients in the point-of-care testing arm had pathogens detected compared to 51 (51%) in the control arm (difference of 20%, 95%CI 7 to 33; p = 0.004). 80 (80%) of patients in the point-of-care group received results-directed therapy, compared with 29 (29%) of 99 in the control group (difference of 51%, 95%CI 39-63; p < 0.0001). Time to results-directed therapy was 2.3 [1.8-7.2] hours in the mPOCT group and 46.1 [23.0-51.5] hours in the control group (difference of -43.8 h, 95% CI -48.9 to -38.6; p < 0.0001). 42 (42%) patients in mPOCT group had antibiotics de-escalated compared with 8 (8%) of 98 in the control group (difference of 34%, 95%CI 23-45; p < 0.0001). Time to de-escalation was 4.8 [2.4-13.0] hours in the mPOCT group compared with 46.5 [26.3-48.6] hours in the control group (difference of -41.4 h, 95%CI -53 to -29.7; p < 0.0001). There was no major difference in antibiotic duration or in clinical or safety outcomes between the two groups. CONCLUSIONS: Use of molecular point-of-care testing in patients with pneumonia returned results more rapidly and identified more pathogens than conventional testing. This was associated with improvements in appropriate antimicrobial use and appeared safe.

Dietary Nitrate Supplementation Does Not Alter Exercise Efficiency at High Altitude - Further Results From the Xtreme Alps Study.

Introduction: Nitrate supplementation in the form of beetroot juice (BRJ) ingestion has been shown to improve exercise tolerance during acute hypoxia, but its effect on exercise physiology remains unstudied during sustained terrestrial high altitude exposure. We hypothesized that performing exercise at high altitude would lower circulating nitrate and nitrite levels and that BRJ ingestion would reverse this phenomenon while concomitantly improving key determinants of aerobic exercise performance. Methods: Twenty seven healthy volunteers (21 male) underwent a series of exercise tests at sea level (SL, London, 75 m) and again after 5-8 days at high altitude (HA, Capanna Regina Margherita or "Margherita Hut," 4,559 m). Using a double-blind protocol, participants were randomized to consume a beetroot/fruit juice beverage (three doses per day) with high levels of nitrate (∼0.18 mmol/kg/day) or a nitrate-depleted placebo (∼11.5 µmoles/kg/day) control drink, from 3 days prior to the exercise trials until completion. Submaximal constant work rate cycle tests were performed to determine exercise efficiency and a maximal incremental ramp exercise test was undertaken to measure aerobic capacity, using breath-by-breath pulmonary gas exchange measurements throughout. Concentrations of nitrate, nitrite and nitrosation products were quantified in plasma samples collected at 5 timepoints during the constant work rate tests. Linear mixed modeling was used to analyze data. Results: At both SL and HA, plasma nitrate concentrations were elevated in the nitrate supplementation group compared to placebo (P < 0.001) but did not change throughout increasing exercise work rate. Delta exercise efficiency was not altered by altitude exposure (P = 0.072) or nitrate supplementation (P = 0.836). V̇O2peak decreased by 24% at high altitude (P < 0.001) and was lower in the nitrate-supplemented group at both sea level and high altitude compared to placebo (P = 0.041). Dietary nitrate supplementation did not alter other peak exercise variables or oxygen consumption at anaerobic threshold. Circulating nitrite and S-nitrosothiol levels unexpectedly rose in a few individuals right after cessation of exercise at high altitude. Conclusion: Whilst regularly consumed during an 8 days expedition to terrestrial high altitude, nitrate supplementation did not alter exercise efficiency and other exercise physiological variables, except decreasing V̇O2peak. These results and those of others question the practical utility of BRJ consumption during prolonged altitude exposure.

Transitioning from Intravenous to Subcutaneous Vedolizumab in Patients with Inflammatory Bowel Disease [TRAVELESS].

BACKGROUND AND AIMS: Subcutaneous [SC] vedolizumab presents the opportunity for inflammatory bowel disease [IBD] patients to manage their treatment at home. There are currently no data on the process of transitioning patients established on intravenous [IV] to SC vedolizumab as part of routine clinical care. The aim of this programme is to evaluate the clinical and biochemical outcomes of switching a cohort of IBD patients established on IV vedolizumab to SC, at 12 weeks following the transition. METHODS: In all, 178 adult patients were offered the opportunity to transition to SC vedolizumab. Patients who agreed were reviewed prior to switching and at Week 12 [W12] after their first SC dose. Evaluation outcomes included disease activity scores, the IBD-Control Patient-Reported Outcome Measures [PROMs], and faecal calprotectin [FCP]. Reasons for patients declining or accepting transitioning, pharmacokinetics, adverse drug reactions, and risk factors for a poor outcome in SARS-CoV-2 infection were also assessed. RESULTS: A total of 124 patients agreed to transition, of whom 106 patients had been on IV vedolizumab for at least 4 months. There were no statistically significant differences in disease activity scores or IBD-Control PROMs between baseline and W12. A statistically significant increase in FCP was observed [31 µg/g vs. 47 µg/g; p = 0.008], although this was unlikely to be clinically relevant. The most common adverse drug reaction reported was injection site reactions [15%]. Based on this cohort of patients, an expected reduction of £572,000 per annum is likely to be achieved. CONCLUSIONS: Transitioning patients established on IV vedolizumab to SC appears to be safe and effective, with high patient satisfaction and multiple benefits for the health service.

The effects of neoadjuvant chemoradiotherapy and an in-hospital exercise training programme on physical fitness and quality of life in locally advanced rectal cancer patients: a randomised controlled trial (The EMPOWER Trial).

BACKGROUND: The EMPOWER trial aimed to assess the effects of a 9-week exercise prehabilitation programme on physical fitness compared with a usual care control group. Secondary aims were to investigate the effect of (1) the exercise prehabilitation programme on psychological health; and (2) neoadjuvant chemoradiotherapy (NCRT) on physical fitness and psychological health. METHODS: Between October 2013 and December 2016, adults with locally advanced rectal cancer undergoing standardised NCRT and surgery were recruited to a multi-centre trial. Patients underwent cardiopulmonary exercise testing (CPET) and completed HRQoL questionnaires (EORTC-QLQ-C30 and EQ-5D-5L) pre-NCRT and post-NCRT (week 0/baseline). At week 0, patients were randomised to exercise prehabilitation or usual care (no intervention). CPET and HRQoL questionnaires were assessed at week 0, 3, 6 and 9, whilst semi-structured interviews were assessed at week 0 and week 9. Changes in oxygen uptake at anaerobic threshold (VO2 at AT (ml kg-1 min-1)) between groups were compared using linear mixed modelling. RESULTS: Thirty-eight patients were recruited, mean age 64 (10.4) years. Of the 38 patients, 33 were randomised: 16 to usual care and 17 to exercise prehabilitation (26 males and 7 females). Exercise prehabilitation significantly improved VO2 at AT at week 9 compared to the usual care. The change from baseline to week 9, when adjusted for baseline, between the randomised groups was + 2.9 ml kg -1 min -1; (95% CI 0.8 to 5.1), p = 0.011. CONCLUSION: A 9-week exercise prehabilitation programme significantly improved fitness following NCRT. These findings have informed the WesFit trial (NCT03509428) which is investigating the effects of community-based multimodal prehabilitation before cancer surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT01914068 . Registered 1 August 2013.

The Wessex Fit-4-Cancer Surgery Trial (WesFit): a protocol for a factorial-design, pragmatic randomised-controlled trial investigating the effects of a multi-modal prehabilitation programme in patients undergoing elective major intra-cavity cancer surgery.

Background: Surgical resection remains the primary curative treatment for intra-cavity cancer. Low physical fitness and psychological factors such as depression are predictive of post-operative morbidity, mortality and length of hospital stay. Prolonged post-operative morbidity is associated with persistently elevated risk of premature death. We aim to investigate whether a structured, responsive exercise training programme, a psychological support programme or combined exercise and psychological support, delivered between treatment decision and major intra-cavity surgery for cancer, can reduce length of hospital stay, compared with standard care. Methods: WesFit is a pragmatic , 2x2 factorial-design, multi-centre, randomised-controlled trial, with planned recruitment of N=1560. Participants will be randomised to one of four groups. Group 1 (control) will receive usual pre-operative care, Group 2 (exercise) patients will undergo 2/3 aerobic, high-intensity interval training sessions per week supervised by personal trainers. Group 3 (psychological support) patients are offered 1 session per week at a local cancer support centre. Group 4 will receive both exercise and psychological support. All patients undergo baseline and pre-operative cardiopulmonary exercise testing, complete self-report questionnaires and will be followed up at 30 days, 12 weeks and 12 months post-operatively. Primary outcome is post-operative length-of-stay. Secondary outcomes include disability-adjusted survival at 1-year postoperatively, post-operative morbidity, and health-related quality of life. Exploratory investigations include objectively measured changes in physical fitness assessed by cardiopulmonary exercise test, disease-free and overall mortality at 1-year postoperatively, longer-term physical activity behaviour change, pre-operative radiological tumour regression, pathological tumour regression, pre and post-operative body composition analysis, health economics analysis and nutritional characterisation and its relationship to post-operative outcome. Conclusions: The WesFit trial will be the first randomised controlled study investigating whether an exercise training programme +/- psychological intervention results in improvements in clinical and patient reported outcomes in patients undergoing major inter-cavity resection of cancer. ClinicalTrials.gov registration: NCT03509428 (26/04/2018).

Psychological impact of caring for critically ill patients during the Covid-19 pandemic and recommendations for staff support.

BACKGROUND: Reports of significant psychological stress among frontline healthcare workers are emerging from the Covid-19 outbreak in China. Concerningly, these match findings from previous infective outbreaks, which resulted in long-term psychological pathology. METHODS: During the Covid-19 pandemic, a multi-disciplinary cohort of Intensive Care staff completed an online survey of psychological well-being and rated the perceived usefulness of supportive interventions. RESULTS: Sixty per cent of invited staff responded. Seventy-seven per cent reported normal/high level of resilience. Thirty-two staff (35%) reported anxiety of a level at which formal psychological assessment is recommended. Sixteen (14%) staff members reported symptomology suggestive of post-traumatic stress disorder (PTSD). Multiple regression analysis revealed a significant relationship between job-related well-being, anxiety (p = 0.003) and PTSD (p = 0.005). Nurses were seven times more likely than doctors to score higher anxiety (OR = 6.8; p = 0.01). Preferred supportive interventions were adequate personal protective equipment, rest facilities and regular breaks. In the subgroup with high anxiety, psychological support was perceived as significantly more useful, with significant reductions reported for rest facilities and PPE. DISCUSSION: We report concerning levels of anxiety and post-traumatic stress symptomology among intensive care staff during the Covid-19 crisis, significantly impacting job-related well-being. Nurses are disproportionately affected. Overall, physiologically protective supportive interventions were preferred by staff; however, staff with established anxiety desire professional psychological help. Our findings match reports from SARS 2003 and China 2019. To mitigate long-term psychological consequences of caring for patients during a pandemic, easily deliverable protective strategies should be instigated, supported by formal and longer-term psychological support. Particular attention should be paid to developing strategies which support nursing staff.

Patient perceived barriers to exercise and their clinical associations in difficult asthma.

BACKGROUND: Exercise is recommended in guidelines for asthma management and has beneficial effects on symptom control, inflammation and lung function in patients with sub-optimally controlled asthma. Despite this, physical activity levels in patients with difficult asthma are often impaired. Understanding the barriers to exercise in people with difficult asthma is crucial for increasing their activity, and in implementing successful, disease modifying, and holistic approaches to improve their health. METHODS: 62 Patients within the WATCH Difficult Asthma Cohort (Southampton, UK) completed an Exercise Therapy Burden Questionnaire (ETBQ). The results were analyzed with contemporaneous asthma-related data to determine relationships between perceived exercise barriers and asthma and comorbidity characteristics. RESULTS: Patients were reflective of a difficult asthma cohort, 66% were female, and 63% were atopic. They had a high BMI (median [inter-quartile range]) of 29.3 [25.5-36.2], age of 53.5 [38.75, 65.25], impaired spirometry with FEV1 73% predicted [59.5, 86.6%] and FEV/FVC ratio of 72 [56.5, 78.0] and poor symptom control, as defined by an Asthma Control Questionnaire (ACQ6) result of 2.4 [1.28, 3.2]. A high perceived barriers to exercise score was significantly correlated with increased asthma symptoms (r = 0.452, p < 0.0001), anxiety (r = 0.375, p = 0.005) and depression (r = 0.363, p = 0.008), poor quality of life (r = 0.345, p = 0.015) and number of rescue oral steroid courses in the past 12 months (r = 0.257, p = 0.048). Lung function, blood eosinophil count, FeNO, Njimegen and SNOT22 scores, BMI and hospitalisations in the previous year were not related to exercise perceptions. CONCLUSION: In difficult asthma, perceived barriers to exercise are related to symptom burden and psychological morbidity. Therefore, exercise interventions combined with psychological input such as CBT to restructure thought processes around these perceived barriers may be useful in facilitating adoption of exercise.

Synbiotics Alter Fecal Microbiomes, But Not Liver Fat or Fibrosis, in a Randomized Trial of Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Dysbiosis of the intestinal microbiota has been associated with nonalcoholic fatty liver disease (NAFLD). We investigated whether administration of a synbiotic combination of probiotic and prebiotic agents affected liver fat content, biomarkers of liver fibrosis, and the composition of the fecal microbiome in patients with NAFLD. METHODS: We performed a double-blind phase 2 trial of 104 patients with NAFLD in the United Kingdom. Participants (mean age, 50.8 ± 12.6 years; 65% men; 37% with diabetes) were randomly assigned to groups given the synbiotic agents (fructo-oligosaccharides, 4 g twice per day, plus Bifidobacterium animalis subspecies lactis BB-12; n = 55) or placebo (n = 49) for 10-14 months. Liver fat content was measured at the start and end of the study by magnetic resonance spectroscopy, and liver fibrosis was determined from a validated biomarker scoring system and vibration-controlled transient elastography. Fecal samples were collected at the start and end of the study, the fecal microbiome were analyzed by 16S ribosomal DNA sequencing. RESULTS: Mean baseline and end-of-study magnetic resonance spectroscopy liver fat percentage values were 32.3% ± 24.8% and 28.5% ± 20.1% in the synbiotic group and 31.3% ± 22% and 25.2% ± 17.2% in the placebo group. In the unadjusted intention-to-treat analysis, we found no significant difference in liver fat reduction between groups (ß = 2.8; 95% confidence interval, -2.2 to 7.8; P = .30). In a fully adjusted regression model (adjusted for baseline measurement of the outcome plus age, sex, weight difference, and baseline weight), only weight loss was associated with a significant decrease in liver fat (ß = 2; 95% confidence interval, 1.5-2.6; P = .03). Fecal samples from patients who received the synbiotic had higher proportions of Bifidobacterium and Faecalibacterium species, and reductions in Oscillibacter and Alistipes species, compared with baseline; these changes were not observed in the placebo group. Changes in the composition of fecal microbiota were not associated with liver fat or markers of fibrosis. CONCLUSIONS: In a randomized trial of patients with NAFLD, 1 year of administration of a synbiotic combination (probiotic and prebiotic) altered the fecal microbiome but did not reduce liver fat content or markers of liver fibrosis. (ClinicalTrials.gov, Number: NCT01680640).

Effects of dietary nitrate supplementation on microvascular physiology at 4559 m altitude - A randomised controlled trial (Xtreme Alps).

Native highlanders (e.g. Sherpa) demonstrate remarkable hypoxic tolerance, possibly secondary to higher levels of circulating nitric oxide (NO) and increased microcirculatory blood flow. As part of the Xtreme Alps study (a randomised placebo-controlled trial of dietary nitrate supplementation under field conditions of hypobaric hypoxia), we investigated whether dietary supplementation with nitrate could improve NO availability and microvascular blood flow in lowlanders. Plasma measurements of nitrate, nitrite and nitroso species were performed together with measurements of sublingual (sidestream dark-field camera) and forearm blood flow (venous occlusion plethysmography) in 28 healthy adult volunteers resident at 4559 m for 1 week; half receiving a beetroot-based high-nitrate supplement and half receiving an identically-tasting low nitrate 'placebo'. Dietary supplementation increased plasma nitrate concentrations 4-fold compared to the placebo group, both at sea level (SL; 19.2 vs 76.9 µM) and at day 5 (D5) of high altitude (22.9 vs 84.3 µM, p < 0.001). Dietary nitrate supplementation also significantly increased both plasma nitrite (0.78 vs. 0.86 µM SL, 0.31 vs. 0.41 µM D5, p = 0.03) and total nitroso product (11.3 vs. 19.7 nM SL, 9.7 vs. 12.3 nM D5, p < 0.001) levels both at sea level and at 4559 m. However, plasma nitrite concentrations were more than 50% lower at 4559 m compared to sea level in both treatment groups. Despite these significant changes, dietary nitrate supplementation had no effect on any measured read-outs of sublingual or forearm blood flow, even when environmental hypoxia was experimentally reversed using supplemental oxygen. In conclusion, dietary nitrate supplementation does not improve microcirculatory function at 4559 m.

Design and rationale of the INSYTE study: A randomised, placebo controlled study to test the efficacy of a synbiotic on liver fat, disease biomarkers and intestinal microbiota in non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of fat-related conditions ranging from simple fatty liver, to non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. There is growing evidence that NAFLD is a multisystem disease, affecting several extra-hepatic organs and regulatory pathways. Furthermore, since the gut and liver are linked anatomically via the portal vein, disturbances of the gut microbiota (dysbiosis) can affect the liver. OBJECTIVES: In patients with NAFLD, we are testing the effects of a synbiotic which is the combination of a prebiotic (fructooligosaccharides; 4 g/day) and a probiotic (Bifidobacterium animalis subsp. lactis BB-12 at a minimum of 10 billion CFU/day) on a) liver fat percentage, b) NAFLD fibrosis algorithm scores, c) gut microbiota composition. Additionally, there will be several hypothesis-generating secondary outcomes to understand the metaorganismal pathways that influence the development and progression of NAFLD, type 2 diabetes, and cardiovascular risk. DESIGN: In a randomised double-blind placebo-controlled trial, 104 participants were randomised to 10-14 months intervention with either synbiotic (n = 55) or placebo (n = 49). Recruitment was completed in April 2017 and the last study visit will be completed by April 2018. METHODS: Change in gut microbiota composition will be assessed using 16S ribosomal RNA gene sequencing. Change in mean liver fat percentage will be quantified by magnetic resonance spectroscopy (MRS). In addition, change in liver fat severity will be measured using two NAFLD fibrosis algorithm scores. The INSYTE study was approved by the local ethics committee (REC: 12/SC/0614) and is registered at www.clinicaltrials.gov as NCT01680640.

Effects of dietary nitrate on respiratory physiology at high altitude - Results from the Xtreme Alps study.

Nitric oxide (NO) production plays a central role in conferring tolerance to hypoxia. Tibetan highlanders, successful high-altitude dwellers for millennia, have higher circulating nitrate and exhaled NO (ENO) levels than native lowlanders. Since nitrate itself can reduce the oxygen cost of exercise in normoxia it may confer additional benefits at high altitude. Xtreme Alps was a double-blinded randomised placebo-controlled trial to investigate how dietary nitrate supplementation affects physiological responses to hypoxia in 28 healthy adult volunteers resident at 4559 m for 1 week; 14 receiving a beetroot-based high-nitrate supplement and 14 receiving a low-nitrate 'placebo' of matching appearance/taste. ENO, vital signs and acute mountain sickness (AMS) severity were recorded at sea level (SL) and daily at altitude. Moreover, standard spirometric values were recorded, and saliva and exhaled breath condensate (EBC) collected. There was no significant difference in resting cardiorespiratory variables, peripheral oxygen saturation or AMS score with nitrate supplementation at SL or altitude. Median ENO levels increased from 1.5/3.0  mPa at SL, to 3.5/7.4 mPa after 5 days at altitude (D5) in the low and high-nitrate groups, respectively (p = 0.02). EBC nitrite also rose significantly with dietary nitrate (p = 0.004), 1.7-5.1  µM at SL and 1.6-6.3 µM at D5, and this rise appeared to be associated with increased levels of ENO. However, no significant changes occurred to levels of EBC nitrate or nitrosation products (RXNO). Median salivary nitrite/nitrate concentrations increased from 56.5/786 µM to 333/5,194  µM  with nitrate supplementation at SL, and changed to 85.6/641 µM and 341/4,553 µM on D5. Salivary RXNO rose markedly with treatment at SL from 0.55 µM to 5.70 µM. At D5 placebo salivary RXNO had increased to 1.90 µM whilst treatment RXNO decreased to 3.26 µM. There was no association with changes in any observation variables or AMS score. In conclusion, dietary nitrate supplementation is well tolerated at altitude and significantly increases pulmonary NO availability and both salivary and EBC NO metabolite concentrations. Surprisingly, this is not associated with changes in hemodynamics, oxygen saturation or AMS development.

Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the Welcome* study.

There is no licensed treatment for non-alcoholic fatty liver disease (NAFLD), a condition that increases risk of chronic liver disease, type 2 diabetes and cardiovascular disease. We tested whether 15-18 months treatment with docosahexaenoic acid (DHA) plus eicosapentaenoic acid (EPA) (Omacor/Lovaza) (4 g/day) decreased liver fat and improved two histologically-validated liver fibrosis biomarker scores (primary outcomes). Patients with NAFLD were randomised in a double blind placebo-controlled trial [DHA+EPA(n=51), placebo(n=52)]. We quantified liver fat percentage (%) by magnetic resonance spectroscopy in three liver zones. We measured liver fibrosis using two validated scores. We tested adherence to the intervention (Omacor group) and contamination (with DHA and EPA) (placebo group) by measuring erythrocyte percentage DHA and EPA enrichment (gas chromatography). We undertook multivariable linear regression to test effects of: a) DHA+EPA treatment (ITT analyses) and b) erythrocyte DHA and EPA enrichment (secondary analysis). Median (IQR) baseline and end of study liver fat% were 21.7 (19.3) and 19.7 (18.0) (placebo), and 23.0 (36.2) and 16.3 (22.0), (DHA+EPA). In the fully adjusted regression model there was a trend towards improvement in liver fat% with DHA+EPA treatment (ß=-3.64 (95%CI -8.0,0.8); p=0.1) but there was evidence of contamination in the placebo group and variable adherence to the intervention in the Omacor group. Further regression analysis showed that DHA enrichment was independently associated with a decrease in liver fat% (for each 1% enrichment, ß=-1.70 (95%CI -2.9,-0.5); p=0.007). No improvement in the fibrosis scores occurred. Conclusion. Erythrocyte DHA enrichment with DHA+EPA treatment is linearly associated with decreased liver fat%. Substantial decreases in liver fat% can be achieved with high percentage erythrocyte DHA enrichment in NAFLD. (Hepatology 2014;).

Early parenteral nutrition and growth outcomes in preterm infants: a systematic review and meta-analysis.

BACKGROUND: The achievement of adequate nutritional intakes in preterm infants is challenging and may explain the poor growth often seen in this group. The use of early parenteral nutrition (PN) is one potential strategy to address this problem, although the benefits and harms are unknown. OBJECTIVE: We determined whether earlier administration of PN benefits growth outcomes in preterm infants. DESIGN: We conducted a systematic review of randomized controlled trials (RCTs) and observational studies. RESULTS: Eight RCTs and 13 observational studies met the inclusion criteria (n = 553 and 1796 infants). The meta-analysis was limited by disparate growth-outcome measures. An assessment of bias was difficult because of inadequate reporting. Results are given as mean differences (95% CIs). Early PN reduced the time to regain birth weight by 2.2 d (1.1, 3.2 d) for RCTs and 3.2 d (2.0, 4.4 d) in observational studies. The maximum percentage weight loss with early PN was lower by 3.1 percentage points (1.7, 4.5 percentage points) for RCTs and by 3.5 percentage points (2.6, 4.3 percentage points) for observational studies. Early PN improved weight at discharge or 36 wk postmenstrual age by 14.9 g (5.3, 24.5 g) (observational studies only), but no benefit was shown for length or head circumference. There was no evidence that early PN significantly affects risk of mortality, necrotizing enterocolitis, sepsis, chronic lung disease, intraventricular hemorrhage, or cholestasis. CONCLUSIONS: The results of this review, although subject to some limitations, show that early PN provides a benefit for some short-term growth outcomes. No evidence that early PN increases morbidity or mortality was found. Neonatal research would benefit from the development of a set of core growth outcome measures.

Practices in the prescription of adrenaline autoinjectors.

BACKGROUND: Anecdotally, the prescription of adrenaline autoinjectors seems to be very variable. We aimed to survey the practice in this area and look at the differences between paediatric allergists and general paediatricians, the factors influencing prescription and implementation of current guidelines. METHODS: We developed an online survey containing 10 paediatric allergy cases and emailed a link to paediatricians. Respondents were asked to identify their prescribing decision in each case, the factors influencing their decisions and which guidelines they had read. RESULTS: Responses were collated from 54 paediatric allergists and 27 general paediatricians. Almost all respondents had read at least one guideline. Prescribing decisions were very inconsistent, and significant influencing factors included peanut or tree nut allergy, trace reactions, remote facilities and parental anxiety. CONCLUSIONS: This study demonstrates that most paediatricians have read at least one anaphylaxis guideline. However, reading the guidelines does not seem to have influenced their daily practice. This suggests that there is a need for improved implementation of anaphylaxis guidelines amongst paediatricians.