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To determine whether nutritional status at hospital admission is independently associated with new-onset delirium (NOD) in elderly, orthopaedic trauma patients.Single-center, retrospective, cross-sectional study.Data from patients at a large teaching hospital in Boston, MA, were analyzed.All patients were ≥65 years and hospitalized for acute surgical management of their major fractures after trauma.None.Nutritional status was assessed at admission using the Mini Nutritional Assessment-Short Form (MNA-SF). Delirium was assessed using the Confusion Assessment Method within 24 hours of admission and daily throughout hospitalization.The incidence of delirium was 20% (94/471). Each unit decrement in MNA-SF was associated with a 14% higher risk of NOD (adjusted OR 1.14; 95% CI 1.05-1.28). Moreover, malnourished patients (MNA-SF score 0-7) were twice as likely to develop NOD (adjusted OR 2.07; 95% CI 1.01-4.35) compared with patients who were not malnourished (MNA-SF score 8-14).In hospitalized, elderly, orthopaedic trauma patients, poor nutritional status may be a modifiable risk factor for NOD. Future studies are needed to determine whether aggressive nutritional interventions can reduce the incidence of NOD and improve outcomes in this cohort of patients.Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Among elderly orthopedic trauma patients, the prevalence of delirium during hospitalization has been reported to be as high as 60%. Frail elderly patients have an increased risk of delirium after elective surgery; however, such an association remains underexplored among trauma patients. Our goal was to investigate whether preoperative frailty is associated with postoperative delirium (POD) in elderly orthopedic trauma patients. We conducted a single-center, retrospective, cross-sectional study. All patients were ≥ 65 years of age and were admitted to the hospital between 01/01/2017 and 08/31/2018 for surgical intervention of a significant extremity fracture. Frailty was assessed using the fatigue, resistance, ambulation, illness, and loss of weight questionnaire. Delirium was assessed using the Confusion Assessment Method. POD was defined as new-onset delirium that occurred within 24 h after surgery. To investigate whether frailty is associated with POD, we performed a multiple variable logistic regression, controlling for biologically relevant confounders. Five hundred fifty-six patients comprised the analytic cohort. Incidence of POD was 14% (n = 80). Multiple variable regression analysis demonstrated that each unit increment in FRAIL score was associated with a 33% higher likelihood of POD (OR 1.33; 95% CI 1.02–1.72, p = 0.03). Our results suggest that preoperative frailty increases the risk of POD in hospitalized, elderly, orthopedic trauma patients. Future studies are needed to determine whether perioperative interventions focused on improving frailty can reduce the risk of POD and improve outcomes in this rapidly growing cohort of patients.

Background Frailty has been associated with increased incidence of postoperative delirium and mortality. We hypothesised that postoperative delirium mediates a clinically significant (≥1%) percentage of the effect of frailty on mortality in older orthopaedic trauma patients. Methods This was a single-centre, retrospective observational study including 558 adults 65 yr and older, who presented with an extremity fracture requiring hospitalisation without initial ICU admission. We used causal statistical inference methods to estimate the relationships between frailty, postoperative delirium, and mortality. Results In the cohort, 180-day mortality rate was 6.5% (36/558). Frail and prefrail patients comprised 23% and 39%, respectively, of the study cohort. Frailty was associated with increased 180 day mortality from 1.4% to 12.2% (11% difference; 95% confidence interval [CI], 8.4–13.6), which translated statistically into an 88.7% (79.9–94.3%) direct effect and an 11.3% (5.7–20.1%) postoperative delirium mediated effect. Prefrailty was also associated with increased 180 day mortality from 1.4% to 4.4% (2.9% difference; 2.4–3.4), which was translated into a 92.5% (83.8–99.9%) direct effect and a 7.5% (0.1–16.2%) postoperative delirium mediated effect. Conclusions Frailty is associated with increased postoperative mortality, and delirium might mediate a clinically significant, but small percentage of this effect. Studies should assess whether, in patients with frailty, attempts to mitigate delirium might decrease postoperative mortality.

Background Poor nutritional status is linked to suboptimal outcomes following elective surgery. Trauma patients do not typically have an opportunity for preoperative nutritional optimization and may be at risk for malnutrition with its related complications. Our goal was to investigate whether nutritional status is associated with development of hospital-acquired infections (HAIs) in elderly, orthopedic trauma patients. Methods We performed a retrospective analysis of data between 01/01/2017 to 08/30/2018 from the Massachusetts General Hospital Geriatric Inpatient Fracture Trauma Service (GIFTS). Admission nutritional status was assessed using the Mini Nutritional Assessment (MNA) and HAIs were validated through the American College of Surgeons National Surgical Quality Improvement Project database. To investigate whether nutritional status is associated with HAIs, we performed a multiple variable logistic regression analysis, controlling for age, sex, Charlson Comorbidity Index, glomerular filtration rate, and type of anesthesia. Results 461 patients comprised the analytic cohort. Multiple variable regression analysis demonstrated that each unit increment in MNA score was associated with a 13% reduction in risk of HAI (OR 0.87; 95%CI 0.79-0.97). Furthermore, adjusting for timing of perioperative antibiotics, perioperative transfusions, or development of pressure injury during hospitalization results did not materially change these results. Conclusion Our results demonstrate that malnutrition is highly prevalent in elderly orthopedic trauma patients and that nutritional status may influence the risk of developing HAIs in this cohort of patients. Further studies are needed to determine whether optimizing perioperative nutritional status in elderly orthopedic trauma patients can reduce infectious complications and improve overall health outcomes. This article is protected by copyright. All rights reserved.

Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and haveled the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system1-7, although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. Obesity converted the classical type 2 T helper (TH2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent TH17 inflammation.We also observed divergent responses to biologic therapies targeting TH2 cytokines, which robustly protected lean mice but exacerbated disease in obese mice. Single-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells from obese mice relative to lean mice. Conditional ablation of PPARγ in T cells revealed that PPARγ is required to focus the in vivo TH response towards a TH2-predominant state and prevent aberrant non-TH2 inflammation. Treatment of obese mice with a small-molecule PPARγ agonist limited development of TH17 pathology and unlocked therapeutic responsiveness to targeted anti-TH2 biologic therapies. These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity.

IntroductionBCG vaccination modulates immune responses to unrelated pathogens. This off-target effect could reduce the impact of emerging pathogens. As a readily available, inexpensive intervention that has a well-established safety profile, BCG is a good candidate for protecting healthcare workers (HCWs) and other vulnerable groups against COVID-19.Methods and analysisThis international multicentre phase III randomised controlled trial aims to determine if BCG vaccination reduces the incidence of symptomatic and severe COVID-19 at 6 months (co-primary outcomes) compared with no BCG vaccination. We plan to randomise 10 078 HCWs from Australia, The Netherlands, Spain, the UK and Brazil in a 1:1 ratio to BCG vaccination or no BCG (control group). The participants will be followed for 1 year with questionnaires and collection of blood samples. For any episode of illness, clinical details will be collected daily, and the participant will be tested for SARS-CoV-2 infection. The secondary objectives are to determine if BCG vaccination reduces the rate, incidence, and severity of any febrile or respiratory illness (including SARS-CoV-2), as well as work absenteeism. The safety of BCG vaccination in HCWs will also be evaluated. Immunological analyses will assess changes in the immune system following vaccination, and identify factors associated with susceptibility to or protection against SARS-CoV-2 and other infections.Ethics and disseminationEthical and governance approval will be obtained from participating sites. Results will be published in peer-reviewed open-access journals. The final cleaned and locked database will be deposited in a data sharing repository archiving system.Trial registrationClinicalTrials.gov NCT04327206

Among elderly orthopedic trauma patients, the prevalence of delirium during hospitalization has been reported to be as high as 60%. Frail elderly patients have an increased risk of delirium after elective surgery; however, such an association remains underexplored among trauma patients.Our goal was to investigate whether preoperative frailty is associated with postoperative delirium (POD) in elderly orthopedic trauma patients.We conducted a single-center, retrospective, cross-sectional study. All patients were ≥ 65 years of age and were admitted to the hospital between 01/01/2017 and 08/31/2018 for surgical intervention of a significant extremity fracture. Frailty was assessed using the fatigue, resistance, ambulation, illness, and loss of weight questionnaire. Delirium was assessed using the Confusion Assessment Method. POD was defined as new-onset delirium that occurred within 24 h after surgery. To investigate whether frailty is associated with POD, we performed a multiple variable logistic regression, controlling for biologically relevant confounders.Five hundred fifty-six patients comprised the analytic cohort. Incidence of POD was 14% (n = 80). Multiple variable regression analysis demonstrated that each unit increment in FRAIL score was associated with a 33% higher likelihood of POD (OR 1.33; 95% CI 1.02-1.72, p = 0.03).Our results suggest that preoperative frailty increases the risk of POD in hospitalized, elderly, orthopedic trauma patients. Future studies are needed to determine whether perioperative interventions focused on improving frailty can reduce the risk of POD and improve outcomes in this rapidly growing cohort of patients.

How obesity affects immune function is not well understood. Clinically, obesity is strongly associated with severe TH2 immunopathology1-3, though the physiological, cellular, and molecular underpinnings of this association remain obscure. Here, we demonstrate that obese mice are susceptible to severe atopic dermatitis (AD), a major manifestation of TH2 immunopathology and disease burden in humans4,5. Mechanistically, we show that dysregulation of the nuclear hormone receptor (NHR) PPARγ (peroxisome proliferator-activated receptor gamma) in T cells is a causal link between obesity and the increased TH2 immunopathology. We find that PPARγ oversees a cellular metabolic transcriptional program that restrains nuclear gene expression of the chief TH2 priming and effector cytokine interleukin-4 (IL-4). Accordingly, thiazolidinediones (TZDs), potent PPARγ agonists, robustly protect obese mice from TH2 immunopathology. Collectively, these findings establish PPARγ as a molecular link between obesity and TH2 immune homeostasis and identify TZDs as novel therapeutic candidates for TH2 immunopathology. Fundamentally, these findings demonstrate that shifting physiologic metabolic states can shape the tone of adaptive immune responses to modulate differential disease susceptibility.

Age-associated insulin resistance (IR) and obesity-associated IR are two physiologically distinct forms of adult-onset diabetes. While macrophage-driven inflammation is a core driver of obesity-associated IR, the underlying mechanisms of the obesity-independent yet highly prevalent age-associated IR are largely unexplored. Here we show, using comparative adipo-immune profiling in mice, that fat-resident regulatory T cells, termed fTreg cells, accumulate in adipose tissue as a function of age, but not obesity. Supporting the existence of two distinct mechanisms underlying IR, mice deficient in fTreg cells are protected against age-associated IR, yet remain susceptible to obesity-associated IR and metabolic disease. By contrast, selective depletion of fTreg cells via anti-ST2 antibody treatment increases adipose tissue insulin sensitivity. These findings establish that distinct immune cell populations within adipose tissue underlie ageing- and obesity-associated IR, and implicate fTreg cells as adipo-immune drivers and potential therapeutic targets in the treatment of age-associated IR.

Directed migration of diverse cell types plays a critical role in biological processes ranging from development and morphogenesis to immune response, wound healing, and regeneration. However, techniques to direct, manipulate, and study cell migration in vitro and in vivo in a specific and facile manner are currently limited. We conceived of a strategy to achieve direct control over cell migration to arbitrary user-defined locations, independent of native chemotaxis receptors. Here, we show that genetic modification of cells with an engineered G protein-coupled receptor allows us to redirect their migration to a bioinert drug-like small molecule, clozapine-N-oxide (CNO). The engineered receptor and small-molecule ligand form an orthogonal pair: The receptor does not respond to native ligands, and the inert drug does not bind to native cells. CNO-responsive migration can be engineered into a variety of cell types, including neutrophils, T lymphocytes, keratinocytes, and endothelial cells. The engineered cells migrate up a gradient of the drug CNO and transmigrate through endothelial monolayers. Finally, we demonstrate that T lymphocytes modified with the engineered receptor can specifically migrate in vivo to CNO-releasing beads implanted in a live mouse. This technology provides a generalizable genetic tool to systematically perturb and control cell migration both in vitro and in vivo. In the future, this type of migration control could be a valuable module for engineering therapeutic cellular devices.