Impact of arginine therapy on mitochondrial function in children with sickle cell disease during vaso-occlusive pain.

Altered mitochondrial function occurs in sickle cell disease (SCD), due in part to low nitric oxide (NO) bioavailability. Arginine, the substrate for NO production, becomes acutely deficient in SCD patients with vaso-occlusive pain episodes (VOE). To determine if arginine improves mitochondrial function, 12 children with SCD-VOE (13.6 ± 3 years; 67% male; 75% hemoglobin-SS) were randomized to 1 of 3 arginine doses: (1) 100 mg/kg IV 3 times/day (TID); (2) loading dose (200 mg/kg) then 100 mg/kg TID; or (3) loading dose (200 mg/kg) followed by continuous infusion (300 mg/kg per day) until discharge. Platelet-rich plasma mitochondrial activity, protein expression, and protein-carbonyls were measured from emergency department (ED) presentation vs discharge. All VOE subjects at ED presentation had significantly decreased complex-V activity compared to a steady-state cohort. Notably, complex-V activity was increased at discharge in subjects from all 3 arginine-dosing schemes; greatest increase occurred with a loading dose (P < .001). Although complex-IV and citrate synthase activities were similar in VOE platelets vs steady state, enzyme activities were significantly increased in VOE subjects after arginine-loading dose treatment. Arginine also decreased protein-carbonyl levels across all treatment doses (P < .01), suggesting a decrease in oxidative stress. Arginine therapy increases mitochondrial activity and reduces oxidative stress in children with SCD/VOE. This trial was registered at www.clinicaltrials.gov as #NCT02536170.

Sustainability of enhanced recovery after surgery programmes in gastrointestinal surgery: A scoping review.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) is an evidence-based intervention that is well-recognised across multiple surgical specialties as having potential to lead to improved patient and hospital outcomes. Little is known about sustainability of ERAS programmes. AIMS: This review aimed to describe available evidence evaluating sustainability of ERAS programmes in gastrointestinal surgery to understand: (a) how sustainability has been defined; (b) examine determinants of sustainability; (c) identify strategies used to facilitate sustainability; (d) identify adaptations to support sustainability; and (e) examine outcomes measured as indicators of sustainability of ERAS programmes. METHODS: This scoping review was conducted following the Joanna Briggs Institute's methodology. Research databases (PubMed, Embase, CINHAL) and the grey literature were searched (inception to September 2022) for studies reporting sustainability of ERAS programmes in gastrointestinal surgery. Included articles reported an aspect of sustainability (i.e., definition, determinants, strategies, adaptations, outcomes and ongoing use) at ≥2 years following initial implementation. Aspects of sustainability were categorised according to relevant frameworks to facilitate synthesis. RESULTS: The search strategy yielded 1852 records; first round screening excluded 1749, leaving 103 articles for full text review. Overall, 22 studies were included in this review. Sustainability was poorly conceptualised and inconsistently reported across included studies. Provision of adequate resources was the most frequently identified enabler to sustainability (n/N = 9/12, 75%); however, relatively few studies (n = 4) provided a robust report of determinants, with no study reporting determinants of sustainability and strategies and adaptations to support sustainability alongside patient and service delivery outcomes. CONCLUSION: Improved reporting, particularly of strategies and adaptations to support sustainability is needed. Refinement of ERAS reporting guidelines should be made to facilitate this, and future implementation studies should plan to document and report changes in context and corresponding programme changes to help researchers and clinicians sustain ERAS programmes locally.

Nutrition-related predictors of complications and length of hospital stay following total pelvic exenteration surgery.

BACKGROUND & AIMS: Pelvic exenteration (PE) surgery is now a widely accepted procedure that is increasingly being performed worldwide but has significant morbidity. Although nutrition status, body mass index (BMI) and postoperative nutrition support practices are modifiable risk factors, few studies have examined the relationship of these with clinical outcomes following PE. The aim of this study was therefore to investigate the impact of these factors on postoperative complications and length of hospital stay (LOHS) following PE. METHODS: This was a retrospective cohort study of all patients having total PE surgery at a tertiary teaching hospital from 2012 to 2021 (n = 69). Multivariable analyses were undertaken to confirm univariate associations and adjust for confounding variables. Binary logistic regression was undertaken to explore predictors of infectious and Grade III or above Clavien-Dindo complications, and negative binomial regression to identify predictors of LOHS. RESULTS: Patients who were malnourished according to the Subjective Global Assessment were 5.66 (OR 5.66, 95% CI 1.07-29.74, p = 0.041) times more likely to develop an infectious complication. Increasing BMI was independently associated with development of Grade III or above Clavien-Dindo complications (p = 0.040). For each additional day until full diet commencement, there was a 19% (OR: 1.19, 95% CI 1.05-1.34, p = 0.005) increased incidence of significant complications and a 5.6% (IRR: 1.056, 95% CI: 1.02-1.09, p = 0.002) longer LOHS on multivariable analysis. There was a high rate of prolonged postoperative ileus (78%). The implementation of a nutrition support pathway with routine postoperative parenteral nutrition (PN) resulted in patients achieving adequate nutrition 7 days faster (p < 0.001) with minimal line-related complications (1.4% line-related thrombus). Routine PN did not impact ileus rates (p = 0.33) or time to diet commencement (p = 0.6). CONCLUSIONS: Preoperative malnutrition and higher BMI were associated with complications following PE. Delay to full diet commencement was associated with increased complications and longer LOHS. Routine postoperative PN appears safe and resulted in patients achieving adequate nutrition faster.

Voxelotor improves red blood cell functionality in children with sickle cell anaemia: An ancillary study of the HOPE-KIDS 1 trial.

INTRODUCTION: Sickle haemoglobin (HbS) polymerisation perturbs red blood cell (RBC) rheology and drives sickle cell disease (SCD) pathophysiology. Voxelotor is an HbS polymerisation inhibitor that increases haemoglobin (Hb)-oxygen affinity. METHODS/RESULTS: In this 48-week, prospective, single-centre translational study, 10 children aged 4-11 years with SCD were treated with voxelotor. Improvements in RBC deformability were observed using osmotic/oxygen gradient ektacytometry, with increases in minimal and maximal elongation index and reductions in point of sickling. Increased Hb and reduced markers of haemolysis were also observed. CONCLUSION: These findings suggest that voxelotor treatment is associated with reduced RBC sickling and haemolysis in children with SCD.

Are we underusing peripheral parenteral nutrition? A 5-year retrospective review of inpatient parenteral nutrition practices.

BACKGROUND: Peripheral parenteral nutrition (PPN) represents an alternative option to central parenteral nutrition (CPN) for patients requiring short-term parenteral nutrition (PN). We hypothesized that the use of PPN could be increased in certain patient cohorts referred for PN in our facility. METHODS: A retrospective observational study investigating the clinical characteristics of patients receiving PN under the nutrition support team over a 5-year period was undertaken. Patients who received PPN were reviewed descriptively. Of the patients who received CPN, representative samples were grouped into those who received PN for ≤7 or >7-28 days (n = 100 each, randomly assigned). Clinical characteristics considered included indication, duration and referring team for PN, and nutrition status. Descriptive statistics and binary logistic regression model for predictors of PN duration of ≤7 or >7-28 days were derived. RESULTS: Only four patients received PPN for a median of 4 days, most of whom required this route because of loss of central venous access for CPN. A high proportion of patients with no enteral access received CPN for ≤7 days, whereas the majority of patients with malabsorption required >7-28 days of CPN. Being referred for PN following upper gastrointestinal surgery increased the likelihood of CPN use for >7 days (relative risk, 5.7; 95% CI, 1.7-18.9; P = 0.004). CONCLUSION: Within our service, PN referrals for no enteral access may represent a group in whom PPN could be used in the first instance; those referred with an indication of malabsorption or following upper gastrointestinal surgery may benefit from early commencement of CPN.

Micronutrient deficiency risk in long-term enterally fed patients: A systematic review.

BACKGROUND AND AIMS: The micronutrient status of those receiving long-term enteral nutrition (EN) is poorly characterised. This systematic review was undertaken to determine prevalence of micronutrient deficiency in those receiving EN; the impact of the route of feeding; whether underlying disease or clinical factors were associated with micronutrient status; and the efficacy of interventions utilised to treat identified micronutrient deficiency. METHODS: Electronic databases (CINAHL, Embase, PubMed, Web of Science) were searched to June 2021 for publications of primary investigation of micronutrient status in adults or children (>5yrs) receiving EN for >2 months in their usual residence. Independent assessment of compliance with inclusion criteria (Covidence®), data extraction of predefined data points, assessment of basis (Academy of Dietetics Quality Checklist) and certainty of evidence (GRADE) was assessed by at least two authors. (PROSPERO Registration: CRD42021261113). RESULTS: Thirty-one studies (n = 744) met inclusion criteria. Deficiency was reported for copper, zinc, selenium, beta-carotene, and vitamins A, D and E: Only copper, zinc and selenium were associated with physical/haematological manifestations of deficiency. Jejunal feeding was associated with the development of copper deficiency and often required gastric or parenteral replacement to resolve the issue. Circumstances leading to deficiency included receiving feed products formulated with inadequate amounts of the implicated nutrient, low feed product volumes in the context of low macronutrient requirements, and nutritional decline prior to commencement of EN. Potential confounding factors such as inflammation were rarely accounted for. No studies investigated the contribution of underlying clinical condition on micronutrient status, and no other clinical or demographic features appeared to impact outcomes. Reported methods for treating identified deficiencies were usually successful in reversing deficiency symptoms. The certainty of evidence is very low, and the level of bias moderate to high. CONCLUSION: While the evidence is very uncertain about the effect of long-term enteral feeding on the development of micronutrient deficiencies, clinicians should be alert to the possibility of micronutrient deficiency developing in long-term EN fed patients. Those who may be at increased risk are those receiving nutrition into the jejunum, those who meet macronutrient requirements in low volumes of EN product, and those commencing EN in a nutritionally deplete state. Further research and surveillance of micronutrient status with contemporary EN products and practices is required.

The effect of oral omega-3 polyunsaturated fatty acid supplementation on muscle maintenance and quality of life in patients with cancer: A systematic review and meta-analysis.

BACKGROUND & AIMS: Omega-3 polyunsaturated fatty acid (PUFA) supplementation has been proposed as a potential therapy for cancer-related malnutrition, which affects up to 70% of patients with cancer. The aim of this systematic review and meta-analysis was to examine the effects of oral omega-3 PUFA supplementation on muscle maintenance, quality of life, body weight and treatment-related toxicities in patients with cancer. METHODS: Randomised controlled trials in patients with cancer aged ≥18 years were retrieved from 5 electronic databases: MEDLINE (via PubMed), EMBASE, CENTRAL, CINAHL (via EBSCOhost), and Web of Science, from database inception until 31st of December 2019. The quality of included studies was assessed using the Cochrane risk of bias tool. Trials supplementing ≥600 mg/d omega-3 PUFA (oral capsules, pure fish oil or oral nutritional supplements) compared with a control intervention for ≥3 weeks were included. Meta-analyses were performed in RevMan to determine the mean differences (MD) in muscle mass, quality of life and body weight, and odds ratio (OR) for the incidence of treatment-related toxicities between omega-3 PUFA and control groups with 95% confidence intervals (CI) and I2 for heterogeneity. RESULTS: We included 31 publications in patients with various types of cancers and degrees of malnutrition. The Cochrane risk of bias tool graded most trials as 'unclear' or 'high' risk of bias. Meta-analyses showed no significant difference between omega-3 PUFA supplements and control intervention on muscle mass, quality of life and body weight. Oral omega-3 PUFA supplements reduced the likelihood of developing chemotherapy-induced peripheral neuropathy (OR: 0.20; 95% CI: 0.10-0.40; p < 0.001; I2 = 0%). CONCLUSION: This systematic review and meta-analysis indicates that oral omega-3 PUFA supplementation does not improve muscle maintenance, quality of life or body weight in patients with cancer, but may reduce the incidence of chemotherapy-induced peripheral neuropathy. Well-designed large-scale randomised controlled trials in homogenous patient cohorts are required to confirm these findings.

Changes in Pain and Psychosocial Functioning and Transition to Chronic Pain in Pediatric Sickle Cell Disease: A Cohort Follow-up Study.

OBJECTIVES: This study aimed to: (1) examine changes in pain, psychosocial functioning, and health care utilization among children and adolescents with sickle cell disease (SCD) over a 2-year period and (2) identify baseline biopsychosocial variables associated with the development and maintenance of chronic SCD pain at follow-up. MATERIALS AND METHODS: Forty-two youth (8 to 18 y old) with SCD completed a battery of self-report measures at baseline and 2-year follow-up. Analgesic, Anesthetic, and Addiction Clinical Trial Translational Innovations Opportunities and Networks and American Pain Society Pain Taxonomy (AAPT) diagnostic criteria were used to categorize patients into pain frequency groups at both timepoints: chronic (pain on most [≥15] d/mo for the past 6 mo, per AAPT diagnostic criteria), episodic (pain on 1 to 14 d/mo), or asymptomatic (0 d/mo). RESULTS: At baseline, 31% (n=13) had chronic pain, 50% (n=21) episodic pain, and 19% (n=8) were asymptomatic. At follow-up, 40.5% (n=17) had chronic pain, 52.4% (n=22) episodic pain, and 7.1% (n=3) were asymptomatic. Between baseline and 2-year follow-up, 12% (n=5) developed chronic SCD pain. Depressive symptoms and admissions for pain significantly increased over time for youth with chronic pain (Ps<0.05). An interaction effect revealed that baseline pain groups differed in their change in pain intensity over time (P<0.01). Baseline psychosocial factors (ie, higher functional disability, greater depressive symptoms, higher pain catastrophizing, and lower quality of life) were significantly associated with chronic pain at follow-up. DISCUSSION: Biopsychosocial factors may be associated with the development and maintenance of chronic SCD pain and their relative contributions warrant further study.

Conducting retrospective impact analysis to inform a medical research charity's funding strategies: the case of Asthma UK.

BACKGROUND: Debate is intensifying about how to assess the full range of impacts from medical research. Complexity increases when assessing the diverse funding streams of funders such as Asthma UK, a charitable patient organisation supporting medical research to benefit people with asthma. This paper aims to describe the various impacts identified from a range of Asthma UK research, and explore how Asthma UK utilised the characteristics of successful funding approaches to inform future research strategies. METHODS: We adapted the Payback Framework, using it both in a survey and to help structure interviews, documentary analysis, and case studies. We sent surveys to 153 lead researchers of projects, plus 10 past research fellows, and also conducted 14 detailed case studies. These covered nine projects and two fellowships, in addition to the innovative case studies on the professorial chairs (funded since 1988) and the MRC-Asthma UK Centre in Allergic Mechanisms of Asthma (the 'Centre') which together facilitated a comprehensive analysis of the whole funding portfolio. We organised each case study to capture whatever academic and wider societal impacts (or payback) might have arisen given the diverse timescales, size of funding involved, and extent to which Asthma UK funding contributed to the impacts. RESULTS: Projects recorded an average of four peer-reviewed journal articles. Together the chairs reported over 500 papers. All streams of funding attracted follow-on funding. Each of the various categories of societal impacts arose from only a minority of individual projects and fellowships. Some of the research portfolio is influencing asthma-related clinical guidelines, and some contributing to product development. The latter includes potentially major breakthroughs in asthma therapies (in immunotherapy, and new inhaled drugs) trialled by university spin-out companies. Such research-informed guidelines and medicines can, in turn, contribute to health improvements. The role of the chairs and the pioneering collaborative Centre is shown as being particularly important. CONCLUSIONS: We systematically demonstrate that all types of Asthma UK's research funding assessed are making impacts at different levels, but the main societal impacts from projects and fellowships come from a minority of those funded. Asthma UK used the study's findings, especially in relation to the Centre, to inform research funding strategies to promote the achievement of impact.