Outcomes reported in randomised trials of surgical prehabilitation: a scoping review.

BACKGROUND: Heterogeneity of reported outcomes can impact the certainty of evidence for prehabilitation. The objective of this scoping review was to systematically map outcomes and assessment tools used in trials of surgical prehabilitation. METHODS: MEDLINE, EMBASE, PsychInfo, Web of Science, CINAHL, and Cochrane were searched in February 2023. Randomised controlled trials of unimodal or multimodal prehabilitation interventions (nutrition, exercise, psychological support) lasting at least 7 days in adults undergoing elective surgery were included. Reported outcomes were classified according to the International Society for Pharmacoeconomics and Outcomes Research framework. RESULTS: We included 76 trials, mostly focused on abdominal or orthopaedic surgeries. A total of 50 different outcomes were identified, measured using 184 outcome assessment tools. Observer-reported outcomes were collected in 86% of trials (n=65), with hospital length of stay being most common. Performance outcomes were reported in 80% of trials (n=61), most commonly as exercise capacity assessed by cardiopulmonary exercise testing. Clinician-reported outcomes were included in 78% (n=59) of trials and most frequently included postoperative complications with Clavien-Dindo classification. Patient-reported outcomes were reported in 76% (n=58) of trials, with health-related quality of life using the 36- or 12-Item Short Form Survey being most prevalent. Biomarker outcomes were reported in 16% of trials (n=12) most commonly using inflammatory markers assessed with C-reactive protein. CONCLUSIONS: There is substantial heterogeneity in the reporting of outcomes and assessment tools across surgical prehabilitation trials. Identification of meaningful outcomes, and agreement on appropriate assessment tools, could inform the development of a prehabilitation core outcomes set to harmonise outcome reporting and facilitate meta-analyses.

Towards a common definition of surgical prehabilitation: a scoping review of randomised trials.

BACKGROUND: There is no universally accepted definition for surgical prehabilitation. The objectives of this scoping review were to (1) identify how surgical prehabilitation is defined across randomised controlled trials and (2) propose a common definition. METHODS: The final search was conducted in February 2023 using MEDLINE, Embase, PsycINFO, Web of Science, CINAHL, and Cochrane. We included randomised controlled trials (RCTs) of unimodal or multimodal prehabilitation interventions (nutrition, exercise, and psychological support) lasting at least 7 days in adults undergoing elective surgery. Qualitative data were analysed using summative content analysis. RESULTS: We identified 76 prehabilitation trials of patients undergoing abdominal (n=26, 34%), orthopaedic (n=20, 26%), thoracic (n=14, 18%), cardiac (n=7, 9%), spinal (n=4, 5%), and other (n=5, 7%) surgeries. Surgical prehabilitation was explicitly defined in more than half of these RCTs (n=42, 55%). Our findings consolidated the following definition: 'Prehabilitation is a process from diagnosis to surgery, consisting of one or more preoperative interventions of exercise, nutrition, psychological strategies and respiratory training, that aims to enhance functional capacity and physiological reserve to allow patients to withstand surgical stressors, improve postoperative outcomes, and facilitate recovery.' CONCLUSIONS: A common definition is the first step towards standardisation, which is needed to guide future high-quality research and advance the field of prehabilitation. The proposed definition should be further evaluated by international stakeholders to ensure that it is comprehensive and globally accepted.

Reporting quality of randomized controlled trials in prehabilitation: a scoping review.

BACKGROUND: Inadequate study reporting precludes interpretation of findings, pooling of results in meta-analyses, and delays knowledge translation. While prehabilitation interventions aim to enhance candidacy for surgery, to our knowledge, a review of the quality of reporting in prehabilitation has yet to be conducted. Our objective was to determine the extent to which randomized controlled trials (RCTs) of prehabilitation are reported according to methodological and intervention reporting checklists. METHODS: Eligibility criteria: RCTs of unimodal or multimodal prehabilitation interventions. SOURCES OF EVIDENCE: search was conducted in March 2022 using MEDLINE, Embase, PsychINFO, Web of Science, CINAHL, and Cochrane. CHARTING METHODS: identified studies were compared to CONSORT, CERT & Modified CERT, TIDieR, PRESENT, and CONSORT-SPI. An agreement ratio (AR) was defined to evaluate if applicable guideline items were correctly reported. Data were analyzed as frequency (n, %) and mean with standard deviation (SD). RESULTS: We identified 935 unique articles and included 70 trials published from 1994 to 2022. Most prehabilitation programs comprised exercise-only interventions (n = 40, 57%) and were applied before oncologic surgery (n = 32, 46%). The overall mean AR was 57% (SD: 20.9%). The specific mean ARs were as follows: CONSORT: 71% (SD: 16.3%); TIDieR: 62% (SD:17.7%); CERT: 54% (SD: 16.6%); Modified-CERT: 40% (SD:17.8%); PRESENT: 78% (SD: 8.9); and CONSORT-SPI: 47% (SD: 22.1). CONCLUSION: Altogether, existing prehabilitation trials report approximately half of the checklist items recommended by methodological and intervention reporting guidelines. Reporting practices may improve with the development of a reporting checklist specific to prehabilitation interventions.

Relationship between Adherence to the 2019 Canada's Food Guide Recommendations on Healthy Food Choices and Nutrient Intakes in Older Adults.

BACKGROUND: Following Canada's food guide (CFG) recommendations should ensure adequate nutrient intakes. Older adults have increased needs for certain nutrients and nutrient density; the extent to which adherence to CFG recommendations can help reduce inadequate nutrient intakes is unknown. OBJECTIVES: We aimed to assess the relationship between adherence to CFG recommendations on healthy food choices and intake of key nutrients in adults 65 y and older from the Canadian Community Health Survey 2015 - Nutrition. METHODS: Secondary analysis of data from 4093 older adults of the Canadian Community Health Survey 2015 - Nutrition (mean age, 73.6 y, 54% females). Dietary intakes were measured using an interviewer-administered 24-h dietary recall, including 1 repeat in a subsample (42%). The National Cancer Institute multivariate method was used to estimate usual (i.e., long-term) dietary intakes. Adherence to CFG recommendations was measured using the Healthy Eating Food Index (HEFI)-2019 score. Simple linear and logistic regression models estimated the effect of increased HEFI-2019 score on usual nutrient intakes and the prevalence of inadequate nutrient intakes (i.e., below the estimated average requirements), respectively. RESULTS: Compared with the prevalence of inadequate intakes at median HEFI-2019 score (46.4/80 points), a higher HEFI-2019 (+11 points) was associated with reductions in the prevalence of inadequate intakes of magnesium, vitamin B6 and protein [-19.8% (95% confidence interval (CI): -30.8, -8.9), -12.7% (95% CI: -22.5, -3.0), and -4.7% (95% CI: -9.4, -0.1), respectively]. In contrast, data for higher HEFI-2019 scores were compatible with increased prevalence of inadequate intakes of folate, vitamin D, and calcium [4.0% (95% CI: -8.4, 16.3), 2.6% (95% CI: 1.1, 4.0), and 2.3% (95% CI: -3.0, 7.5), respectively]. CONCLUSIONS: Based on dietary intakes of Canadian older adults in 2015, increasing the degree of adherence to CFG recommendations on healthy food choices may reduce nutrient intake inadequacy for most key nutrients except folate, vitamin D, and calcium.

Lifestyle Behavior Changes and Associated Risk Factors During the COVID-19 Pandemic: Results from the Canadian COVIDiet Online Cohort Study.

BACKGROUND: The COVID-19 pandemic and related lockdowns have impacted lifestyle behaviors, including eating habits and physical activity; yet, few studies have identified the emerging patterns of such changes and associated risk factors. OBJECTIVE: This study aims to identify the patterns of weight and lifestyle behavior changes, and the potential risk factors, resulting from the pandemic in Canadian adults. METHODS: Analyses were conducted on 1609 adults (18-89 years old; n=1450, 90.1%, women; n=1316, 81.8%, White) of the Canadian COVIDiet study baseline data (May-December 2020). Self-reported current and prepandemic weight, physical activity, smoking status, perceived eating habits, alcohol intake, and sleep quality were collected through online questionnaires. Based on these 6 indicator variables, latent class analysis (LCA) was used to identify lifestyle behavior change patterns. Associations with potential risk factors, including age, gender, ethnicity, education, income, chronic diseases, body image perception, and changes in the stress level, living situation, and work arrangement, were examined with logistic regressions. RESULTS: Participants' mean BMI was 26.1 (SD 6.3) kg/m2. Of the 1609 participants, 980 (60.9%) had a bachelor's degree or above. Since the pandemic, 563 (35%) had decreased income and 788 (49%) changed their work arrangement. Most participants reported unchanged weight, sleep quality, physical activity level, and smoking and alcohol consumption, yet 708 (44%) reported a perceived decrease in eating habit quality. From LCA, 2 classes of lifestyle behavior change emerged: healthy and less healthy (probability: 0.605 and 0.395, respectively; Bayesian information criterion [BIC]=15574, entropy=4.8). The healthy lifestyle behavior change group more frequently reported unchanged weight, sleep quality, smoking and alcohol intake, unchanged/improved eating habits, and increased physical activity. The less healthy lifestyle behavior change group reported significant weight gain, deteriorated eating habits and sleep quality, unchanged/increased alcohol intake and smoking, and decreased physical activity. Among risk factors, body image dissatisfaction (odds ratio [OR] 8.8, 95% CI 5.3-14.7), depression (OR 1.8, 95% CI 1.3-2.5), increased stress level (OR 3.4, 95% CI 2.0-5.8), and gender minority identity (OR 5.5, 95% CI 1.3-22.3) were associated with adopting less healthy behaviors in adjusted models. CONCLUSIONS: The COVID-19 pandemic has appeared to have influenced lifestyle behaviors unfavorably in some but favorably in others. Body image perception, change in stress level, and gender identity are factors associated with behavior change patterns; whether these will sustain over time remains to be studied. Findings provide insights into developing strategies for supporting adults with poorer mental well-being in the postpandemic context and promoting healthful behaviors during future disease outbreaks. TRIAL REGISTRATION: ClinicalTrials.gov NCT04407533; https://clinicaltrials.gov/ct2/show/NCT04407533.

Altered serum bile acid profile in fibromyalgia is associated with specific gut microbiome changes and symptom severity.

ABSTRACT: Alterations in the composition and function of the gut microbiome in women with fibromyalgia have recently been demonstrated, including changes in the relative abundance of certain bile acid-metabolizing bacteria. Bile acids can affect multiple physiological processes, including visceral pain, but have yet to be explored for association to the fibromyalgia gut microbiome. In this study, 16S rRNA sequencing and targeted metabolomic approaches were used to characterize the gut microbiome and circulating bile acids in a cohort of 42 women with fibromyalgia and 42 healthy controls. Alterations in the relative abundance of several bacterial species known to metabolize bile acids were observed in women with fibromyalgia, accompanied by significant alterations in the serum concentration of secondary bile acids, including a marked depletion of α-muricholic acid. Statistical learning algorithms could accurately detect individuals with fibromyalgia using the concentration of these serum bile acids. Serum α-muricholic acid was highly correlated with symptom severity, including pain intensity and fatigue. Taken together, these findings suggest serum bile acid alterations are implicated in nociplastic pain. The changes observed in the composition of the gut microbiota and the concentration of circulating secondary bile acids seem congruent with the phenotype of increased nociception and are quantitatively correlated with symptom severity. This is a first demonstration of circulating bile acid alteration in individuals with fibromyalgia, potentially secondary to upstream gut microbiome alterations. If corroborated in independent studies, these observations may allow for the development of molecular diagnostic aids for fibromyalgia as well as mechanistic insights into the syndrome.

Dietary Intake Is Unlikely to Explain Symptom Severity and Syndrome-Specific Microbiome Alterations in a Cohort of Women with Fibromyalgia.

BACKGROUND: Significant alterations were recently identified in the composition and putative function of the gut microbiome in women with fibromyalgia. As diet can influence the composition of the gut microbiome, differences in nutritional intake could, in theory, account for some of these specific fibromyalgia microbiome alterations. The current study aims to compare the diet of women with fibromyalgia to that of controls in order to explore possible associations between the intake of certain nutrients, symptom severity and gut microbiome composition. METHODS: The study population was comprised of 56 women with fibromyalgia and 68 controls. Dietary intake was assessed using the NIH Automated Self-Administered 24 h recall, following dietitian's instructions and the completion of a three-day dietary recall. The gut microbiome was assessed by 16S ribosomal RNA gene sequencing of stool samples. RESULTS: Most demographic and anthropometric characteristics were comparable between groups. The average energy and macronutrient intake (total and relative) and overall diet quality score were not different between patients and controls, nor were the main vitamins, minerals, fatty acids, alcohol, caffeine, sugar or fiber intakes. The daily intake of micronutrients and normalized macronutrients in women with fibromyalgia was largely not correlated with disease-specific measures, including pain intensity, fatigue, cognitive symptoms and quality of sleep, or with the relative quantity of almost any of the gut microbiome bacterial taxa differentially abundant in fibromyalgia. CONCLUSION: These data demonstrate that dietary intakes, as evaluated by self-reported questionnaires, probably cannot explain the syndrome-specific differences in gut microbiome or the clinical phenotype of fibromyalgia.

A 16-week randomized controlled trial of a fish oil and whey protein-derived supplement to improve physical performance in older adults losing autonomy-A pilot study.

BACKGROUND: Low functional capacity may lead to the loss of independence and institutionalization of older adults. A nutritional intervention within a rehabilitation program may attenuate loss of muscle function in this understudied population. OBJECTIVE: This pilot study assessed the feasibility for a larger RCT of a nutritional supplementation in older adults referred to an outpatient assessment and rehabilitation program. METHODS: Participants were randomized to receive a supplement (EXP: 2g fish oil with 1500 IU vitamin D3 1x/d + 20-30g whey protein powder with 3g leucine 2x/d) or isocaloric placebo (CTR: corn oil + maltodextrin powder) for 16 weeks. Handgrip and knee extension strength (using dynamometry), physical performance tests and plasma phospholipid n-3 fatty acids (using GCMS) were evaluated at weeks 0, 8 and 16; and lean soft tissue mass (using DXA), at weeks 0 and 16. RESULTS: Over 2 years, 244 patients were screened, 46 were eligible (18.9%), 20 were randomized, 10 completed the study (6 CTR, 4 EXP). Median age was 87 y (77-94 y; 75% women) and gait speed was 0.69 m/s; 55% had low strength, and all performed under 420m on the 6-minute walk test, at baseline. Overall self-reported compliance to powder and oil was high (96% and 85%) but declined at 16 weeks for fish oil (55%). The EXP median protein intake surpassed the target 1.2-1.5 g/kg/d, without altering usual diet. Proportions of plasma phospholipid EPA and DHA increased significantly 3- and 1.5-fold respectively, at week 8 in EXP, with no change in CTR. Participants were able to complete most assessments with sustained guidance. CONCLUSION: Because of low eligibility, the pilot study was interrupted and deemed non-feasible; adherence to rigorous study assessments and to supplements was adequate except for long-term fish oil. The non-amended protocol may be applied to populations with greater functional capacity. TRIAL REGISTRATION: ClinicalTrials.gov NCT04454359.

Feasibility of a novel mixed-nutrient supplement in a multimodal prehabilitation intervention for lung cancer patients awaiting surgery: A randomized controlled pilot trial.

OBJECTIVE: To investigate, in lung cancer patients awaiting elective surgery, the feasibility of delivering a novel four-week multimodal prehabilitation intervention and its effects on preoperative functional capacity and health-related quality of life (HRQoL), compared to standard hospital care. METHODS: Adult patients awaiting elective thoracotomy for lung cancer stages I, II or IIIa, were approached to participate in an open-label, randomized controlled trial of two parallel arms: multimodal prehabilitation combining a mixed-nutrient supplement with structured supervised and home-based exercise training, and relaxation-strategies (Prehab) or standard hospital care (Control). Feasibility was assessed based on recruitment and adherence rates to the intervention and study outcome assessment. Functional capacity, measured by the 6-min walk test (6MWT), and HRQoL were measured at baseline and after four weeks (preoperative). RESULTS: Within 5 months, 34 patients were enrolled and randomized (2:1) to Prehab (n = 24; median age = 67 years) or Control (n = 10; median age = 69 years); recruitment rate of 58.6%. The study was interrupted by the COVID-19 pandemic. Adherence to the prescribed intensity of the supervised exercise program was 84.1% (SD 23.1). Self-reported adherence to the home-based exercise program was 88.2% (SD 21) and to the nutritional supplement, 93.2% (SD 14.2). Adherence to patients' preoperative assessment was 82% and 88% in Prehab and Control, respectively. The mean adjusted difference in 4-week preoperative 6MWT between groups was 37.7 m (95% CI, -6.1 to 81.4), p = 0.089. There were no differences in HRQoL between groups. CONCLUSION: Within a preoperative timeframe, it was feasible to deliver this novel multimodal prehabilitation intervention in lung cancer patients awaiting surgery.

Effects of multimodal prehabilitation on muscle size, myosteatosis, and dietary intake of surgical patients with lung cancer - a randomized feasibility study.

Many patients with lung cancer undergo surgery, which can increase the risk for muscle loss, leading to worsened outcomes. A multimodal prehabilitation intervention integrating dietary and muscle assessment may help clinicians better understand changes in these outcomes. This pilot assessed feasibility of multimodal prehabilitation in early-stage surgical lung cancer patients and explored relationships between body composition, muscle characteristics and dietary intake, as well as muscle changes due to prehabilitation. Patients were randomized to 1 of 2 groups: multimodal prehabilitation including nutritional supplements (fish oil with vitamin D3 + whey protein with leucine), exercise and relaxation, or standard of care. Physical function, dietary intake and muscle were evaluated at 0 and 4 weeks pre-operatively. Of 87 patients assessed for eligibility, 34 (39%) were randomized and 3 (9%) were lost to follow-up. Median age was 69 years and baseline protein intake was 1.0 g/kg/day. Adherence to exercise (86%) and supplements was high (93%); 3 patients (16%) reported side effects. Supplements significantly increased protein, omega-3 fatty acid, leucine and vitamin D intake. There were no significant changes in muscle characteristics. Multimodal prehabilitation with dietary and muscle analyses proved to be feasible. An adequately powered randomized controlled trial is warranted. ClinicalTrials.gov registration no: NCT04610606. Novelty: Multimodal prehabilitation incorporating dietary assessment and muscle analysis is feasible for early-stage surgical lung cancer patients. An adequately powered randomized controlled trial is warranted to further explore functional and post-operative outcomes.

Effects of preoperative nutrition and multimodal prehabilitation on functional capacity and postoperative complications in surgical lung cancer patients: a systematic review.

OBJECTIVE: To determine the effect of preoperative nutrition and multimodal prehabilitation on clinical and functional outcomes in surgical lung cancer patients. METHODS: We searched MEDLINE, Cochrane Library and CENTRAL, EMBASE, Scopus, and clinical trial registries ( clinicaltrials.gov , International Clinical Trials Registry Platform and Google Scholar) to identify studies involving a preoperative nutrition-based intervention or multimodal prehabilitation (nutrition with exercise) of at least 7 days, in lung cancer patients awaiting surgery. Studies must have reported results on at least one of the following outcomes: functional capacity, pulmonary function, postoperative complications, and length of hospital stay. The quality of included studies was assessed using the Cochrane risk of bias assessment tool for randomized trials and the modified Newcastle-Ottawa scale for non-controlled trials. RESULTS: Five studies were included (1 nutrition-only and 4 multimodal prehabilitation studies). Due to substantial heterogeneity in the interventions across studies, a meta-analysis was not conducted. Findings suggest that multimodal prehabilitation, compared with standard hospital care, is associated with improvements in both functional walking capacity and pulmonary function during the preoperative period; however it does not appear to have an effect on postoperative outcomes. Rather, the finding of significantly lower rates of postoperative complications in the intervention group was unique to the nutrition-only study. CONCLUSION: Multimodal prehabilitation programs that combine nutrition and exercise may have beneficial effects on various physical function outcomes in patients with lung cancer awaiting surgery. Optimizing preoperative nutrition may have postoperative benefits which remain to be confirmed.

Malnourished lung cancer patients have poor baseline functional capacity but show greatest improvements with multimodal prehabilitation.

OBJECTIVE: The objective is to characterize the presence of malnutrition, examine the association between malnutrition and baseline functional capacity (FC), and the extent to which patients benefit from preoperative multimodal prehabilitation in patients undergoing lung resection for cancer. METHODS: Data from 162 participants enrolled in multimodal prehabilitation or control before lung cancer surgery were analyzed. Malnutrition was measured using the Patient-Generated Subjective Global Assessment (PG-SGA) according to triage levels: low-nutrition-risk (PG-SGA 0-3), moderate-nutrition-risk (4-8) and high-nutrition-risk (≥9). Baseline differences in FC, measured by the 6-minute walk test (6MWT), were compared. Factorial analysis of covariance (ANCOVA) was conducted to examine the effect of nutrition status and intervention on mean change in 6MWT preoperatively. RESULTS: 51.2% patients were considered low-nutrition-risk, 37.7% moderate-nutrition-risk, and 11.1% high-nutrition-risk. Low-nutrition-risk patients had significantly higher 6MWT at baseline (mean of 484 m [standard deviation (SD) = 88]) compared with moderate-nutrition-risk (432 m [SD = 107], P = .005) and high-nutrition-risk groups (416 m [SD = 90], P = .022). The adjusted mean change in 6MWT between prehabilitation vs control was 18.1 (95% confidence interval, 3.8 to 32.3) vs 5.6 m (-14.1 to 25.4) in low-nutrition-risk (P = .309), 28.5 (11 to 46) vs -4 m (-31.3 to 23.4) in moderate-nutrition-risk (P = .053), and 58.9 (16.7 to 101.2) vs -39.7 m (-80.2 to 0.826) in high-nutrition-risk group (P = .001). CONCLUSIONS: Lung cancer patients at high-nutrition-risk awaiting surgery had significantly lower baseline FC compared with low-nutrition-risk patients but experienced significant improvements in preoperative FC upon receiving multimodal prehabilitation.

Physical function-derived cut-points for the diagnosis of sarcopenia and dynapenia from the Canadian longitudinal study on aging.

BACKGROUND: Aging is associated with sarcopenia (low muscle mass) and dynapenia (low muscle strength) leading to disability and mortality. Widely used previous cut-points for sarcopenia were established from dated, small, or pooled cohorts. We aimed to identify cut-points of low strength as a determinant of impaired physical performance and cut-points of low appendicular lean mass (ALM) as a predictor of low strength in a single, large, and contemporary cohort of community-dwelling older adults and compare these criteria with others. METHODS: Cross-sectional analyses were conducted on baseline data from 4725 and 4363 community-dwelling men and women (65-86 years, 96.8% Caucasian) of the Canadian longitudinal study on aging comprehensive cohort. Physical performance was evaluated from gait speed, timed up-and-go, chair rise, and balance tests; a weighted-sum score was computed using factor analysis. Strength was measured by handgrip dynamometry; ALM, by dual-energy X-ray absorptiometry and ALM index (ALMI; kg/m2 ), was calculated. Classification and regression tree analyses determined optimal sex-specific cut-points of ALMI predicting low strength and of strength predicting impaired physical performance (score < 1.5 SD below the sex-specific mean). RESULTS: Modest associations were found between ALMI and strength and between strength and physical performance score in both sexes. ALMI was not an independent predictor of physical performance score. Cut-points of <33.1 and <20.4 kg were found to define dynapenia in men and in women, respectively, corresponding to 21.5% and 24.0% prevalence rates. Sarcopenia cut-points were <7.76 kg/m2 in men and <5.72 kg/m2 in women; prevalence rates of 21.7% and 13.7%. Overall, 8.3% of men and 5.5% of women had sarco-dynapenia. Sarcopenic were older and had lower fat mass and body mass index (BMI) than non-sarcopenic participants. While the agreement between current criteria and the updated European Working Group for Sarcopenia in Older Persons recommendations was fair, we found only slight agreement with the Foundation for the National Institute of Health sarcopenia project. Older persons identified with sarcopenia as per the Foundation for the National Institute of Health criteria (using ALM/BMI as the index) have higher BMI and fat mass compared with non-sarcopenic and have normal ALMI as per our criteria. CONCLUSIONS: The proposed function-derived cut-points established from this single, large, and contemporary Canadian cohort should be used for the identification of sarcopenia and dynapenia in Caucasian older adults. We advise on using criteria based on ALMI in the diagnosis of sarcopenia. The modest agreement between sarcopenia and dynapenia denotes potential distinct health implications justifying to study both components separately.

Altered microbiome composition in individuals with fibromyalgia.

Fibromyalgia (FM) is a prevalent syndrome, characterised by chronic widespread pain, fatigue, and impaired sleep, that is challenging to diagnose and difficult to treat. The microbiomes of 77 women with FM and that of 79 control participants were compared using 16S rRNA gene amplification and whole-genome sequencing. When comparing FM patients with unrelated controls using differential abundance analysis, significant differences were revealed in several bacterial taxa. Variance in the composition of the microbiomes was explained by FM-related variables more than by any other innate or environmental variable and correlated with clinical indices of FM. In line with observed alteration in butyrate-metabolising species, targeted serum metabolite analysis verified differences in the serum levels of butyrate and propionate in FM patients. Using machine-learning algorithms, the microbiome composition alone allowed for the classification of patients and controls (receiver operating characteristic area under the curve 87.8%). To the best of our knowledge, this is the first demonstration of gut microbiome alteration in nonvisceral pain. This observation paves the way for further studies, elucidating the pathophysiology of FM, developing diagnostic aids and possibly allowing for new treatment modalities to be explored.

Modulation by Polymyxin-B Hemoperfusion of Inflammatory Response Related to Severe Peritonitis.

Conflicting results have been reported on the influence of Polymyxin-B hemoperfusion treatment on systemic inflammation markers. The aim of the study was to assess in a randomized control trial the influence on plasma cytokine concentrations of Polymyxin-B hemoperfusion in septic shock due to peritonitis. A panel of 10 pro- or anti-inflammatory cytokines was measured in 213 patients with peritonitis-induced septic shock enrolled in the randomized trial ABDOMIX testing the impact of 2 Polymyxin-B hemoperfusion sessions with standard treatment. Gram-negative bacteria were identified in 69% of patients. In the overall population, baseline plasma cytokine concentrations were not different between the two groups. Circulating tumor necrosis factor-α, interleukin (IL)-1ß, IL-10, IL-6, and IL-1RA decreased significantly over time in both groups (P <0.0001 for all in controls, and P = 0.0002, 0.003, and <0.0001 in patients treated with Polymyxin-B hemoperfusion). IL-17A decreased significantly in patients treated with Polymyxin B hemoperfusion (P = 0.045) but not in controls. At the end of the second Polymyxin-B hemoperfusion session or at corresponding time in controls, plasma levels of cytokines did not differ between the two groups. Similar results were found in the subgroup of patients with gram-negative peritonitis who completed two Polymyxin-B hemoperfusion sessions. These results do not support a significant influence of Polymyxin-B hemoperfusion on circulating cytokines assessed except for IL-17A which clinical significance remains to be elucidated.

The impact of ageing, physical activity, and pre-frailty on skeletal muscle phenotype, mitochondrial content, and intramyocellular lipids in men.

BACKGROUND: The exact impact of ageing on skeletal muscle phenotype and mitochondrial and lipid content remains controversial, probably because physical activity, which greatly influences muscle physiology, is rarely accounted for. The present study was therefore designed to investigate the effects of ageing, physical activity, and pre-frailty on skeletal muscle phenotype, and mitochondrial and intramyocellular lipid content in men. METHODS: Recreationally active young adult (20-30 yo; YA); active (ACT) and sedentary (SED) middle-age (50-65 yo; MA-ACT and MA-SED); and older (65 + yo; 65 + ACT and 65 + SED) and pre-frail older (65 + PF) men were recruited. Muscle biopsies from the vastus lateralis were collected to assess, on muscle cross sections, muscle phenotype (using myosin heavy chain isoforms immunolabelling), the fibre type-specific content of mitochondria (by quantifying the succinate dehydrogenase stain intensity), and the fibre type-specific lipid content (by quantifying the Oil Red O stain intensity). RESULTS: Only 65 + SED and 65 + PF displayed significantly lower overall and type IIa fibre sizes vs. YA. 65 + SED displayed a lower type IIa fibre proportion vs. YA. MA-SED and 65 + SED displayed a higher hybrid type IIa/IIx fibre proportion vs. YA. Sedentary and pre-frail, but not active, men displayed lower mitochondrial content irrespective of fibre type vs. YA. 65 + SED, but not 65 + ACT, displayed a higher lipid content in type I fibres vs. YA. Finally, mitochondrial content, but not lipid content, was positively correlated with indices of muscle function, functional capacity, and insulin sensitivity across all subjects. CONCLUSIONS: Taken altogether, our results indicate that ageing in sedentary men is associated with (i) complex changes in muscle phenotype preferentially affecting type IIa fibres; (ii) a decline in mitochondrial content affecting all fibre types; and (iii) an increase in lipid content in type I fibres. They also indicate that physical activity partially protects from the effects of ageing on muscle phenotype, mitochondrial content, and lipid accumulation. No skeletal specific muscle phenotype of pre-frailty was observed.

Inactivation of the ubiquitin-specific protease 19 deubiquitinating enzyme protects against muscle wasting.

The ubiquitin system plays a critical role in muscle wasting. Previous work has focused on the roles of ubiquitination. However, a role for deubiquitination in this process has not been established. Because ubiquitin-specific protease (USP)19 deubiquitinating enzyme is induced in skeletal muscle in many catabolic conditions, we generated USP19 knockout (KO) mice. These mice lost less muscle mass than wild-type (WT) animals in response to glucocorticoids, a common systemic cause of muscle atrophy as well as in response to denervation, a model of disuse atrophy. KO mice retained more strength and had less myofiber atrophy with both type I and type IIb fibers being protected. Rates of muscle protein synthesis were similar in WT and KO mice, suggesting that the sparing of atrophy was attributed to suppressed protein degradation. Consistent with this, expression of the ubiquitin ligases MuRF1 and MAFbx/atrogin-1 as well as several autophagy genes was decreased in the muscles of catabolic KO mice. Expression of USP19 correlates with that of MuRF1 and MAFbx/atrogin-1 in skeletal muscles from patients with lung cancer or gastrointestinal cancer, suggesting that USP19 is involved in human muscle wasting. Inhibition of USP19 may be a useful approach to the treatment of many muscle-wasting conditions.

Anthracycline-containing chemotherapy causes long-term impairment of mitochondrial respiration and increased reactive oxygen species release in skeletal muscle.

Anticancer treatments for childhood acute lymphoblastic leukaemia (ALL) are highly effective but are now implicated in causing impaired muscle function in long-term survivors. However, no comprehensive assessment of skeletal muscle mitochondrial functions in long-term survivors has been performed and the presence of persistent chemotherapy-induced skeletal muscle mitochondrial dysfunction remains a strong possibility. Non-tumour-bearing mice were treated with two drugs that have been used frequently in ALL treatment (doxorubicin and dexamethasone) for up to 4 cycles at 3-week intervals and euthanized 3 months after the 4th cycle. Treated animals had impaired growth and lower muscle mass as well as reduced mitochondrial respiration and increased reactive oxygen species production per unit oxygen consumption. Mitochondrial DNA content and protein levels of key mitochondrial membrane proteins and markers of mitochondrial biogenesis were unchanged, but protein levels of Parkin were reduced. This suggests a novel pattern of chemotherapy-induced mitochondrial dysfunction in skeletal muscle that persists because of an acquired defect in mitophagy signaling. The results could explain the observed functional impairments in adult survivors of childhood ALL and may also be relevant to long-term survivors of other cancers treated with similar regimes.

Cancer cachexia and diabetes: similarities in metabolic alterations and possible treatment.

Cancer cachexia is a metabolic syndrome featuring many alterations typical of type 2 diabetes (T2D). While muscle wasting is a hallmark of cachexia, epidemiological evidence also supports an accelerated age-related muscle loss in T2D. Insulin resistance manifests in both conditions and impairs glucose disposal and protein anabolism by tissues. A greater contribution of gluconeogenesis to glucose production may limit amino acid availability for muscle protein synthesis, further aggravating muscle loss. In the context of inter-dependence between glucose and protein metabolism, the present review summarizes the current state of knowledge on alterations that may lead to muscle wasting in human cancer. By highlighting the similarities with T2D, a disease that has been more extensively studied, the objective of this review is to provide a better understanding of the pathophysiology of cancer cachexia and to consider potential treatments usually targeted for T2D. Nutritional approaches aimed at stimulating protein anabolism might include specially formulated food with optimal protein and amino acid composition. Because the gradual muscle loss in T2D may be attenuated by diabetes treatment, anti-diabetic drugs might be considered in cachexia treatment. Metformin emerges as a choice candidate as it acts both on reducing gluconeogenesis and improving insulin sensitivity, and has demonstrated tumour suppressor properties in multiple cancer types. Such a multimodal approach to slow or reverse muscle wasting in cachexia warrants further investigation.

Do patients with advanced cancer have any potential for protein anabolism in response to amino acid therapy?

PURPOSE OF REVIEW: There is evidence that protein anabolism is achievable before cancer evolves into refractory cachexia with attenuation of muscle loss and even muscle gain. This review summarizes recent observations on the role of total and specific amino acids in promoting protein anabolism in human cancer and revisits prior studies in this context. RECENT FINDINGS: Analysis of muscle changes in advanced cancer patients indicated opportunities for inducing anabolism. Maintenance and gain in muscle was reported in a majority of patients, from initiation of oncologic treatment and before the final refractory stage. In addition to being substrates, some amino acids, for example leucine, act as intracellular signals to promote protein synthesis. Recent acute studies demonstrated that provision of amino acids, sufficient to considerably elevate circulating leucine concentrations concurrent with other amino acid and nutrient availability, resulted in significant protein anabolism in cancer patients. This occurred even during weight loss and inflammation. SUMMARY: Patients with cancer have an anabolic potential to be exploited early on in cachexia development. High-leucine and protein supplements are worth testing as part of a multimodal anabolic approach in long-term trials to confirm their efficacy to sustain anabolism, and attenuate or even reverse muscle wasting.