Systems Thinking and Sustainable Food Systems in Dietetics Education: A Survey of Directors.

BACKGROUND: Systems thinking is recommended, but not required, for teaching food and water system sustainability in nutrition and dietetics education. OBJECTIVE: This study investigated systems thinking and sustainable, resilient, and healthy food and water systems (SRHFWS) in nutrition and dietetics programs. It examined program directors' practices, values, attitudes, confidence levels, and the relationships between systems thinking, teaching SRHFWS topics, confidence levels, and years of experience as a dietitian and program director. DESIGN: Conducted in September 2022, the study used a descriptive design with a validated 20-item Systems Thinking Scale and a researcher-designed survey with 1-5 Likert-type scales. PARTICIPANTS AND SETTING: The online survey was distributed to 611 Accreditation Council for Education in Nutrition and Dietetics program directors, with a 27% (N = 163) response. STATISTICAL ANALYSIS: Descriptive statistics (frequency or mean ± SD) were calculated using Excel. Inferential statistics were examined using R. Analysis of variance was used to compare experience as a registered dietitian nutritionist and experience as a program director to confidence levels in teaching each SRHFWS topic. Linear regression was used determine the relationship between total Systems Thinking Scale score and demographic and programmatic variables. RESULTS: Seventy-seven percent of program directors scored high on the Systems Thinking Scale (mean score = 65.2 ± 8.4 on a 0 to 80 scale), and more than 85% of directors agreed that including systems thinking in dietetics was important. However, only 32.1% reported teaching systems thinking. Less than half of program directors agreed that systems thinking was adequately addressed in Accreditation Council for Education in Nutrition and Dietetics standards, and nearly 80% of program directors agreed there was room to strengthen systems thinking content. Directors neither agreed nor disagreed there are adequate Accreditation Council for Education in Nutrition and Dietetics standards addressing SRHFWS and reported SRHFWS topics were inconsistently taught. Confidence levels were lowest for teaching economic and environmental topics. Awareness and use of resources developed by the Academy of Nutrition and Dietetics Foundation was low. CONCLUSIONS: Integration of systems thinking in nutrition and dietetics education presents promising opportunities to address complexity in the field. Applying systems thinking to teach SRHFWS may narrow the disparity between educators' perceived importance and program coverage. Enhancing program directors' awareness and utilization of Academy of Nutrition and Dietetics Foundation resources and improved alignment between practice standards and accreditation standards may empower program directors to use systems thinking to teach sustainability-related challenges in nutrition and dietetics.

Subthreshold micropulse laser versus standard laser for the treatment of central-involving diabetic macular oedema with central retinal thickness of <400µ: a cost-effectiveness analysis from the DIAMONDS trial.

OBJECTIVES: To estimate the economic costs, health-related quality-of-life outcomes and cost-effectiveness of subthreshold micropulse laser (SML) versus standard laser (SL) for the treatment of diabetic macular oedema (DMO) with central retinal thickness (CRT) of <400µ. DESIGN: An economic evaluation was conducted within a pragmatic, multicentre, randomised clinical trial, DIAbetic Macular Oedema aNd Diode Subthreshold. SETTING: 18 UK Hospital Eye Services. PARTICIPANTS: Adults with diabetes and centre involving DMO with CRT<400µ. INTERVENTIONS: Participants (n=266) were randomised 1:1 to receive SML or SL. METHODS: The base-case used an intention-to-treat approach conducted from a UK National Health Service (NHS) and personal social services (PSS) perspective. Costs (2019-2020 prices) were collected prospectively over the 2-year follow-up period. A bivariate regression of costs and quality-adjusted life-years (QALYs), with multiple imputation of missing data, was conducted to estimate the incremental cost per QALY gained and the incremental net monetary benefit of SML in comparison to SL. Sensitivity analyses explored uncertainty and heterogeneity in cost-effectiveness estimates. RESULTS: One participant in the SL arm withdrew consent for data to be used; data from the remaining 265 participants were included in analyses. Mean (SE) NHS and PSS costs over 24 months were £735.09 (£111.85) in the SML arm vs £1099.70 (£195.40) in the SL arm (p=0.107). Mean (SE) QALY estimates were 1.493 (0.024) vs 1.485 (0.020), respectively (p=0.780), giving an insignificant difference of 0.008 QALYs. The probability SML is cost-effective at a threshold of £20 000 per QALY was 76%. CONCLUSIONS: There were no statistically significant differences in EQ-5D-5L scores or costs between SML and SL. Given these findings and the fact that SML does not burn the retina, unlike SL and has equivalent efficacy to SL, it may be preferred for the treatment of people with DMO with CRT<400µ. TRIAL REGISTRATION NUMBERS: ISRCTN17742985; NCT03690050.

Lower Airway Dysbiosis Augments Lung Inflammatory Injury in Mild-to-Moderate Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and healthcare costs. Cigarette smoke is a causative factor; however, not all heavy smokers develop COPD. Microbial colonization and infections are contributing factors to disease progression in advanced stages. Objectives: We investigated whether lower airway dysbiosis occurs in mild-to-moderate COPD and analyzed possible mechanistic contributions to COPD pathogenesis. Methods: We recruited 57 patients with a >10 pack-year smoking history: 26 had physiological evidence of COPD, and 31 had normal lung function (smoker control subjects). Bronchoscopy sampled the upper airways, lower airways, and environmental background. Samples were analyzed by 16S rRNA gene sequencing, whole genome, RNA metatranscriptome, and host RNA transcriptome. A preclinical mouse model was used to evaluate the contributions of cigarette smoke and dysbiosis on lower airway inflammatory injury. Measurements and Main Results: Compared with smoker control subjects, microbiome analyses showed that the lower airways of subjects with COPD were enriched with common oral commensals. The lower airway host transcriptomics demonstrated differences in markers of inflammation and tumorigenesis, such as upregulation of IL-17, IL-6, ERK/MAPK, PI3K, MUC1, and MUC4 in mild-to-moderate COPD. Finally, in a preclinical murine model exposed to cigarette smoke, lower airway dysbiosis with common oral commensals augments the inflammatory injury, revealing transcriptomic signatures similar to those observed in human subjects with COPD. Conclusions: Lower airway dysbiosis in the setting of smoke exposure contributes to inflammatory injury early in COPD. Targeting the lower airway microbiome in combination with smoking cessation may be of potential therapeutic relevance.

Fish oil supplementation fails to modulate indices of muscle damage and muscle repair during acute recovery from eccentric exercise in trained young males.

We aimed to investigate the influence of 4-wk of fish oil (FO) supplementation on markers of muscle damage, inflammation, muscle soreness, and muscle function during acute recovery from eccentric exercise in moderately trained males. Sixteen moderately-trained males ingested 5 g/d of FO (n = 8) or soybean oil (placebo) capsules (n = 8) for 4-wk prior to- and 3-d following an acute eccentric exercise bout. Eccentric exercise consisted of 12 sets of isokinetic knee extension and knee flexion. Indices of muscle damage, soreness, function and inflammation were measured at baseline and during exercise recovery. Eccentric exercise elicited an increase in muscle soreness (p < 0.010) and thigh volume (p < 0.001), and reduced peak isometric torque by 31.7 ± 6.9%, (p < 0.05, 95% CI 10.6-52.8) during 3-d of recovery. Blood omega-3 polyunsaturated fatty acid concentration was 14.9 ± 2.4% higher in FO than PLA (p < 0.01, 95% CI 9.8-20.1). However, FO did not ameliorate the cumulative creatine kinase response (expressed as AUC; p = 0.368), inflammation (p = 0.400), muscle soreness (p > 0.140), or muscle function (p > 0.249) following eccentric exercise. FO supplementation confers no clear benefit in terms of ameliorating the degree of muscle damage, or facilitating the muscle repair process, during acute eccentric exercise recovery. These data suggest that FO supplementation does not provide an effective nutritional strategy to promote exercise recovery, at least in moderately-trained young men.Abbreviations: ANOVA: Analysis of variance; AUC: Area under curve; CI: Confidence interval; CK: Creatine kinase; CMJ: Countermovement jump; COX: Cyclooxygenase; CRP: C-reactive protein; DHA: Docosahexaenoic acid; DOMS: Delayed-onset muscle soreness; EIMD: Exercise-induced muscle damage; En%: Energy percent; EPA: Eicosapentaenoic acid; FO: Fish oil; IL-6: Interleukin-6; LDH: Lactate dehydrogenase; LOX: Lipoxygenase; Mb: Myoglobin; mTOR: Mechanistic target of rapamycin; PLA: Placebo; ROM: Range of motion; ROS: Reactive oxygen species; SD: Standard deviation; SEM: Standard error of the mean; TNF-α: Tumour necrosis factor alpha; VAS: Visual analogue scale; Ω3-PUFA: Omega-3 polyunsaturated fatty acids; Ω6-PUFA: Omega-6 polyunsaturated fatty acidsHighlightsThe anti-inflammatory properties of omega-3 polyunsaturated fatty acids, alongside their propensity to incorporate into the muscle phospholipid membrane underpins the idea that fish oil supplementation may attenuate muscle damage and promote muscle repair following eccentric-based exercise.Four weeks of high-dose (5 g/d) fish oil supplementation prior to eccentric exercise failed to attenuate the rise in creatine kinase concentration and muscle soreness during acute exercise recovery in physically-active young men.Future studies are warranted to investigate the efficacy of combining omega-3 polyunsaturated fatty acids with other nutrients (i.e. protein/amino acids) for the promotion of muscle recovery following eccentric-based damaging exercise.

Valaciclovir for Epstein-Barr Virus Suppression in Moderate-to-Severe COPD: A Randomized Double-Blind Placebo-Controlled Trial.

BACKGROUND: Epstein-Barr virus (EBV) frequently is measured at high levels in COPD using sputum quantitative polymerase chain reaction, whereas airway immunohistochemistry analysis has shown EBV detection to be common in severe disease. RESEARCH QUESTION: Is valaciclovir safe and effective for EBV suppression in COPD? STUDY DESIGN AND METHODS: The Epstein-Barr Virus Suppression in COPD (EViSCO) trial was a randomized double-blind placebo-controlled trial conducted at the Mater Hospital Belfast, Northern Ireland. Eligible patients had stable moderate-to-severe COPD and sputum EBV (measured using quantitative polymerase chain reaction) and were assigned randomly (1:1) to valaciclovir (1 g tid) or matching placebo for 8 weeks. The primary efficacy outcome was sputum EBV suppression (defined as ≥ 90% sputum viral load reduction) at week 8. The primary safety outcome was the incidence of serious adverse reactions. Secondary outcome measures were FEV1 and drug tolerability. Exploratory outcomes included changes in quality of life, sputum cell counts, and cytokines. RESULTS: From November 2, 2018, through March 12, 2020, 84 patients were assigned randomly (n = 43 to valaciclovir). Eighty-one patients completed trial follow-up and were included in the intention-to-treat analysis of the primary outcome. A greater number of participants in the valaciclovir group achieved EBV suppression (n = 36 [87.8%] vs n = 17 [42.5%]; P < .001). Valaciclovir was associated with a significant reduction in sputum EBV titer compared with placebo (-90,404 copies/mL [interquartile range, -298,000 to -15,200 copies/mL] vs -3,940 copies/mL [interquartile range, -114,400 to 50,150 copies/mL]; P = .002). A statistically nonsignificant 24-mL numerical FEV1 increase was shown in the valaciclovir group (difference, -44 mL [95% CI, -150 to 62 mL]; P = .41). However, a reduction in sputum white cell count was noted in the valaciclovir group compared with the placebo group (difference, 2.89 [95% CI, 1.5 × 106-7.4 × 106]; P = .003). INTERPRETATION: Valaciclovir is safe and effective for EBV suppression in COPD and may attenuate the sputum inflammatory cell infiltrate. The findings from the current study provide support for a larger trial to evaluate long-term clinical outcomes. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03699904; URL: www. CLINICALTRIALS: gov.

Diabetic Macular Edema and Diode Subthreshold Micropulse Laser: A Randomized Double-Masked Noninferiority Clinical Trial.

PURPOSE: To determine clinical effectiveness, safety, and cost-effectiveness of subthreshold micropulse laser (SML), compared with standard laser (SL), for diabetic macular edema (DME) with central retinal thickness (CRT) < 400 µm. DESIGN: Pragmatic, multicenter, allocation-concealed, double-masked, randomized, noninferiority trial. PARTICIPANTS: Adults with center-involved DME < 400 µm and best-corrected visual acuity (BCVA) of > 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in one/both eyes. METHODS: Randomization 1:1 to 577 nm SML or SL treatment. Retreatments were allowed. Rescue with intravitreal anti-vascular endothelial growth factor therapies or steroids was permitted if 10 or more ETDRS letter loss occurred, CRT increased > 400 µm, or both. MAIN OUTCOME MEASURES: Primary outcome was mean change in BCVA in the study eye at 24 months (noninferiority margin 5 ETDRS letters). Secondary outcomes were mean change from baseline to month 24 in binocular BCVA; CRT and mean deviation of Humphrey 10-2 visual field in the study eye; percentage meeting driving standards; EuroQoL EQ-5D-5L, 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), and Vision and Quality of Life Index (VisQoL) scores; cost per quality-adjusted life-years (QALYs) gained; adverse effects; and number of laser and rescue treatments. RESULTS: The study recruited fully (n = 266); 87% of SML-treated and 86% of SL-treated patients had primary outcome data. Mean ± standard deviation BCVA change from baseline to month 24 was -2.43 ± 8.20 letters and -0.45 ± 6.72 letters in the SML and SL groups, respectively. Subthreshold micropulse laser therapy was deemed not only noninferior but also equivalent to SL therapy because the 95% confidence interval (CI; -3.9 to -0.04 letters) lay wholly within both upper and lower margins of the permitted maximum difference (5 ETDRS letters). No statistically significant difference was found in binocular BCVA (0.32 ETDRS letters; 95% CI, -0.99 to 1.64 ETDRS letters; P = 0.63); CRT (-0.64 µm; 95% CI, -14.25 to 12.98 µm; P = 0.93); mean deviation of the visual field (0.39 decibels (dB); 95% CI, -0.23 to 1.02 dB; P = 0.21); meeting driving standards (percentage point difference, 1.6%; 95% CI, -25.3% to 28.5%; P = 0.91); adverse effects (risk ratio, 0.28; 95% CI, 0.06-1.34; P = 0.11); rescue treatments (percentage point difference, -2.8%; 95% CI, -13.1% to 7.5%; P = 0.59); or EQ-5D, NEI-VFQ-25, or VisQoL scores. Number of laser treatments was higher in the SML group (0.48; 95% CI, 0.18-0.79; P = 0.002). Base-case analysis indicated no differences in costs or QALYs. CONCLUSIONS: Subthreshold micropulse laser therapy was equivalent to SL therapy, requiring slightly higher laser treatments.

Standard threshold laser versus subthreshold micropulse laser for adults with diabetic macular oedema: the DIAMONDS non-inferiority RCT.

BACKGROUND: The National Institute for Health and Care Excellence recommends macular laser to treat diabetic macular oedema with a central retinal subfield thickness of < 400 µm on optical coherence tomography. The DIAMONDS (DIAbetic Macular Oedema aNd Diode Subthreshold micropulse laser) trial compared standard threshold macular laser with subthreshold micropulse laser to treat diabetic macular oedema suitable for macular laser. OBJECTIVES: Determining the clinical effectiveness, safety and cost-effectiveness of subthreshold micropulse laser compared with standard threshold macular laser to treat diabetic macular oedema with a central retinal subfield thickness of < 400 µm. DESIGN: A pragmatic, multicentre, allocation-concealed, double-masked, randomised, non-inferiority, clinical trial. SETTING: Hospital eye services in the UK. PARTICIPANTS: Adults with diabetes and centre-involving diabetic macular oedema with a central retinal subfield thickness of < 400 µm, and a visual acuity of > 24 Early Treatment Diabetic Retinopathy Study letters (Snellen equivalent > 20/320) in one/both eyes. INTERVENTIONS: Participants were randomised 1 : 1 to receive 577 nm subthreshold micropulse laser or standard threshold macular laser (e.g. argon laser, frequency-doubled neodymium-doped yttrium aluminium garnet 532 nm laser); laser treatments could be repeated as needed. Rescue therapy with intravitreal anti-vascular endothelial growth factor therapies or steroids was allowed if a loss of ≥ 10 Early Treatment Diabetic Retinopathy Study letters between visits occurred and/or central retinal subfield thickness increased to > 400 µm. MAIN OUTCOME MEASURES: The primary outcome was the mean change in best-corrected visual acuity in the study eye at 24 months (non-inferiority margin 5 Early Treatment Diabetic Retinopathy Study letters). Secondary outcomes included the mean change from baseline to 24 months in the following: binocular best-corrected visual acuity; central retinal subfield thickness; the mean deviation of the Humphrey 10-2 visual field in the study eye; the percentage of people meeting driving standards; and the EuroQol-5 Dimensions, five-level version, National Eye Institute Visual Function Questionnaire - 25 and Vision and Quality of Life Index scores. Other secondary outcomes were the cost per quality-adjusted life-years gained, adverse effects, number of laser treatments and additional rescue treatments. RESULTS: The DIAMONDS trial recruited fully (n = 266); 87% of participants in the subthreshold micropulse laser group and 86% of participants in the standard threshold macular laser group had primary outcome data. Groups were balanced regarding baseline characteristics. Mean best-corrected visual acuity change in the study eye from baseline to month 24 was -2.43 letters (standard deviation 8.20 letters) in the subthreshold micropulse laser group and -0.45 letters (standard deviation 6.72 letters) in the standard threshold macular laser group. Subthreshold micropulse laser was deemed to be not only non-inferior but also equivalent to standard threshold macular laser as the 95% confidence interval (-3.9 to -0.04 letters) lay wholly within both the upper and lower margins of the permitted maximum difference (5 Early Treatment Diabetic Retinopathy Study letters). There was no statistically significant difference between groups in any of the secondary outcomes investigated with the exception of the number of laser treatments performed, which was slightly higher in the subthreshold micropulse laser group (mean difference 0.48, 95% confidence interval 0.18 to 0.79; p = 0.002). Base-case analysis indicated no significant difference in the cost per quality-adjusted life-years between groups. FUTURE WORK: A trial in people with ≥ 400 µm diabetic macular oedema comparing anti-vascular endothelial growth factor therapy alone with anti-vascular endothelial growth factor therapy and macular laser applied at the time when central retinal subfield thickness has decreased to < 400 µm following anti-vascular endothelial growth factor injections would be of value because it could reduce the number of injections and, subsequently, costs and risks and inconvenience to patients. LIMITATIONS: The majority of participants enrolled had poorly controlled diabetes. CONCLUSIONS: Subthreshold micropulse laser was equivalent to standard threshold macular laser but required a slightly higher number of laser treatments. TRIAL REGISTRATION: This trial is registered as EudraCT 2015-001940-12, ISRCTN17742985 and NCT03690050. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 50. See the NIHR Journals Library website for further project information.

The retina is a layer at the back of the eye. Its centre is called the macula and is responsible for central vision. Some people with diabetes develop diabetic macular oedema. In diabetic macular oedema fluid leaks from retinal blood vessels and builds up at the macula, resulting in sight loss. Diabetic macular oedema can be mild or severe; this can be determined measuring the thickness of the macula, which is measured in micrometres (µm). One micrometre is one thousandth of a millimetre. In mild diabetic macular oedema, the thickness of the macula increases, but is less than 400 µm. Patients with mild diabetic macular oedema can be treated with a laser and there are two laser types. The standard threshold macular laser has been available for many years. It clears the diabetic macular oedema but produces a 'burn' in the retina. The subthreshold micropulse laser is newer. It does not produce a burn but also clears the diabetic macular oedema. The lack of a burn, however, has led to doubts about whether or not this laser works as well as the standard threshold macular laser because 'no burn' was taken to mean 'less benefit'. These doubts led to our establishing the DIAMONDS (DIAbetic Macular Oedema aNd Diode Subthreshold micropulse laser) trial, which compared these two lasers for people with mild diabetic macular oedema. A total of 266 people suitable for either laser joined the study at 16 NHS hospitals across the UK; 133 received standard threshold macular laser and 133 received subthreshold micropulse laser. The choice of laser was determined by chance. The DIAMONDS trial found that the subthreshold micropulse laser was as good as the standard threshold macular laser (i.e. 'clinically equivalent') in terms of improving people's vision, reducing macula thickness, allowing people to meet driving standards and maintaining their quality of life, both in general terms and for vision in particular. There was a small increase (less than one session on average per person) in the number of laser treatment sessions needed with subthreshold micropulse laser. The costs of both laser treatments were about the same.

Repair of acute respiratory distress syndrome by stromal cell administration (REALIST): a structured study protocol for an open-label dose-escalation phase 1 trial followed by a randomised, triple-blind, allocation concealed, placebo-controlled phase 2 trial.

BACKGROUND: Mesenchymal stromal cells (MSCs) may be of benefit in ARDS due to immunomodulatory and reparative properties. This trial investigates a novel CD362 enriched umbilical cord derived MSC product (REALIST ORBCEL-C), produced to Good Manufacturing Practice standards, in patients with moderate to severe ARDS due to COVID-19 and ARDS due to other causes. METHODS: Phase 1 is a multicentre open-label dose-escalation pilot trial. Patients will receive a single infusion of REALIST ORBCEL-C (100 × 106 cells, 200 × 106 cells or 400 × 106 cells) in a 3 + 3 design. Phase 2 is a multicentre randomised, triple blind, allocation concealed placebo-controlled trial. Two cohorts of patients, with ARDS due to COVID-19 or ARDS due to other causes, will be recruited and randomised 1:1 to receive either a single infusion of REALIST ORBCEL-C (400 × 106 cells or maximal tolerated dose in phase 1) or placebo. Planned recruitment to each cohort is 60 patients. The primary safety outcome is the incidence of serious adverse events. The primary efficacy outcome is oxygenation index at day 7. The trial will be reported according to the Consolidated Standards for Reporting Trials (CONSORT 2010) statement. DISCUSSION: The development and manufacture of an advanced therapy medicinal product to Good Manufacturing Practice standards within NHS infrastructure are discussed, including challenges encountered during the early stages of trial set up. The rationale to include a separate cohort of patients with ARDS due to COVID-19 in phase 2 of the trial is outlined. TRIAL REGISTRATION: ClinicalTrials.gov NCT03042143. Registered on 3 February 2017. EudraCT Number 2017-000584-33.

Oral tranexamic acid for an additional 24 hours postoperatively versus a single preoperative intravenous dose for reducing blood loss in total knee arthroplasty: results of a randomized controlled trial (TRAC-24).

AIMS: In total knee arthroplasty (TKA), blood loss continues internally after surgery is complete. Typically, the total loss over 48 postoperative hours can be around 1,300 ml, with most occurring within the first 24 hours. We hypothesize that the full potential of tranexamic acid (TXA) to decrease TKA blood loss has not yet been harnessed because it is rarely used beyond the intraoperative period, and is usually withheld from 'high-risk' patients with a history of thromboembolic, cardiovascular, or cerebrovascular disease, a patient group who would benefit greatly from a reduced blood loss. METHODS: TRAC-24 was a prospective, phase IV, single-centre, open label, parallel group, randomized controlled trial on patients undergoing TKA, including those labelled as high-risk. The primary outcome was indirect calculated blood loss (IBL) at 48 hours. Group 1 received 1 g intravenous (IV) TXA at the time of surgery and an additional 24-hour postoperative oral regime of four 1 g doses, while Group 2 only received the intraoperative dose and Group 3 did not receive any TXA. RESULTS: Between July 2016 and July 2018, 552 patients were randomized to either Group 1 (n = 241), Group 2 (n = 243), or Group 3 (n = 68), and 551 were included in the final analysis. The blood loss did differ significantly between the two intervention groups (733.5 ml (SD 384.0) for Group 1 and 859.2 ml (SD 363.6 ml) for Group 2; mean difference -125.8 ml (95% confidence interval -194.0 to -57.5; p < 0.001). No differences in mortality or thromboembolic events were observed in any group. CONCLUSION: These data support the hypothesis that in TKA, a TXA regime consisting of IV 1 g perioperatively and four oral 1 g doses over 24 hours postoperatively significantly reduces blood loss beyond that achieved with a single IV 1 g perioperative dose alone. TXA appears safe in patients with history of thromboembolic, cardiovascular, and cerebrovascular disease. Cite this article: Bone Joint J 2021;103-B(10):1595-1603.

Oral tranexamic acid for an additional 24 hours postoperatively versus a single preoperative intravenous dose for reducing blood loss in total hip arthroplasty: results of a randomized controlled trial (TRAC-24).

AIMS: A typical pattern of blood loss associated with total hip arthroplasty (THA) is 200 ml intraoperatively and 1.3 l in the first 48 postoperative hours. Tranexamic acid (TXA) is most commonly given as a single preoperative dose only and is often withheld from patients with a history of thromboembolic disease as they are perceived to be "high-risk" with respect to postoperative venous thromboembolism (VTE). The TRanexamic ACid for 24 hours trial (TRAC-24) aimed to identify if an additional 24-hour postoperative TXA regime could further reduce blood loss beyond a once-only dose at the time of surgery, without excluding these high-risk patients. METHODS: TRAC-24 was a prospective, phase IV, single centre, open label, parallel group, randomized controlled trial (RCT) involving patients undergoing primary unilateral elective THA. The primary outcome measure was the indirect calculated blood loss (IBL) at 48 hours. The patients were randomized into three groups. Group 1 received 1 g intravenous (IV) TXA at the time of surgery and an additional oral regime for 24 hours postoperatively, group 2 only received the intraoperative dose, and group 3 did not receive any TXA. RESULTS: A total of 534 patients were randomized, with 233 in group 1, 235 in group 2, and 66 in group 3; 92 patients (17.2%) were considered high-risk. The mean IBL did not differ significantly between the two intervention groups (848.4 ml (SD 463.8) for group 1, and 843.7 ml (SD 478.7) for group 2; mean difference -4.7 ml (95% confidence interval -82.9 to 92.3); p = 0.916). No differences in mortality or incidence of VTE were observed between any group. CONCLUSION: The addition of oral TXA for 24 hours postoperatively does not reduce blood loss beyond that achieved with a single 1 g IV perioperative dose alone. There may be a clinically relevant difference in patients with a normal BMI, which warrants further investigation. Critically, there were no safety issues in patients with a history of thromboembolic, cardiovascular, or cerebrovascular disease. Cite this article: Bone Joint J 2021;103-B(7):1197-1205.

Leveraging Online Learning to Promote Systems Thinking for Sustainable Food Systems Training in Dietetics Education.

Educating and training a multisectoral food systems workforce is a critical part of developing sustainable, resilient, and healthy food and water systems. This paper shares perspectives from a working group of educators, learners, and food systems subject matter experts that collaborated over the course of a year to develop, pilot test, and evaluate two interactive webinar series with a multi-site cohort of dietetics interns and graduate students. The three-part webinar series format included a training webinar, a practice activity, and a synthesis webinar. In reflecting on the effectiveness of this format, we provide direct assessments of student learning from subject matter experts alongside indirect assessments from pre- and post-surveys fielded with learners. Learners who participated in an interactive webinar series demonstrated skills in several dimensions of systems thinking and gained confidence in food systems learning outcomes. Learners also shared valuable feedback on the opportunities and challenges of using online platforms for this experience. As online learning opportunities become more common, it will become increasingly important for educators to prioritize strategies that effectively equip students with the higher-order thinking skills, such as systems thinking, needed to address the complexities of sustainable food systems. The interactive webinar series format described here provides an opportunity to leverage didactic webinars in combination with interactive experiences that enable learners to deepen their knowledge through practice with peers and subject matter experts. Though this format was piloted within dietetics education programs, many of the lessons learned are transferable to other food systems educational contexts.

Repair of Acute Respiratory Distress Syndrome by Stromal Cell Administration in COVID-19 (REALIST-COVID-19): A structured summary of a study protocol for a randomised, controlled trial.

OBJECTIVES: The primary objective of the study is to assess the safety of a single intravenous infusion of Mesenchymal Stromal Cells (MSCs) in patients with Acute Respiratory Distress Syndrome (ARDS) due to COVID-19. Secondary objectives are to determine the effects of MSCs on important clinical outcomes, as described below. TRIAL DESIGN: REALIST COVID 19 is a randomised, placebo-controlled, triple blinded trial. PARTICIPANTS: The study will be conducted in Intensive Care Units in hospitals across the United Kingdom. Patients with moderate to severe ARDS as defined by the Berlin definition, receiving invasive mechanical ventilation and with a diagnosis of COVID-19 based on clinical diagnosis or PCR test will be eligible. Patients will be excluded for the following reasons: more than 72 hours from the onset of ARDS; age < 16 years; patient known to be pregnant; major trauma in previous 5 days; presence of any active malignancy (other than non-melanoma skin cancer); WHO Class III or IV pulmonary hypertension; venous thromboembolism currently receiving anti-coagulation or within the past 3 months; patient receiving extracorporeal life support; severe chronic liver disease (Child-Pugh > 12); Do Not Attempt Resuscitation order in place; treatment withdrawal imminent within 24 hours; prisoners; declined consent; non-English speaking patients or those who do not adequately understand verbal or written information unless an interpreter is available; previously enrolled in the REALIST trial. INTERVENTION AND COMPARATOR: Intervention: Allogeneic donor CD362 enriched human umbilical cord derived mesenchymal stromal cells (REALIST ORBCEL-C) supplied as sterile, single-use cryopreserved cell suspension of a fixed dose of 400 x106 cells in 40ml volume, to be diluted in Plasma-Lyte 148 to a total volume of 200mls for administration. Comparator (placebo): Plasma-Lyte 148 Solution for Infusion (200mls). The cellular product (REALIST ORBCEL-C) was developed and patented by Orbsen Therapeutics. MAIN OUTCOMES: The primary safety outcome is the incidence of serious adverse events. The primary efficacy outcome is Oxygenation Index (OI) at day 7. Secondary outcomes include: OI at days 4 and 14; respiratory compliance, driving pressure and PaO2/FiO2 ratio (PF ratio) at days 4, 7 and 14; Sequential Organ Failure Assessment (SOFA) score at days 4, 7 and 14; extubation and reintubation; ventilation free days at day 28; duration of mechanical ventilation; length of ICU and hospital stay; 28-day and 90-day mortality. RANDOMISATION: After obtaining informed consent, patients will be randomised via a centralised automated 24-hour telephone or web-based randomisation system (CHaRT, Centre for Healthcare Randomised Trials, University of Aberdeen). Randomisation will be stratified by recruitment centre and by vasopressor use and patients will be allocated to REALIST ORBCEL-C or placebo control in a 1:1 ratio. BLINDING (MASKING): The investigator, treating physician, other members of the site research team and participants will be blinded. The cell therapy facility and clinical trials pharmacist will be unblinded to facilitate intervention and placebo preparation. The unblinded individuals will keep the treatment information confidential. The infusion bag will be masked at the time of preparation and will be administered via a masked infusion set. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A sample size of 60 patients with 30 patients randomised to the intervention and 30 to the control group. If possible, recruitment will continue beyond 60 patients to provide more accurate and definitive trial results. The total number of patients recruited will depend on the pandemic and be guided by the data monitoring and ethics committee (DMEC). TRIAL STATUS: REALIST Phase 1 completed in January 2020 prior to the COVID-19 pandemic. This was an open label dose escalation study of REALIST ORBCEL-C in patients with ARDS. The COVID-19 pandemic emerged as REALIST Phase 2 was planned to commence and the investigator team decided to repurpose the Phase 2 trial as a COVID-19 specific trial. This decision was discussed and approved by the Trial Steering Committee (TSC) and DMEC. Submissions were made to the Research Ethics Committee (REC) and MHRA to amend the protocol to a COVID-19 specific patient population and the protocol amendment was accepted by the REC on 27th March 2020 and MHRA on 30th March 2020 respectively. Other protocol changes in this amendment included an increase in the time of onset of ARDS from 48 to 72 hours, inclusion of clinical outcomes as secondary outcomes, the provision of an option for telephone consent, an indicative sample size and provision to continue recruitment beyond this indicative sample size. The current protocol in use is version 4.0 23.03.2020 (Additional file 1). Urgent Public Health status was awarded by the NIHR on 2 April 2020 and the trial opened to recruitment and recruited the first participant the same day. At the time of publication the trial was open to recruitment at 5 sites across the UK (Belfast Health and Social Care Trust, King's College London, Guys and St Thomas' Hospital London, Birmingham Heartlands Hospital and the Queen Elizabeth Hospital Birmingham) and 12 patients have been recruited across these sites. Additional sites are planned to open and appropriate approvals for these are being obtained. It is estimated recruitment will continue for 6 months. TRIAL REGISTRATION: ClinicalTrials.gov NCT03042143 (Registered 3 Feb 2017). EudraCT 2017-000585-33 (Registered 28 Nov 2017). FULL PROTOCOL: The full protocol (version 4.0 23.03.2020) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

A 2 × 2 factorial, randomised, open-label trial to determine the clinical and cost-effectiveness of hypertonic saline (HTS 6%) and carbocisteine for airway clearance versus usual care over 52 weeks in adults with bronchiectasis: a protocol for the CLEAR clinical trial.

BACKGROUND: Current guidelines for the management of bronchiectasis (BE) highlight the lack of evidence to recommend mucoactive agents, such as hypertonic saline (HTS) and carbocisteine, to aid sputum removal as part of standard care. We hypothesise that mucoactive agents (HTS or carbocisteine, or a combination) are effective in reducing exacerbations over a 52-week period, compared to usual care. METHODS: This is a 52-week, 2 × 2 factorial, randomized, open-label trial to determine the clinical effectiveness and cost effectiveness of HTS 6% and carbocisteine for airway clearance versus usual care - the Clinical and cost-effectiveness of hypertonic saline (HTS 6%) and carbocisteine for airway clearance versus usual care (CLEAR) trial. Patients will be randomised to (1) standard care and twice-daily nebulised HTS (6%), (2) standard care and carbocisteine (750 mg three times per day until visit 3, reducing to 750 mg twice per day), (3) standard care and combination of twice-daily nebulised HTS and carbocisteine, or (4) standard care. The primary outcome is the mean number of exacerbations over 52 weeks. Key inclusion criteria are as follows: adults with a diagnosis of BE on computed tomography, BE as the primary respiratory diagnosis, and two or more pulmonary exacerbations in the last year requiring antibiotics and production of daily sputum. DISCUSSION: This trial's pragmatic research design avoids the significant costs associated with double-blind trials whilst optimising rigour in other areas of trial delivery. The CLEAR trial will provide evidence as to whether HTS, carbocisteine or both are effective and cost effective for patients with BE. TRIAL REGISTRATION: EudraCT number: 2017-000664-14 (first entered in the database on 20 October 2017). ISRCTN.com, ISRCTN89040295. Registered on 6 July/2018. Funder: National Institute for Health Research, Health Technology Assessment Programme (15/100/01). SPONSOR: Belfast Health and Social Care Trust. Ethics Reference Number: 17/NE/0339. Protocol version: v3.0 Final_14052018.

Diabetic macular oedema and diode subthreshold micropulse laser (DIAMONDS): study protocol for a randomised controlled trial.

BACKGROUND: In the UK, macular laser is the treatment of choice for people with diabetic macular oedema with central retinal subfield thickness (CST) < 400 µm, as per National Institute for Health and Care Excellence guidelines. It remains unclear whether subthreshold micropulse laser is superior and should replace standard threshold laser for the treatment of eligible patients. METHODS: DIAMONDS is a pragmatic, multicentre, allocation-concealed, randomised, equivalence, double-masked clinical trial that aims to determine the clinical effectiveness and cost-effectiveness of subthreshold micropulse laser compared with standard threshold laser, for the treatment of diabetic macular oedema with CST < 400 µm. The primary outcome is the mean change in best-corrected visual acuity in the study eye from baseline to month 24 post treatment. Secondary outcomes (at 24 months) include change in binocular best corrected visual acuity; CST; mean deviation of the Humphrey 10-2 visual field; change in percentage of people meeting driving standards; European Quality of Life-5 Dimensions, National Eye Institute Visual Functioning Questionnaire-25 and VisQoL scores; incremental cost per quality-adjusted life year gained; side effects; number of laser treatments and use of additional therapies. The primary statistical analysis will be per protocol rather than intention-to-treat analysis because the latter increases type I error in non-inferiority or equivalence trials. The difference between lasers for change in best-corrected visual acuity (using 95% CI) will be compared to the permitted maximum difference of five Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Linear and logistic regression models will be used to compare outcomes between treatment groups. A Markov-model-based cost-utility analysis will extend beyond the trial period to estimate longer-term cost-effectiveness. DISCUSSION: This trial will determine the clinical effectiveness and cost-effectiveness of subthreshold micropulse laser, when compared with standard threshold laser, for the treatment of diabetic macular oedema, the main cause of sight loss in people with diabetes mellitus. TRIAL REGISTRATION: International Standard Randomised Controlled Trials, ISRCTN17742985 . Registered on 19 May 2017 (retrospectively registered).

Prevention of post-operative complications by using a HMG-CoA reductase inhibitor in patients undergoing one-lung ventilation for non-cardiac surgery: study protocol for a randomised controlled trial.

BACKGROUND: Postoperative pulmonary complications (PPC) and peri-operative myocardial infarction (MI) have a significant impact on the long-term mortality of surgical patients. Patients undergoing one-lung ventilation (OLV) for surgery are at a high risk of developing these complications. These complications could be associated with intensive care unit (ICU) admissions and longer hospital stay with associated resource and economic burden. Simvastatin, a HMG-CoA reductase enzyme inhibitor has been shown to have pleiotropic anti-inflammatory effects as well as being endothelial protective. The benefits of statins have been shown in various observational studies and in small proof-of-concept studies. There is an urgent need for a well-designed, large clinical trial powered to detect clinical outcomes. The Prevention HARP 2 trial will test the hypothesis 'simvastatin 80 mg when compared to placebo will reduce cardiac and pulmonary complications in patients undergoing elective oesophagectomy, lobectomy or pneumonectomy'. METHODS/DESIGN: The Prevention HARP 2 trial is a UK multi-centre, randomised, double-blind, placebo-controlled trial. Adult patients undergoing elective oesophagectomy, lobectomy or pneumonectomy will be eligible. Patients who are already on statins will be excluded from this trial. Patients will be randomised to receive simvastatin 80 mg or matched placebo for 4 days pre surgery and for up to 7 days post surgery. The primary outcome is a composite outcome of PPC and MI within 7 days post surgery. Various secondary outcome measures including clinical outcomes, safety outcomes and health economic outcomes will be collected. The study aims to recruit 452 patients in total across 12 UK sites. DISCUSSION: The results of the Prevention HARP 2 trial should add to our understanding of the benefits of peri-operative statins and influence clinical decision-making. Analysis of blood and urine samples from the patients will provide insight into the mechanism of simvastatin action. TRIAL REGISTRATION: International Standard Randomised Controlled Trials registry, ID: ISRCTN48095567 . Registered on 11 November 2016.

Assessment of the effect of addition of 24 hours of oral tranexamic acid post-operatively to a single intraoperative intravenous dose of tranexamic acid on calculated blood loss following primary hip and knee arthroplasty (TRAC-24): a study protocol for a randomised controlled trial.

BACKGROUND: While it is has been proven that tranexamic acid (TXA) reduces blood loss in primary total hip and knee arthroplasty (THA and TKA), there is little published evidence on the use of TXA beyond 3 h post-operatively. Most blood loss occurs after wound closure and the primary aim of this study is to determine if the use of oral TXA post-operatively for up to 24 h will reduce calculated blood loss at 48 h beyond an intra-operative intravenous bolus alone following primary THA and TKA. To date, most TXA studies have excluded patients with a history of thromboembolic disease. METHODS/DESIGN: This is a phase IV, single-centred, open-label, parallel-group, randomised controlled trial. Participants are randomised to one of three groups: group 1, an intravenous (IV) bolus of TXA peri-operatively plus oral TXA post-operatively for 24 h; group 2, an IV bolus of TXA peri-operatively or group 3, standard care (no TXA). Eligible participants, including those with a history of thromboembolic disease, are allocated to these groups with a 2:2:1 allocation ratio. The primary outcome is the indirectly calculated blood loss 48 h after surgery. Researchers and patients are not blinded to the treatment; however, staff processing blood samples are. Originally 1166 participants were required to complete this study, 583 THA and 583 TKA. However, following an interim analysis after 100 THA and 100 TKA participants had been recruited to the study, the data monitoring ethics committee recommended stopping group 3 (standard care). DISCUSSION: TRAC-24 will help to determine whether an extended TXA dosing regimen can further reduce blood loss following primary THA and TKA. By including patients with a history of thromboembolic disease, this study will add to our understanding of the safety profile of TXA in this clinical situation. TRIAL REGISTRATION: ISRCTN registry, ISRCTN58790500 . Registered on 3 June 2016, EudraCT: 2015-002661-36.

5-Flurouracil disrupts nuclear export and nuclear pore permeability in a calcium dependent manner.

Regulation of nuclear transport is an essential component of apoptosis. As chemotherapy induced cell death progresses, nuclear transport and the nuclear pore complex (NPC) are slowly disrupted and dismantled. 5-Fluorouracil (5-FU) and the camptothecin derivatives irinotecan and topotecan, are linked to altered nuclear transport of specific proteins; however, their general effects on the NPC and transport during apoptosis have not been characterized. We demonstrate that 5-FU, but not topotecan, increases NPC permeability, and disrupts Ran-mediated nuclear transport before the disruption of the NPC. This increased permeability is dependent on increased cellular calcium, as the Ca2+ chelator BAPTA-AM, abolishes the effect. Furthermore, increased calcium alone was sufficient to disrupt the Ran gradient. Combination treatments of 5-FU with topotecan or irinotecan, similarly disrupted nuclear transport before disassembly of the NPC. In both single and combination treatments nuclear transport was disrupted before caspase 9 activation, indicating that 5-FU induces an early caspase-independent increase in NPC permeability and alteration of nuclear transport. Because Crm1-mediated nuclear export of tumor suppressors is linked to drug resistance we also examined the effect of 5-FU on the nuclear export of a specific target, topoisomerase. 5-FU treatment led to accumulation of topoisomerase in the nucleus and recovered the loss nuclear topoisomerase induced by irinotecan or topotecan, a known cause of drug resistance. Furthermore, 5-FU retains its ability to cause nuclear accumulation of p53 in the presence of irinotecan or topotecan. Our results reveal a new mechanism of action for these therapeutics during apoptosis, opening the door to other potential combination chemotherapies that employ 5-FU as a calcium mediated inhibitor of Crm1-induced nuclear export of tumor suppressors.

Adherence to physical activity guidelines in mid-pregnancy does not reduce sedentary time: an observational study.

BACKGROUND: Physical activity (PA) interventions designed to prevent prenatal complications have focused on increasing moderate PA yielding conflicting results. Minimal attention has focused on the evaluation of sleep, sedentary behavior (SB), light activity or total daily PA during pregnancy. The purpose of this prospective, longitudinal study was to 1) objectively quantify and compare habitual PA and SB during the 2nd and 3rd trimester; and 2) evaluate differences in activity patterns for women meeting prenatal PA guidelines versus those that did not. METHODS: Forty-six participants wore 2 PA monitors (SenseWear Mini and activPAL) during week 18 and week 35 of pregnancy. We compared differences in sleep duration, postural allocation, daily steps, and PA between the 2nd and 3rd trimester and for women who met and did not meet PA guidelines. RESULTS: During the 2(nd) trimester, 30% of the women's day (24-hours) was total sleep; 52% SB; 13% light; 3% moderate; and 0% vigorous PA. Light (P = 0.05), vigorous (P = 0.02), and moderate-vigorous PA (MET-minutes; P = 0.02), decreased with a trend in increased SB (P = 0.07). Activity of other intensities and sleep duration did not significantly change. Only 39% and 37% of participants slept between 7-9 hours/night at week 18 and 35, respectively. Forty-six percent (n = 21) and 28% (n = 13) of participants met prenatal PA guidelines during the 2(nd) and 3(rd) trimester, respectively. At week 18, no differences in total sleep, SB, or light PA existed for women who met PA guidelines versus those who did not; total PA was significantly greater for women who met guidelines. At week 35, women that met PA guidelines had significantly less SB (P < 0.005) than women who did not. CONCLUSIONS: This study demonstrates that pregnant women spend the majority of their day in SB. Significant reductions in total activity across pregnancy may be attributed, in part to shifts in light PA and increased SB. Based on the lifestyle of our sample, regardless of meeting PA guidelines in mid-pregnancy, no significant difference exists in time spent in SB, however meeting PA recommendations in late pregnancy may reduce SB. Future interventions should target reducing SB by increasing light and moderate PA beyond volitional exercise.

Nutrition, metabolism, and integrative approaches in cancer survivors.

OBJECTIVES: To review emerging issues about metabolic changes occurring in cancer survivors during and as a result of therapy, the role of nutrition, weight control, stress management, nutritional supplements, and other complementary diet therapies, methods of mitigating side effects of treatment affecting dietary intake, and to suggest future research directions. DATA SOURCES: Literature review and professional clinical experience with oncology patients. CONCLUSION: Enhancing cancer survivorship requires knowledge and application of nutritional science and integrative health care approaches. IMPLICATIONS FOR NURSING PRACTICE: Reliable, personalized, team-generated nutritional advice must be provided to cancer patients and cancer survivors to reduce risk of recurrence, optimize energy balance, and improve quality of life.