Systematic development and feasibility testing of a multibehavioural digital prehabilitation intervention for patients approaching major surgery (iPREPWELL): A study protocol.

Improving outcomes for people undergoing major surgery, specifically reducing perioperative morbidity and mortality remains a global health challenge. Prehabilitation involves the active preparation of patients prior to surgery, including support to tackle risk behaviours that mediate and undermine physical and mental health and wellbeing. The majority of prehabilitation interventions are delivered in person, however many patients express a preference for remotely-delivered interventions that provide them with tailored support and the flexibility. Digital prehabilitation interventions offer scalability and have the potential to benefit perioperative healthcare systems, however there is a lack of robustly developed and evaluated digital programmes for use in routine clinical care. We aim to systematically develop and test the feasibility of an evidence and theory-informed multibehavioural digital prehabilitation intervention 'iPREPWELL' designed to prepare patients for major surgery. The intervention will be developed with reference to the Behaviour Change Wheel, COM-B model, and the Theoretical Domains Framework. Codesign methodology will be used to develop a patient intervention and accompanying training intervention for healthcare professionals. Training will be designed to enable healthcare professionals to promote, support and facilitate delivery of the intervention as part of routine clinical care. Patients preparing for major surgery and healthcare professionals involved with their clinical care from two UK National Health Service centres will be recruited to stage 1 (systematic development) and stage 2 (feasibility testing of the intervention). Participants recruited at stage 1 will be asked to complete a COM-B questionnaire and to take part in a qualitative interview study and co-design workshops. Participants recruited at stage 2 (up to twenty healthcare professionals and forty participants) will be asked to take part in a single group intervention study where the primary outcomes will include feasibility, acceptability, and fidelity of intervention delivery, receipt, and enactment. Healthcare professionals will be trained to promote and support use of the intervention by patients, and the training intervention will be evaluated qualitatively and quantitatively. The multifaceted and systematically developed intervention will be the first of its kind and will provide a foundation for further refinement prior to formal efficacy testing.

The Microbiome in Bronchial Biopsies from Smokers and Ex-Smokers with Stable COPD - A Metatranscriptomic Approach.

Current knowledge about the respiratory microbiome is mainly based on 16S ribosomal RNA gene sequencing. Newer sequencing approaches, such as metatranscriptomics, offer the technical ability to measure the viable microbiome response to environmental conditions such as smoking as well as to explore its functional role by investigating host-microbiome interactions. However, knowledge about its feasibility in respiratory microbiome research, especially in lung biopsies, is still very limited. RNA sequencing was performed in bronchial biopsies from clinically stable smokers (n = 5) and ex-smokers (n = 6) with COPD not using (inhaled) steroids. The Trinity assembler was used to assemble non-human reads in order to allow unbiased taxonomical and microbial transcriptional analyses. Subsequently, host-microbiome interactions were analyzed based on associations with host transcriptomic data. Ultra-low levels of microbial mass (0.009%) were identified in the RNA-seq data. Overall, no differences were identified in microbiome diversity or transcriptional profiles of microbial communities or individual microbes between COPD smokers and ex-smokers in the initial test dataset as well as a larger replication dataset. We identified an upregulated host gene set, related to the simultaneous presence of Bradyrhizobium, Roseomonas, Brevibacterium.spp., which were related to PERK-mediated unfolded protein response (UPR) and expression of the microRNA-155-5p. Our results show that metatranscriptomic profiling in bronchial biopsy samples from stable COPD patients yields ultra-low levels of microbial mass. Further, this study illustrates the potential of using transcriptional profiling of the host and microbiome to gain more insight into their interaction in the airways.

Determinants of SARS-CoV-2 receptor gene expression in upper and lower airways.

The recent outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has led to a worldwide pandemic. One week after initial symptoms develop, a subset of patients progresses to severe disease, with high mortality and limited treatment options. To design novel interventions aimed at preventing spread of the virus and reducing progression to severe disease, detailed knowledge of the cell types and regulating factors driving cellular entry is urgently needed. Here we assess the expression patterns in genes required for COVID-19 entry into cells and replication, and their regulation by genetic, epigenetic and environmental factors, throughout the respiratory tract using samples collected from the upper (nasal) and lower airways (bronchi). Matched samples from the upper and lower airways show a clear increased expression of these genes in the nose compared to the bronchi and parenchyma. Cellular deconvolution indicates a clear association of these genes with the proportion of secretory epithelial cells. Smoking status was found to increase the majority of COVID-19 related genes including ACE2 and TMPRSS2 but only in the lower airways, which was associated with a significant increase in the predicted proportion of goblet cells in bronchial samples of current smokers. Both acute and second hand smoke were found to increase ACE2 expression in the bronchus. Inhaled corticosteroids decrease ACE2 expression in the lower airways. No significant effect of genetics on ACE2 expression was observed, but a strong association of DNA- methylation with ACE2 and TMPRSS2- mRNA expression was identified in the bronchus.

Serum periostin does not reflect type 2-driven inflammation in COPD.

Although Th2 driven inflammation is present in COPD, it is not clearly elucidated which COPD patients are affected. Since periostin is associated with Th2 driven inflammation and inhaled corticosteroid (ICS)-response in asthma, it could function as a biomarker in COPD. The aim of this study was to analyze if serum periostin is elevated in COPD compared to healthy controls, if it is affected by smoking status, if it is linked to inflammatory cell counts in blood, sputum and endobronchial biopsies, and if periostin can predict ICS-response in COPD patients.Serum periostin levels were measured using Elecsys Periostin immunoassay. Correlations between periostin and inflammatory cell count in blood, sputum and endobronchial biopsies were analyzed. Additionally, the correlation between serum periostin levels and treatment responsiveness after 6 and 30 months was assessed using i.e. ΔFEV1% predicted, ΔCCQ score and ΔRV/TLC ratio. Forty-five COPD smokers, 25 COPD past-smokers, 22 healthy smokers and 23 healthy never-smokers were included. Linear regression analysis of serum periostin showed positive correlations age (B = 0.02, 95%CI 0.01-0.03) and FEV1% predicted (B = 0.01, 95%CI 0.01-0.02) in healthy smokers, but not in COPD patients In conclusion, COPD -smokers and -past-smokers have significantly higher periostin levels compared to healthy smokers, yet periostin is not suitable as a biomarker for Th2-driven inflammation or ICS-responsiveness in COPD.

Clinical guideline and recommendations on pre-operative exercise training in patients awaiting major non-cardiac surgery.

Despite calls for the routine implementation of pre-operative exercise programmes to optimise patient fitness before elective major surgery, there is no practical guidance for providing safe and effective exercise in this specific context. The following clinical guideline was developed following a review of the evidence on the effects of pre-operative exercise interventions. We developed a series of best-practice and, where possible, evidence-based statements to advise on patient care with respect to exercise training in the peri-operative period. These statements cover: patient selection for exercise training in surgical patients; integration of exercise training into multi-modal prehabilitation programmes; and advice on exercise prescription factors and follow-up. Although we acknowledge that further research is needed to identify the optimal exercise prescription in different clinical scenarios, we urge peri-operative teams to make use of these recommendations.

Supervised exercise training as an adjunct therapy for venous leg ulcers: a randomized controlled feasibility trial.

BACKGROUND: Venous leg ulcers (VLUs) are typically painful and heal slowly. Compression therapy offers high healing rates; however, improvements are not usually sustained. Exercise is a low-cost, low-risk and effective strategy for improving physical and mental health. Little is known about the feasibility and efficacy of supervised exercise training used in combination with compression therapy patients with VLUs. OBJECTIVES: To assess the feasibility of a 12-week supervised exercise programme as an adjunct therapy to compression in patients with VLUs. METHODS: This was a two-centre, two-arm, parallel-group, randomized feasibility trial. Thirty-nine patients with venous ulcers were recruited and randomized 1 : 1 either to exercise (three sessions weekly) plus compression therapy or compression only. Progress/success criteria included exercise attendance rate, loss to follow-up and patient preference. Baseline assessments were repeated at 12 weeks, 6 months and 1 year, with healing rate and time, ulcer recurrence and infection incidents documented. Intervention and healthcare utilization costs were calculated. Qualitative data were collected to assess participants' experiences. RESULTS: Seventy-two per cent of the exercise group participants attended all scheduled exercise sessions. No serious adverse events and only two exercise-related adverse events (both increased ulcer discharge) were reported. Loss to follow-up was 5%. At 12 months, median ulcer healing time was lower in the exercise group (13 vs. 34·7 weeks). Mean National Health Service costs were £813·27 for the exercise and £2298·57 for the control group. CONCLUSIONS: The feasibility and acceptability of both the supervised exercise programme in conjunction with compression therapy and the study procedures is supported.

Randomized feasibility trial of high-intensity interval training before elective abdominal aortic aneurysm repair.

BACKGROUND: This study assessed the feasibility of a preoperative high-intensity interval training (HIT) programme in patients awaiting elective abdominal aortic aneurysm repair. METHODS: In this feasibility trial, participants were allocated by minimization to preoperative HIT or usual care. Patients in the HIT group were offered three exercise sessions per week for 4 weeks, and weekly maintenance sessions if surgery was delayed. Feasibility and acceptability outcomes were: rates of screening, eligibility, recruitment, retention, outcome completion, adverse events and adherence to exercise. Data on exercise enjoyment (Physical Activity Enjoyment Scale, PACES), cardiorespiratory fitness (anaerobic threshold and peak oxygen uptake), quality of life, postoperative morbidity and mortality, duration of hospital stay and healthcare utilization were also collected. RESULTS: Twenty-seven patients were allocated to HIT and 26 to usual care (controls). Screening, eligibility, recruitment, retention and outcome completion rates were 100 per cent (556 of 556), 43·2 per cent (240 of 556), 22·1 per cent (53 of 240), 91 per cent (48 of 53) and 79-92 per cent respectively. The overall exercise session attendance rate was 75·8 per cent (276 of 364), and the mean(s.d.) PACES score after the programme was 98(19) ('enjoyable'); however, the intensity of exercise was generally lower than intended. The mean anaerobic threshold after exercise training (adjusted for baseline score and minimization variables) was 11·7 ml per kg per min in the exercise group and 11·4 ml per kg per min in controls (difference 0·3 (95 per cent c.i. -0·4 to 1·1) ml per kg per min). There were trivial-to-small differences in postoperative clinical and patient-reported outcomes between the exercise and control groups. CONCLUSION: Despite the intensity of exercise being generally lower than intended, the findings support the feasibility and acceptability of both preoperative HIT and the trial procedures. A definitive trial is warranted. Registration number: ISRCTN09433624 ( https://www.isrctn.com/).

Systematic review: height-adjustable workstations to reduce sedentary behaviour in office-based workers.

BACKGROUND: Time spent sitting in the workplace is an important contributor to overall sedentary risk. Installation of height-adjustable workstations has been proposed as a feasible approach for reducing occupational sitting time in office workers. AIMS: To provide an accurate overview of the controlled trials that have evaluated the effects of height-adjustable workstation interventions on workplace sitting time in office-based workers. METHODS: A comprehensive search was conducted up until March 2014 in the following databases: Medline, PsychINFO, CENTRAL, EMBASE and PEDro. To identify unpublished studies and grey literature, the reference lists of relevant official or scientific web pages were also checked. Studies assessing the effectiveness of height-adjustable workstations using a randomized or non-randomized controlled design were included. RESULTS: The initial search yielded a total of 8497 citations. After a thorough selection process, five studies were included with 172 participants. A formal quality assessment indicated that risk of bias was high in all studies and heterogeneity in interventions and outcomes prevented meta-analysis. Nevertheless, all studies reported that height-adjustable workstation interventions reduced occupational sitting time in office workers. There was insufficient evidence to determine effects on other relevant health outcomes (e.g. body composition, musculoskeletal symptoms, mental health). CONCLUSIONS: There is insufficient evidence to make firm conclusions regarding the effects of installing height-adjustable workstations on sedentary behaviour and associated health outcomes in office workers. Larger and longer term controlled studies are needed, which include more representative populations.

Systematic review of home-based exercise programmes for individuals with intermittent claudication.

We aimed to conduct a systematic review of the evidence for structured, home-based exercise programmes (HEPs) in patients with intermittent claudication. The Medline, PsycINFO, EMBASE, and Cochrane databases were searched up to April 2013 for terms related to walking, self-management, and intermittent claudication. Descriptive, methodological and outcome data were extracted from eligible articles. Trial quality was assessed using the GRADE system. Seventeen studies were included with 1,457 participants. Six studies compared HEPs with supervised exercise training, five compared HEPs with usual care/observation control, and seven evaluated HEPs in a single-group design. Trial heterogeneity prevented meta-analysis. Nevertheless, there was "low-level" evidence that HEPs can improve walking capacity and quality of life in patients with intermittent claudication when compared with baseline or in comparison to usual care/observation control. In addition, improvements with HEPs may be inferior to those evoked by supervised exercise training. Considerable uncertainty exists regarding the long-term clinical and cost effectiveness of HEPs in patients with intermittent claudication. Thus, more robust trials are needed to build evidence about these interventions. Nevertheless, clinicians should consider using structured interventions to promote self-managed walking in patients with intermittent claudication, as opposed to simple "go home and walk" advice, when supervised exercise training is unavailable or impractical.

Exercise training and the control of skin blood flow in older adults.

The ability to control skin blood flow decreases with primary aging, making older adults less able to adequately thermoregulate and repair cutaneous wounds. Lifestyle factors such as physical activity, diet, and smoking might interact with the aging process to modulate "normal" age-associated changes in the cutaneous microcirculation. The main focus of this brief review is the effects of exercise training on the control of skin blood flow in older adults.

Poly(lactic acid)-poly(ethylene oxide) block copolymers: new directions in self-assembly and biomedical applications.

In this review, we focus on recent developments in biomaterials of poly(lactic acid)-poly(ethylene oxide)-poly(lactic acid) (PLA-PEO-PLA) triblock copolymers. This system has been widely explored for a number of applications in controlled and sustained release of drugs and in tissue engineering devices. New insights into self-assembly of these materials have resulted in new PLA-PEOPLA solutions and gels with novel structural, mechanical, and drug release properties. Recent innovations include hydrogels with nanoscale crystalline domains, solutions and gels based on PLA stereocomplexes, and nanoparticle-copolymer assemblies. We first briefly review synthetic approaches to these materials. We then describe characterization of the solution properties, formation of micelles, drug release characteristics, and investigation of the sol-gel transition. The properties of PLA-PEO-PLA hydrogels are then discussed, including the effect of crystalline domains on the gel microstructure and efforts to tune the elastic modulus and degredation properties of gels through the addition of chemical crosslinks. In the second half of the review, we discuss the wide variety of biomedical applications currently being pursued for PLA-PEO-PLA triblock copolymer systems. Polymer-nanoparticle complexes have been investigated to facilitate the formation of metal nanoclusters used as biosensors, as well as to enhance the elastic modulus of hydrogels. Thin polymer films have also been investigated for use as tissue engineering scaffolds and as drug-eluding coatings for stents and other medical implants. Finally, we discuss future directions for biomedical applications of this system, including new strategies for improving the specificity and cell affinity of PLA-based biomaterials.

Baseline autoantibody profiles predict normalization of complement and anti-dsDNA autoantibody levels following rituximab treatment in systemic lupus erythematosus.

B cells are thought to play a major role in the pathogenesis of systemic lupus erythematosus (SLE). Rituximab (RTX), a chimeric anti-CD20 mAb, effectively depletes CD20( +) peripheral B cells. Recent results from EXPLORER, a placebo-controlled trial of RTX in addition to aggressive prednisone and immunosuppressive therapy, showed similar levels of clinical benefit in patients with active extra-renal SLE despite effective B cell depletion. We performed further data analyses to determine whether significant changes in disease activity biomarkers occurred in the absence of clinical benefit. We found that RTX-treated patients with baseline autoantibodies (autoAbs) had decreased anti-dsDNA and anti-cardiolipin autoAbs and increased complement levels. Patients with anti-dsDNA autoAb who lacked baseline RNA binding protein (RBP) autoAbs showed increased complement and decreased anti-dsDNA autoAb in response to RTX. Other biomarkers, such as baseline BAFF levels or IFN signature status did not predict enhanced effects of RTX therapy on complement or anti-dsDNA autoAb levels. Finally, platelet levels normalized in RTX-treated patients who entered the study with low baseline counts. Together, these findings demonstrate clear biologic activity of RTX in subsets of SLE patients, despite an overall lack of incremental clinical benefit with RTX in the EXPLORER trial.

Exercise training improves cutaneous microvascular endothelial function in post-surgical varicose vein patients.

This study investigated the effects of exercise training on cutaneous microvascular function in post-surgical varicose vein patients. Sixteen post-surgical (4-5 weeks) varicose vein patients were randomised to a treadmill-walking exercise group or a non-exercise control group. The exercise group trained twice weekly for 8 weeks. Changes in cutaneous microvascular function of the gaiter area were assessed using laser Doppler flowmetry combined with incremental-dose iontophoretic administration of acetylcholine chloride (ACh) and sodium nitroprusside (SNP) in both supine and standing positions. At 8 weeks, peak flux responses to ACh in the supine position were increased in the exercise group (44+/-30 to 62+/-33 PU; P=0.03) with a similar trend in the standing position (37+/-27 to 74+/-31 PU; P=0.08). There were no such changes in the control group (P>0.05). Additionally, peak flux responses to SNP were unchanged in both groups and body positions (P>0.05). The results suggest that moderate-intensity lower-limb exercise training improves microvascular endothelial vasodilator function in post-surgical varicose vein patients.

Physiological predictors of maximum treadmill walking performance in patients with intermittent claudication.

The purpose of this investigation was to identify physiological predictors of maximum treadmill walking performance (MWD) in patients with intermittent claudication. Forty-five claudicants performed a graded treadmill test to determine MWD, peak oxygen uptake, and gas exchange threshold. Calf muscle oxygenation (StO (2)) at 1 min and time to minimum StO (2) were also measured using near-infrared spectroscopy. On other occasions, peak calf blood flow, resting ankle-brachial index, and pulmonary oxygen uptake kinetics during steady-state walking were assessed. A forward stepwise multiple regression analysis was performed to determine predictors of MWD. A regression model comprising time to minimum StO (2), peak oxygen uptake, and StO (2) at 1 min explained 64% of the variation in MWD. The results suggest that cardiopulmonary fitness and the ability to match oxygen delivery to metabolic demand are important determinants of walking performance in claudicants, and that certain near-infrared spectroscopy variables might be useful in studies that evaluate the mechanisms of clinical improvement with different treatment interventions.

Nordic poles immediately improve walking distance in patients with intermittent claudication.

OBJECTIVES: To investigate the immediate effects of Nordic pole walking (NPW) on walking distance and cardiopulmonary workload in patients with intermittent claudication. METHODS: Using a standardised treadmill test (3.2 km h(-1) at 4% gradient), walking distance, cardiopulmonary responses, leg pain and perceived exertion during NPW were compared to responses evoked by normal walking in 20 patients with intermittent claudication. The distance to onset of claudication pain (claudication distance: CD) and to maximum walking distance (MWD), heart rate (HR), expired gas parameters, leg pain (Borg's CR-10 Scale) and perceived exertion (Borg's Rating of Perceived Exertion: RPE Scale) were compared. RESULTS: CD increased significantly from a median (range) distance of 77 m (28-503) to 130 m (41-1080) and MWD increased significantly from 206 m (81-1078) to 285 m (107-1080) when patients used the Nordic poles (P=0.000). The level of leg pain at MWD was also significantly reduced during NPW (P=0.002). Perceived exertion at MWD did not increase despite an increase in cardiopulmonary work, as indicated by an increase in oxygen consumption (16.5%; P=0.000). CONCLUSION: These results show that NPW immediately enables patients with intermittent claudication to walk further with less pain, despite a higher workload. NPW might also be a useful exercise strategy for improving the cardiovascular fitness of patients with intermittent claudication.

The effect of prophylactic metaraminol on systemic hypotension caused by induction of anaesthesia with propofol in patients over 55 years old.

We conducted a double-blind, randomised, placebo-controlled study evaluating the efficacy of prophylactic metaraminol for preventing propofol-induced hypotension. Thirty patients aged 55-75 years undergoing general anaesthesia were randomly allocated to receive either metaraminol 0.5 mg or saline before administration of fentanyl 1 microg.kg(-1) and propofol 2 mg.kg(-1). Induction of anaesthesia was associated with a decrease in mean and systolic arterial pressure in both groups (p = 0.0001). However, there was no significant difference between the two groups. These results show that prophylactic use of metaraminol 0.5 mg does not prevent the decrease in blood pressure following fentanyl and propofol induction in older patients.