Anti-inflammatory therapy enables robot-actuated regeneration of aged muscle.

Robot-actuated mechanical loading (ML)-based therapies ("mechanotherapies") can promote regeneration after severe skeletal muscle injury, but the effectiveness of such approaches during aging is unknown and may be influenced by age-associated decline in the healing capacity of skeletal muscle. To address this knowledge gap, this work used a noninvasive, load-controlled robotic device to impose highly defined tissue stresses to evaluate the age dependence of ML on muscle repair after injury. The response of injured muscle to robot-actuated cyclic compressive loading was found to be age sensitive, revealing not only a lack of reparative benefit of ML on injured aged muscles but also exacerbation of tissue inflammation. ML alone also disrupted the normal regenerative processes of aged muscle stem cells. However, these negative effects could be reversed by introducing anti-inflammatory therapy alongside ML application, leading to enhanced skeletal muscle regeneration even in aged mice.

Investigation of the gut microbiome, bile acid composition and host immunoinflammatory response in a model of azoxymethane-induced colon cancer at discrete timepoints.

BACKGROUND: Distinct sets of microbes contribute to colorectal cancer (CRC) initiation and progression. Some occur due to the evolving intestinal environment but may not contribute to disease. In contrast, others may play an important role at particular times during the tumorigenic process. Here, we describe changes in the microbiota and host over the course of azoxymethane (AOM)-induced tumorigenesis. METHODS: Mice were administered AOM or PBS and were euthanised 8, 12, 24 and 48 weeks later. Samples were analysed using 16S rRNA gene sequencing, UPLC-MS and qRT-PCR. RESULTS: The microbiota and bile acid profile showed distinct changes at each timepoint. The inflammatory response became apparent at weeks 12 and 24. Moreover, significant correlations between individual taxa, cytokines and bile acids were detected. One co-abundance group (CAG) differed significantly between PBS- and AOM-treated mice at week 24. Correlation analysis also revealed significant associations between CAGs, bile acids and the bile acid transporter, ASBT. Aberrant crypt foci and adenomas were first detectable at weeks 24 and 48, respectively. CONCLUSION: The observed changes precede host hyperplastic transformation and may represent early therapeutic targets for the prevention or management of CRC at specific timepoints in the tumorigenic process.

Reading a preoperative CT scan to guide complex abdominal wall reconstructive surgery.

Computed tomography (CT) scanning is the imaging modality of choice when planning the overall management and operative approach to complex abdominal wall hernias. Despite its availability and well-recognised benefits there are no guidelines or recommendations regarding how best to read or report such scans for this application. In this paper we aim to outline an approach to interpreting preoperative CT scans in abdominal wall reconstruction (AWR). This approach breaks up the interpretive process into 4 steps-concentrating on the hernia or hernias, any complicating features of the hernia(s), the surrounding soft tissues and the abdominopelvic cavity as a whole-and was developed as a distillation of the authors' collective experience. We describe the key features that should be looked for at each of the four steps and the rationale for their inclusion.

Separating the components of an abdominal wall fellowship.

Complex abdominal wall reconstruction is an emerging subspecialty yet, despite the abundance of abdominal wall hernias requiring treatment and the increasing complexity of this type of surgery, there are few opportunities for surgeons to gain subspecialist training in this field. In this paper we discuss the need for focused training in complex abdominal wall reconstruction, outline some of the problems that may be hindering the availability of such opportunities and propose potential solutions to these issues.

Comprehensive multi-cohort transcriptional meta-analysis of muscle diseases identifies a signature of disease severity.

Muscle diseases share common pathological features suggesting common underlying mechanisms. We hypothesized there is a common set of genes dysregulated across muscle diseases compared to healthy muscle and that these genes correlate with severity of muscle disease. We performed meta-analysis of transcriptional profiles of muscle biopsies from human muscle diseases and healthy controls. Studies obtained from public microarray repositories fulfilling quality criteria were divided into six categories: (i) immobility, (ii) inflammatory myopathies, (iii) intensive care unit (ICU) acquired weakness (ICUAW), (iv) congenital muscle diseases, (v) chronic systemic diseases, (vi) motor neuron disease. Patient cohorts were separated in discovery and validation cohorts retaining roughly equal proportions of samples for the disease categories. To remove bias towards a specific muscle disease category we repeated the meta-analysis five times by removing data sets corresponding to one muscle disease class at a time in a "leave-one-disease-out" analysis. We used 636 muscle tissue samples from 30 independent cohorts to identify a 52 gene signature (36 up-regulated and 16 down-regulated genes). We validated the discriminatory power of this signature in 657 muscle biopsies from 12 additional patient cohorts encompassing five categories of muscle diseases with an area under the receiver operating characteristic curve of 0.91, 83% sensitivity, and 85.3% specificity. The expression score of the gene signature inversely correlated with quadriceps muscle mass (r = -0.50, p-value = 0.011) in ICUAW and shoulder abduction strength (r = -0.77, p-value = 0.014) in amyotrophic lateral sclerosis (ALS). The signature also positively correlated with histologic assessment of muscle atrophy in ALS (r = 0.88, p-value = 1.62 × 10-3) and fibrosis in muscular dystrophy (Jonckheere trend test p-value = 4.45 × 10-9). Our results identify a conserved transcriptional signature associated with clinical and histologic muscle disease severity. Several genes in this conserved signature have not been previously associated with muscle disease severity.

Physical activity recommendations pre and post abdominal wall reconstruction: a scoping review of the evidence.

PURPOSE: There are no universally agreed guidelines regarding which types of physical activity are safe and/or recommended in the perioperative period for patients undergoing ventral hernia repair or abdominal wall reconstruction (AWR). This study is intended to identify and summarise the literature on this topic. METHODS: Database searches of PubMed, CINAHL, Allied & Complementary medicine database, PEDro and Web of Science were performed followed by a snowballing search using two papers identified by the database search and four hand-selected papers of the authors' choosing. Inclusion-cohort studies, randomized controlled trials, prospective or retrospective. Studies concerning complex incisional hernia repairs and AWRs including a "prehabilitation" and/or "rehabilitation" program targeting the abdominal wall muscles in which the interventions were of a physical exercise nature. RoB2 and Robins-I were used to assess risk of bias. Prospero CRD42021236745. No external funding. Data from the included studies were extracted using a table based on the Cochrane Consumers and Communication Review Group's data extraction template. RESULTS: The database search yielded 5423 records. After screening two titles were selected for inclusion in our study. The snowballing search identified 49 records. After screening one title was selected for inclusion in our study. Three total papers were included-two randomised studies and one cohort study (combined 423 patients). All three studies subjected their patients to varying types of physical activity preoperatively, one study also prescribed these activities postoperatively. The outcomes differed between the studies therefore meta-analysis was impossible-two studies measured hernia recurrence, one measured peak torque. All three studies showed improved outcomes in their study groups compared to controls however significant methodological flaws and confounding factors existed in all three studies. No adverse events were reported. CONCLUSIONS: The literature supporting the advice given to patients regarding recommended physical activity levels in the perioperative period for AWR patients is sparse. Further research is urgently required on this subject.

Individualization of exosuit assistance based on measured muscle dynamics during versatile walking.

Variability in human walking depends on individual physiology, environment, and walking task. Consequently, in the field of wearable robotics, there is a clear need for customizing assistance to the user and task. Here, we developed a muscle-based assistance (MBA) strategy wherein exosuit assistance was derived from direct measurements of individuals' muscle dynamics during specific tasks. We recorded individuals' soleus muscle dynamics using ultrasonographic imaging during multiple walking speeds and inclines. From these prerecorded images, we estimated the force produced by the soleus through inefficient concentric contraction and designed the exosuit assistance profile to be proportional to that estimated force. We evaluated this approach with a bilateral ankle exosuit at each measured walking task. Compared with not wearing a device, the MBA ankle exosuit significantly reduced metabolic demand by an average of 15.9, 9.7, and 8.9% for level walking at 1.25, 1.5, and 1.75 meters second−1, respectively, and 7.8% at 1.25 meters second−1 at 5.71° incline while applying lower assistance levels than in existing literature. In an additional study (n = 2), we showed for multiple walking tasks that the MBA profile outperforms other bioinspired strategies and the average profile from a previous optimization study. Last, we show the feasibility of online assistance generation in a mobile version for overground outdoor walking. This muscle-based approach enables relatively rapid (~10 seconds) generation of individualized low-force assistance profiles that provide metabolic benefit. This approach may help support the adoption of wearable robotics in real-world, dynamic locomotor tasks by enabling comfortable, tailored, and adaptive assistance.

Theatre ventilation.

INTRODUCTION: Owing to the COVID-19 pandemic, there has been significant disruption to all surgical specialties. In the UK, units have cancelled elective surgery and a decrease in aerosol generating procedures (AGPs) was favoured. Centres around the world advocate the use of negative pressure environments for AGPs in reducing the spread of infectious airborne particles. We present an overview of operating theatre ventilation systems and the respective evidence with relation to surgical site infection (SSI) and airborne pathogen transmission in light of COVID-19. METHODS: A literature search was conducted using the PubMed, Cochrane Library and MEDLINE databases. Search terms included "COVID-19", "theatre ventilation", "laminar", "turbulent" and "negative pressure". FINDINGS: Evidence for laminar flow ventilation in reducing the rate of SSI in orthopaedic surgery is widely documented. There is little evidence to support its use in general surgery. Following previous viral outbreaks, some centres have introduced negative pressure ventilation in an attempt to decrease exposure of airborne pathogens to staff and surrounding areas. This has again been suggested during the COVID-19 pandemic. A limited number of studies show some positive results for the use of negative pressure ventilation systems and reduction in spread of pathogens; however, cost, accessibility and duration of conversion remain an unexplored issue. Overall, there is insufficient evidence to advocate large scale conversion at this time. Nevertheless, it may be useful for each centre to have its own negative pressure room available for AGPs and high risk patients.

Preoperative mechanical and oral antibiotic bowel preparation to reduce infectious complications of colorectal surgery - the need for updated guidelines.

BACKGROUND: Increasing evidence indicates that combined mechanical and oral antibiotic bowel preparation reduces the infectious complications of colorectal surgery. Anecdotal evidence suggests the combination is rarely used in the UK and Europe. AIM: To establish colorectal surgeons' current use and awareness of the benefits of such bowel preparation, and to identify decision-making influences surrounding preoperative bowel preparation. METHOD: An electronic survey was emailed to all members of the Association of Coloproctology of Great Britain and Ireland, and promoted via Twitter. FINDINGS: A total of 495 respondents completed the survey: 413 (83.2%) UK, 39 (7.9%) other European, 43 (8.7%) non-European. Respondents used oral antibiotics for 12-20% of cases. Mechanical bowel preparation (MBP), phosphate enema, and no preparation, respectively, ranged between 9 and 80%. Combined MBP and oral antibiotic bowel preparation ranged between 5.5 and 18.6%. Fifty-three percent (260/495) agreed that combined mechanical and oral antibiotic bowel preparation reduces surgical site infection; 32% (157/495) agreed that the combination reduces risk of anastomotic leak. Kappa statistics between 0.06 and 0.27 indicate considerable incongruity between surgeons' awareness of the literature, and day-to-day practice. Twenty-four percent (96/495) believed MBP to be incompatible with enhanced recovery after surgery (ERAS); 41% (204/495) believed that MBP delays return to normal intestinal function. CONCLUSIONS: Few UK and European colorectal surgeons use mechanical and oral antibiotic bowel preparation, despite evidence of its efficacy in reducing infectious complications. The influence of ERAS pathways and UK and European guidelines may explain this. In contradiction to the UK and Europe, North American guidelines recommend incorporating combined mechanical and oral antibiotic bowel preparation into ERAS programmes. This study suggests that future UK and European guidelines incorporate combined mechanical and oral antibiotic bowel preparation into the ERAS pathway.

The Association of Coloproctology of Great Britain and Ireland consensus guidelines in surgery for inflammatory bowel disease.

AIM: There is a requirement of an expansive and up to date review of surgical management of inflammatory bowel disease (IBD) that can dovetail with the medical guidelines produced by the British Society of Gastroenterology. METHODS: Surgeons who are members of the ACPGBI with a recognised interest in IBD were invited to contribute various sections of the guidelines. They were directed to produce a procedure based document using literature searches that were systematic, comprehensible, transparent and reproducible. Levels of evidence were graded. An editorial board was convened to ensure consistency of style, presentation and quality. Each author was asked to provide a set of recommendations which were evidence based and unambiguous. These recommendations were submitted to the whole guideline group and scored. They were then refined and submitted to a second vote. Only those that achieved >80% consensus at level 5 (strongly agree) or level 4 (agree) after 2 votes were included in the guidelines. RESULTS: All aspects of surgical care for IBD have been included along with 157 recommendations for management. CONCLUSION: These guidelines provide an up to date and evidence based summary of the current surgical knowledge in the management of IBD and will serve as a useful practical text for clinicians performing this type of surgery.

Post-operative C-reactive protein profile following abdominal wall reconstruction with transversus abdominis posterior components separation.

INTRODUCTION: Abdominal wall reconstruction using posterior component separation with transversus abdominis release (AWTAR) produces a unique post-operative CRP profile, when compared to routine elective colorectal operations. Therefore, we aim to establish the normal post-operative C-reactive protein (poCRP) profile following AWRTAR and reduce the unnecessary invasive interventions in patients already at greater risk of septic complications. METHODS: A retrospective analysis of daily poCRP levels was performed both for patients who underwent uncomplicated AWRTAR (n=12), and a comparator group of uncomplicated open right hemicolectomies (RH) matched for age and sex (n=24). All operations in both groups were performed by a single surgeon from 2013 to 2015. RESULTS: The median (IQR) age was 62 (16) and 67 (16) years respectively, with a higher proportion of males to females in both groups (10:2 vs. 17:7). The poCRP profile follows an initial steep rise, peaking at day 2 followed by a gradual washout phase. The poCRP peak is significantly greater in the AWRTAR group compared to the RH group (274 [95%CI ±25] vs. 160 [95%CI±27]; p=0.0001), with a positive correlation between day 2 CRP levels and operative length (r=0.56). CONCLUSIONS: We have demonstrated that uncomplicated AWRTAR provokes a significantly greater poCRP rise (>200) compared to that well described in the literature for uncomplicated open colectomy. As poCRP is an important marker of post-operative recovery with abnormally high levels associated with septic complications, these data should help clinicians interpret the post-operative clinical course after AWRTAR.

Assistance magnitude versus metabolic cost reductions for a tethered multiarticular soft exosuit.

When defining requirements for any wearable robot for walking assistance, it is important to maximize the user's metabolic benefit resulting from the exosuit assistance while limiting the metabolic penalty of carrying the system's mass. Thus, the aim of this study was to isolate and characterize the relationship between assistance magnitude and the metabolic cost of walking while also examining changes to the wearer's underlying gait mechanics. The study was performed with a tethered multiarticular soft exosuit during normal walking, where assistance was directly applied at the ankle joint and indirectly at the hip due to a textile architecture. The exosuit controller was designed such that the delivered torque profile at the ankle joint approximated that of the biological torque during normal walking. Seven participants walked on a treadmill at 1.5 meters per second under one unpowered and four powered conditions, where the peak moment applied at the ankle joint was varied from about 10 to 38% of biological ankle moment (equivalent to an applied force of 18.7 to 75.0% of body weight). Results showed that, with increasing exosuit assistance, net metabolic rate continually decreased within the tested range. When maximum assistance was applied, the metabolic rate of walking was reduced by 22.83 ± 3.17% relative to the powered-off condition (mean ± SEM).

Reducing the metabolic cost of running with a tethered soft exosuit.

Assisting hip extension with a tethered exosuit and a simulation-optimized force profile reduces metabolic cost of running.

Initial UK experience with transversus abdominis muscle release for posterior components separation in abdominal wall reconstruction of large or complex ventral hernias: a combined approach by general and plastic surgeons.

Introduction Large, complicated ventral hernias are an increasingly common problem. The transversus abdominis muscle release (TAMR) is a recently described modification of posterior components separation for repair of such hernias. We describe our initial experience with TAMR and sublay mesh to facilitate abdominal wall reconstruction. Methods The study is a retrospective review of patients undergoing TAMR performed synchronously by gastrointestinal and plastic surgeons. Results Twelve consecutive patients had their ventral hernias repaired using the TAMR technique from June 2013 to June 2014. Median body mass index was 30.8kg/m2 (range 19.0-34.4kg/m2). Four had a previous ventral hernia repair. Three had previous laparostomies. Four had previous stomas and three had stomas created at the time of the abdominal wall reconstruction. Average transverse distance between the recti was 13cm (3-20cm). Median operative time was 383 minutes (150-550 minutes) and mesh size was 950cm2 (532-2400cm2). Primary midline fascial closure was possible in all cases, with no bridging. Median length of hospital stay was 7.5 days (4-17 days). Three developed minor abdominal wall wound complications. At median review of 24 months (18-37 months), there have been no significant wound problems, mesh infections or explants, and none has developed recurrence of their midline ventral hernia. Visual analogue scales revealed high patient satisfaction levels overall and with their final aesthetic appearance. Conclusions We believe that TAMR offers significant advantages over other forms of components separation in this patient group. The technique can be adopted successfully in UK practice and combined gastrointestinal and plastic surgeon operating yields good results.

Exacerbation risk in severe asthma is stratified by inflammatory phenotype using longitudinal measures of sputum eosinophils.

BACKGROUND: Airway inflammatory phenotyping is increasingly applied to subjects with asthma. However, its relationship to clinical outcomes in difficult asthma is incompletely elucidated. OBJECTIVE: The goal of our study was to determine the relationship between exacerbation rates and phenotypes of difficult asthma based on the longitudinal measures of sputum eosinophils and neutrophils. METHODS: Subjects in the longitudinal observational study from two tertiary care centres that completed 1 year of observation and provided at least three sputum samples were classified by inflammatory phenotypes using previously established thresholds. Kaplan-Meier curves and univariable and multivariable Cox proportional hazard models were used to determine the association between inflammatory phenotypes and exacerbation rate. RESULTS: During the study, 115 exacerbations occurred in 73 severe asthmatic subjects. Subjects with the persistently eosinophilic phenotype had a significantly shorter time to first exacerbation and greater risk of exacerbation over a 1-year period than those with the non-eosinophilic phenotype based on the univariable and multivariable Cox proportional hazard model (hazard ratio [HR], 3.24; 95% confidence interval [CI], 1.35-7.72; adjusted HR, 3.90; 95% CI, 1.34-11.36). No significant differences in time to first exacerbation or exacerbation risk over a 1-year period were observed among the neutrophilic phenotypes. CONCLUSIONS: The persistent eosinophilic phenotype is associated with increased exacerbation risk compared with the non-eosinophilic phenotype in severe asthma. No differences in time to first exacerbation or exacerbation risk over a 1-year period were detected among neutrophilic phenotypes.

Phenotyping of difficult asthma using longitudinal physiological and biomarker measurements reveals significant differences in stability between clusters.

BACKGROUND: Although the heterogeneous nature of asthma has prompted asthma phenotyping with physiological or biomarker data, these studies have been mostly cross-sectional. Longitudinal studies that assess the stability of phenotypes based on a combination of physiological, clinical and biomarker data are currently lacking. Our objective was to assess the longitudinal stability of clusters derived from repeated measures of airway and physiological data over a 1-year period in moderate and severe asthmatics. METHODS: A total of 125 subjects, 48 with moderate asthma (MA) and 77 with severe asthma (SA) were evaluated every 3 months and monthly, respectively, over a 1-year period. At each 3-month time point, subjects were grouped into 4 asthma clusters (A, B, C, D) based on a combination of clinical (duration of asthma), physiological (FEV1 and BMI) and biomarker (sputum eosinophil count) variables, using k-means clustering. RESULTS: Majority of subjects in clusters A and C had severe asthma (93 % of subjects in cluster A and 79.5 % of subjects in cluster C at baseline). Overall, a total of 59 subjects (47 %) had stable cluster membership, remaining in clusters with the same subjects at each evaluation time. Cluster A was the least stable (21 % stability) and cluster B was the most stable cluster (71 % stability). Cluster stability was not influenced by changes in the dosage of inhaled corticosteroids. CONCLUSION: Asthma phenotyping based on clinical, physiologic and biomarker data identified clusters with significant differences in longitudinal stability over a 1-year period. This finding indicates that the majority of patients within stable clusters can be phenotyped with reasonable accuracy after a single measurement of lung function and sputum eosinophilia, while patients in unstable clusters will require more frequent evaluation of these variables to be properly characterized.