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Este artigo traz à discussão as relações entre a Pedagogia de Projetos e a Formação Humana Integral, buscando, de forma sistemática e crítica, superar a visão de ensino-aprendizagem desvinculada de uma formação crítica, inventiva e comprometida com a transformação social. Para tanto, se propôs a analisar a utilização da Pedagogia de Projetos como metodologia de ensino visando uma formação humana integral dos discentes, percebendo-os como sujeitos ativos de seu processo de aprendizagem. Durante a pesquisa, são destacadas as principais características da Pedagogia de Projetos e suas contribuições para a formação Humana Integral. Para tanto, foi desenvolvido um estudo de caso de uma turma do curso Técnico em Administração na Forma Integrada do IFAM campus Coari, de modo a apontar as descobertas realizadas e os resultados alcançados após a reflexão e análise do processo. O levantamento de dados foi feito a partir da aplicação de entrevista semiestruturada e observação remota dos participantes. Os resultados tiveram seus dados tabulados e submetidos ao tratamento da metodologia de Analise Textual Discursiva, para análise dos resultados obtidos.

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of eye movement desensitisation and reprocessing (EMDR), a psychological intervention programme, on symptoms related to traumatic stress in survivors of life-threatening medical events., Secondary Objectives: to evaluate whether the effects of EMDR differ according to the nature of the medical event (associated diagnosis or setting), measured outcome (post-traumatic stress disorder (PTSD), anxiety, depression, or quality of life), or intervention (online, face-to-face, group or individual sessions)., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: MecROX is a mechanistic sub-study of the UK-ROX trial which was designed to evaluate the clinical and cost-effectiveness of a conservative approach to oxygen therapy for invasively ventilated adults in intensive care. This is based on the scientific rationale that excess oxygen is harmful. Epithelial cell damage with alveolar surfactant deficiency is characteristic of hyperoxic acute lung injury. Additionally, hyperoxaemia (excess blood oxygen levels) may exacerbate whole-body oxidative stress leading to cell death, autophagy, mitochondrial dysfunction, bioenergetic failure and multi-organ failure resulting in poor clinical outcomes. However, there is a lack of in-vivo human models evaluating the mechanisms that underpin oxygen-induced organ damage in mechanically ventilated patients., Aim: The aim of the MecROX mechanistic sub-study is to assess lung surfactant composition and global systemic redox status to provide a mechanistic and complementary scientific rationale to the UK-ROX trial findings. The objectives are to quantify in-vivo surfactant composition, synthesis, and metabolism with markers of oxidative stress and systemic redox disequilibrium (as evidenced by alterations in the 'reactive species interactome') to differentiate between groups of conservative and usual oxygen targets., Methods and Design: After randomisation into the UK-ROX trial, 100 adult participants (50 in the conservative and 50 in usual care group) will be recruited at two trial sites. Blood and endotracheal samples will be taken at 0, 48 and 72 hours following an infusion of 3 mg/kg methyl -D 9 -choline chloride. This is a non-radioactive, stable isotope of choline (vitamin), which has been extensively used to study surfactant phospholipid kinetics in humans. This study will mechanistically evaluate the in-vivo surfactant synthesis and breakdown (by hydrolysis and oxidation), oxidative stress and redox disequilibrium from sequential plasma and bronchial samples using an array of analytical platforms. We will compare conservative and usual oxygenation groups according to the amount of oxygen administered. Trial registration: ISRCTNISRCTN61929838, 27/03/2023 https://doi.org/10.1186/ISRCTN61929838., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Dushianthan A et al.)

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 PaO 2 /FiO 2 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., (© 2023. The Author(s).)

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., Competing Interests: Declaration of Competing Interest TWC has received equipment and consumables free-of-charge from Biofire diagnostics and BioMeriuex to support this work. TWC has received speaker fees, honoraria, travel reimbursement, and equipment and consumables at discount or free of charge for the purposes independent of research, outside of this submitted study, from BioFire diagnostics, BioMerieux and QIAGEN. TWC has received consultancy fees from Cepheid, Synairgen research, Randox laboratories and Cidara therapeutics. He has received honoraria for participation in advisory boards from Cepheid, Roche, Janssen and Shionogi. He is a member of independent data monitoring committees for trials sponsored by Roche. He has acted as the UK chief investigator for studies sponsored by Janssen. All other authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare: no support from any organisation for the submitted work no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2022. Published by Elsevier Ltd.)

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., (Copyright © 2022 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

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 Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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). V̇O 2 peak 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 V̇O 2 peak. These results and those of others question the practical utility of BRJ consumption during prolonged altitude exposure., Competing Interests: MG serves on the medical advisory board of Sphere Medical Ltd. and is a director of Oxygen Control Systems Ltd., received honoraria for speaking for and/or travel expenses from BOC Medical (Linde Group), Edwards Lifesciences, and Cortex GmBH, leads the Xtreme-Everest Oxygen Research Consortium and the Fit-4-Surgery research collaboration, and serves as the UK NIHR CRN national specialty group lead for Anaesthesia, Perioperative Medicine and Pain and is an elected council member of the Royal College of Anaesthetists. DM has received lecture and consultancy fees from Siemens Healthineers and Edwards Lifesciences. MM is a paid Consultant for Edwards Lifesciences, his University Chair was sponsored by Smiths Medical, founding Editor of the Journal of Perioperative Medicine and sits on the Editorial Board of the British Journal of Anaesthesia, and Editor-in-Chief of TopMedTalk. HP was employed by the company AURAPA Würzungen GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hennis, Cumpstey, O’Doherty, Fernandez, Gilbert-Kawai, Mitchell, Moyses, Cobb, Meale, Pöhnl, Mythen, Grocott, Levett, Martin, Feelisch and The Xtreme Alps Research Group.)

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., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Intensive Care Society 2020.)

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 a randomised controlled study investigating whether a high-intensity 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)., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 West M et al.)

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 (VO 2 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 VO 2 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.

To simulate an early 20th century viral pneumonia radiotherapy treatment using modern fluoroscopy and evaluated it according to current dose guidelines. Monte Carlo was used to assess the dose distribution on an anthropomorphic phantom. Critical organs were: skin, breasts, esophagus, ribs, vertebrae, heart, thymus, and spinal cord. A 100 kV p beam with 3 mm Al HVL, 25 × 25 cm 2 posterior-anterior (PA) field and 50 cm source-to-surface distance were simulated. Simulations had a resolution of 0.4 × 0.4 × 0.06 cm 3 and a 6% uncertainty. Hundred percent dose was normalized to the skin surface and results were displayed in axial, coronal, and sagittal planes. Dose volume histograms were generated in MATLAB for further analysis. Prescription doses of 0.3, 0.5, and 1.0 Gy were applied to the 15% isodose for organ-dose comparison to current tolerances and potential risk of detriment. Ninety-five and ninety-seven percent of the right and left lung volumes, respectively, were well-covered by the 15% isodose line. For the 0.3, 0.5, and 1.0 Gy prescriptions, the maximum skin doses were 2.9, 4.8, and 9.6 Gy compared to a 2.0 Gy transient erythema dose threshold; left/right lung maximum doses were 1.44/1.46, 2.4/2.4, and 4.8/4.9 Gy compared to a 6.5 Gy pneumonitis and 30 Gy fibrosis thresholds; maximum heart doses were 0.5, 0.9, and 1.8 Gy compared to the 0.5 Gy ICRP-recommendation; maximum spinal cord doses were 1.4, 2.3, and 4.6 Gy compared to 7.0 Gy single fraction dose threshold. Maximum doses to other critical organs were below modern dose thresholds. A 100 kV p PA field could deliver a 0.3 Gy or 0.5 Gy dose without risk of complications. However, a 1.0 Gy dose treatment could be problematic. Critical organ doses could be further reduced if more than one treatment field is used., (Copyright © 2020 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Competing interestsK.S reports grants from AstraZeneca, grants from Asthma UK, outside the submitted work. T. W reports personal fees and other from MyMHealth, grants from Innovate UK, grants from GSK, grants and personal fees from AstraZeneca, grants and personal fees from Synairgen and personal fees from BI, outside the submitted work. A. F, D. H, C. N, H. M, A. A, D. K, L. P, M. H, HM. H, A. W and R. K report no potential conflicts of interest., (© The Author(s) 2020.)

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., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

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 (E NO ) 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. E NO , 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 E NO 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 E NO . 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., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: There is wide inter-institutional variation in the interval between neoadjuvant chemoradiotherapy (NACRT) and surgery for locally advanced rectal cancer. We aimed to assess the association of magnetic resonance imaging (MRI) at 9 and 14 weeks post-NACRT; T-staging (ymrT) and post-NACRT tumour regression grading (ymrTRG) with histopathological outcomes; histopathological T-stage (ypT) and histopathological tumour regression grading (ypTRG) in order to inform decision-making about timing of surgery., Patients and Methods: We prospectively studied 35 consecutive patients (26 males) with MRI-defined resection margin threatened rectal cancer who had completed standardized NACRT. Patients underwent a MRI at Weeks 9 and 14 post-NACRT, and surgery at Week 15. Two readers independently assessed MRIs for ymrT, ymrTRG and volume change. ymrT and ymrTRG were analysed against histopathological ypT and ypTRG as predictors by logistic regression modelling and receiver operating characteristic (ROC) curve analyses., Results: Thirty-five patients were recruited. Inter-observer agreement was good for all MR variables (Kappa > 0.61). Considering ypT as an outcome variable, a stronger association of favourable ymrTRG and volume change at Week 14 compared to Week 9 was found (ymrTRG - p = 0.064 vs. p = 0.010; Volume change - p = 0.062 vs. p = 0.007). Similarly, considering ypTRG as an outcome variable, a greater association of favourable ymrTRG and volume change at Week 14 compared to Week 9 was found (ymrTRG - p = 0.005 vs. p = 0.042; Volume change - p = 0.004 vs. 0.055)., Conclusion: Following NACRT, greater tumour down-staging and volume reduction was observed at Week 14. Timing of surgery, in relation to NACRT, merits further investigation., Trial Registration Number: NCT01325909., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We describe colloidal Janus particles with metallic and dielectric faces that swim vigorously when illuminated by defocused optical tweezers without consuming any chemical fuel. Rather than wandering randomly, these optically-activated colloidal swimmers circulate back and forth through the beam of light, tracing out sinuous rosette patterns. We propose a model for this mode of light-activated transport that accounts for the observed behavior through a combination of self-thermophoresis and optically-induced torque. In the deterministic limit, this model yields trajectories that resemble rosette curves known as hypotrochoids.

Sixty-one patients with FIGO IB cervical cancer treated with planned preoperative radiotherapy (dose to point A: 52-93 Gy, mean 73 Gy) and hysterectomy from 1969 to 1993 were retrospectively reviewed. Patient characteristics and treatment parameters and their association with residual tumor in the hysterectomy specimen were analyzed. Glandular (adenocarcinoma and adenosquamous) tumors were smaller than squamous tumors: 6/11 (55%) were < 6 cm in diameter, versus 12/50 (24%) squamous tumors (p = 0.03). Glandular tumors had a higher incidence of residual disease: 10/11 (91%) versus 24/50 (48%) (p = 0.01). There was no association between presence of pathologic residual disease in the hysterectomy specimen and tumor size, morphology (endophytic vs. exophytic), patient age, dose to point A, time to deliver radiotherapy, or interval between radiotherapy and hysterectomy. Overall 34/61 (56%) patients had residual disease in their hysterectomy specimens after planned preoperative radiotherapy. There were significantly more glandular tumors than squamous tumors with residual disease, even though glandular tumors were a group of smaller tumors.