David B. Bartlett

Understanding how we age: insights into inflammaging

Inflammaging is characterized by the upregulation of the inflammatory response that occurs with advancing age; its roots are strongly embedded in evolutionary theory.Inflammaging is believed to be a consequence of a remodelling of the innate and acquired immune system, resulting in chronic inflammatory cytokine production.Complex interrelated genetic, environmental and age-related factors determine an individual’s vulnerability or resilience to inflammaging. These factors include polymorphisms to the promoter regions of cytokines, cytokine receptors and antagonists, age-related decreases in autophagy and increased adiposity. Anti-inflammaging describes the upregulation of the hypothalamic-pituitary axis in response to inflammaging, leading to higher levels of cortisol, which in turn may be detrimental, contributing to less successful ageing and frailty. This may be countered by the adrenal steroid dehydroepiandrosterone, which itself declines with age, leaving certain individuals more vulnerable. Inflammaging and anti-inflammaging have both been linked with a number of age-related outcomes, including chronic morbidity, functional decline and mortality. This important area of research offers unique insights into the ageing process and the potential for screening and targeted interventions.

The age-related increase in low-grade systemic inflammation (Inflammaging) is not driven by cytomegalovirus infection

Aging is accompanied by the development of low‐grade systemic inflammation, termed ‘inflammaging’, characterized by raised serum C‐reactive protein (CRP) and pro‐inflammatory cytokines. Importantly, inflammaging is implicated in the pathogenesis of several of the major age‐related diseases including cardiovascular disease, type 2 diabetes, and dementia and is associated with increased mortality. The incidence of infection with the persistent herpes virus cytomegalovirus (CMV) also increases with age. Cross‐sectional studies have proposed CMV infection as a significant driver of inflammaging, but a definitive case for CMV as a causative agent in inflammaging has not yet been made. We studied longitudinally 249 subjects (153 men, 96 women) who participated in the Hertfordshire Ageing Study at baseline (1993/5, mean age 67·5 years) and at 10 year follow‐up. At both times, anthropometric measurements were made and subjects provided blood samples for analysis of inflammatory status and CMV seropositivity. In the cohort as a whole, serum CRP (P < 0·02) and pro‐inflammatory cytokines TNFα (P < 0·001) and IL‐6 (P < 0·001) were increased between baseline and follow‐up sampling whereas levels of the anti‐inflammatory cytokine IL‐10 were decreased (P < 0·001). These changes to cytokine status over time occurred equally in the 60% of subjects who were seropositive for CMV at baseline and follow‐up, the 8% who were CMV negative at baseline but who became CMV positive by the 10 year follow‐up, and also in the 32% who were CMV seronegative throughout. We conclude that CMV infection is not a primary causative factor in the age‐related increase in systemic inflammation.

Habitual physical activity is associated with the maintenance of neutrophil migratory dynamics in healthy older adults

Highlights • Physical activity associates with neutrophil migration in the elderly.• Effects occur independently of inflammation or surface receptor expression.• Adiponectin levels may positively influence neutrophil migration.

Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma

Multiple myeloma (MM), an incurable plasma cell malignancy, requires localisation within the bone marrow. This microenvironment facilitates crucial interactions between the cancer cells and stromal cell types that permit the tumour to survive and proliferate. There is increasing evidence that the bone marrow mesenchymal stem cell (BMMSC) is stably altered in patients with MM—a phenotype also postulated to exist in patients with monoclonal gammopathy of undetermined significance (MGUS) a benign condition that precedes MM. In this study, we describe a mechanism by which increased expression of peptidyl arginine deiminase 2 (PADI2) by BMMSCs in patients with MGUS and MM directly alters malignant plasma cell phenotype. We identify PADI2 as one of the most highly upregulated transcripts in BMMSCs from both MGUS and MM patients, and that through its enzymatic deimination of histone H3 arginine 26, PADI2 activity directly induces the upregulation of interleukin-6 expression. This leads to the acquisition of resistance to the chemotherapeutic agent, bortezomib, by malignant plasma cells. We therefore describe a novel mechanism by which BMMSC dysfunction in patients with MGUS and MM directly leads to pro-malignancy signalling through the citrullination of histone H3R26.

The effect of trainee research collaboratives in the UK

Trainee-led networks have pioneered a novel collaborative approach to research in the UK. Established at a similar time to the UK National Institute for Health Research in 2006, collaborative groups have developed new pathways for doctors in full-time specialty training to design, disseminate, and deliver high-quality, multicentre research. In parallel, the National Institute for Health Research set up Clinical Research Networks (CRNs) to coordinate delivery of research across 30 clinical specialties and 15 English regional networks. Analogous networks have also been established by the devolved administrations in Scotland, Northen Ireland, and Wales. CRNs provide infrastructure to promote and coordinate research, including funding research support staff and providing research skills training. Using gastrointestinal surgery as an example, we sought to quantify trainee-led collaborative research network engagement and compare hospital participation with CRN studies. We only considered CRN and trainee-led collaborative studies involving ten or more hospitals with information available about participating sites. We searched the CRN portfolio for closed gastrointestinal and general surgery studies. We contacted trainee networks via a national mailing list to identify trainee studies. We derived denominators from the total number of hospitals offering emergency or major elective gastrointestinal surgery. Overall, 238 (99%) of 241 UK hospitals providing general surgery services participated in one or more trainee-led collaborative studies over the past decade compared with 191 (79%) of 241 for CRN studies. With the three trainee-led studies that had been adopted into the CRN portfolio excluded, participation in trainee-led research remained similar, at 236 (98%) of 241. Trainee groups delivered 15 studies overall: 12 observational studies and three randomised controlled trials (RCTs), coordinated by five regional and two national trainee networks (appendix). These numbers compared with three observational studies and eight RCTs coordinated by the CRN. We noted strong participation in trainee collaborative studies, even in regions with low CRN coverage, with the mean number of studies per hospital greater for collaboratives than for CRNs (appendix). Regions with a Royal College of Surgeons Surgical Trials Centre had greater participation in both trainee and CRN studies: the mean number of studies per hospital was 8·2 versus 6·0 in regions without. Trainee-led collaboratives have driven substantial additional research participation across the UK, on top of that achievable through CRNs alone, and have engaged additional gastrointestinal surgery units with little infrastructure or associated costs. This success is now being replicated in other specialties, with the British Neurosurgical Trainee Research Collaborative engaging 26 of 30 UK adult trauma-receiving neurosurgical units in the RESCUE-ASDH RCT. As the collaborative model is extended globally, it offers a powerful opportunity to promote a collaborative research culture and grow capacity with minimal investment. Synergy between trainee-led networks and CRNs could maximise delivery of high-quality research across the UK.

Neutrophil and Monocyte Bactericidal Responses to 10 Weeks of Low-Volume High-Intensity Interval or Moderate-Intensity Continuous Training in Sedentary Adults.

Neutrophils and monocytes are key components of the innate immune system that undergo age-associated declines in function. This study compared the impact of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on immune function in sedentary adults. Twenty-seven (43 ± 11 years) healthy sedentary adults were randomized into ten weeks of either a HIIT (>90% maximum heart rate) or MICT (70% maximum heart rate) group training program. Aerobic capacity (VO2peak), neutrophil and monocyte bacterial phagocytosis and oxidative burst, cell surface receptor expression, and systemic inflammation were measured before and after the training. Total exercise time commitment was 57% less for HIIT compared to that for MICT while both significantly improved VO2peak similarly. Neutrophil phagocytosis and oxidative burst and monocyte phagocytosis and percentage of monocytes producing an oxidative burst were improved by training similarly in both groups. Expression of monocyte but not neutrophil CD16, TLR2, and TLR4 was reduced by training similarly in both groups. No differences in systemic inflammation were observed for training; however, leptin was reduced in the MICT group only. With similar immune-enhancing effects for HIIT compared to those for MICT at 50% of the time commitment, our results support HIIT as a time efficient exercise option to improve neutrophil and monocyte function.

Alterations in bone marrow metabolism are an early and consistent feature during the development of MGUS and multiple myeloma

Alterations in bone marrow metabolism are an early and consistent feature during the development of MGUS and multiple myeloma

Use of an online e-learning module to standardise the assessment and reporting of a subjective endpoint in a multicentre rct

Conclusion The online learning resource provided effective training and accreditation to wound reviewers at multiple sites in a convenient and reproducible manner. This adjunct to our trial served to standardise outcome assessment and hopefully reduced inter-observer variability. Authors’ details West Midlands Research Collaborative, Birmingham, UK. Primary Care Clinical Sciences, University of Birmingham, Birmingham, UK. Academic Department of Surgery, University of Birmingham, Birmingham, UK.

Association of the Composite Inflammatory Biomarker GlycA, with Exercise-Induced Changes in Body Habitus in Men and Women with Prediabetes

GlycA is a new composite measure of systemic inflammation and a predictor of many inflammatory diseases. GlycA is the nuclear magnetic resonance spectroscopy-derived signal arising from glucosamine residues on acute-phase proteins. This study aimed to evaluate how exercise-based lifestyle interventions modulate GlycA in persons at risk for type 2 diabetes. GlycA, fitness, and body habitus were measured in 169 sedentary adults (45–75 years) with prediabetes randomly assigned to one of four six-month exercise-based lifestyle interventions. Interventions included exercise prescription based on the amount (energy expenditure (kcal/kg weight/week (KKW)) and intensity (%VO2peak). The groups were (1) low-amount/moderate-intensity (10KKW/50%) exercise; (2) high-amount/moderate-intensity (16KKW/50%) exercise; (3) high-amount/vigorous-intensity (16KKW/75%) exercise; and (4) a Clinical Lifestyle (combined diet plus low-amount/moderate-intensity exercise) intervention. Six months of exercise training and/or diet-reduced GlycA (mean Δ: −6.8 ± 29.2 μmol/L; p = 0.006) and increased VO2peak (mean Δ: 1.98 ± 2.6 mL/kg/min; p < 0.001). Further, visceral (mean Δ: −21.1 ± 36.6 cm2) and subcutaneous fat (mean Δ: −24.3 ± 41.0 cm2) were reduced, while liver density (mean Δ: +2.3 ± 6.5HU) increased, all p < 0.001. When including individuals in all four interventions, GlycA reductions were associated with reductions in visceral adiposity (p < 0.03). Exercise-based lifestyle interventions reduced GlycA concentrations through mechanisms related to exercise-induced modulations of visceral adiposity. This trial is registered with Clinical Trial Registration Number NCT00962962.

Dexamethasone reduces emesis after major gastrointestinal surgery (DREAMS)

BackgroundPostoperative nausea and vomiting is one of the most common complications affecting patients after surgery and causes significant morbidity and increased length of hospital stay. It is accepted that patients undergoing surgery on the bowel are at a higher risk. In the current era of minimally invasive colorectal surgery combined with enhanced recovery, reducing the incidence and severity of postoperative nausea and vomiting is particularly important. Dexamethasone is widely, but not universally used. It is known to improve appetite and gastric emptying, thus reduce vomiting. However, this benefit is not established in patients undergoing bowel surgery, and dexamethasone has possible side effects such as increased risk of wound infection and anastomotic leak that could adversely affect recovery.DesignDREAMS is a phase III, double-blind, multicenter, randomized controlled trial with the primary objective of determining if preoperative dexamethasone reduces postoperative nausea and vomiting in patients undergoing elective gastrointestinal resections. DREAMS aims to randomize 1,350 patients over 2.5 years.Patients undergoing laparoscopic or open colorectal resections for malignant or benign pathology are randomized between 8 mg intravenous dexamethasone and control (no dexamethasone). All patients are given one additional antiemetic at the time of induction, prior to randomization. Both the patient and their surgeon are blinded as to the treatment arm.Secondary objectives of the DREAMS trial are to determine whether there are other measurable benefits during recovery from surgery with the use of dexamethasone, including quicker return to oral diet and reduced length of stay. Health-related quality of life, fatigue and risks of infections will be investigated.Trial registrationISRCTN21973627