Obesity alters pathology and treatment response in inflammatory disease.

Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led 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.

Spectroscopic Manifestations Of (Anti)Aromaticity In Oxidized And Reduced Porphyrin And Norcorrole.

Aromaticity and antiaromaticity are foundational principes in organic chemistry, regularly invoked to explain stability, structure, and magnetic and electronic properties. There are ongoing challenges in assigning molecules as aromatic or antiaromatic using optical spectroscopy. Here we report spectroelectrochemical and computational analyses of porphyrin (18π neutral, aromatic) and norcorrole (16π neutral, antiaromatic), and their oxidized (16π porphyrin dication) and reduced (norcorrole 18π dianion) forms. Our results show that while the visible spectra are characteristic of (anti)aromaticity consistent with Hückel's rules, the IR spectra are much less informative, owing to the relative rigidity of norcorrole. The results have implications for the assignment of (anti)aromaticity in both ground-state and time-resolved excited-state spectra.

Association of preoperative frailty with postoperative delirium in elderly orthopedic trauma patients.

BACKGROUND: 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. AIM: Our goal was to investigate whether preoperative frailty is associated with postoperative delirium (POD) in elderly orthopedic trauma patients. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Postoperative delirium mediates 180-day mortality in orthopaedic trauma 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.

Depletion of fat-resident Treg cells prevents age-associated insulin resistance.

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.

Synthetic control of mammalian-cell motility by engineering chemotaxis to an orthogonal bioinert chemical signal.

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.

Hydrogen-bonded frameworks containing aliphatic 3D linkers show high-capacity water vapour sorption.

Hydrogen-bonded frameworks were prepared from a tetra-amidinium component and three-dimensional cubane and bicyclopentane dicarboxylate linkers. Despite the incorporation of aliphatic components, the frameworks demonstrate strong and reversible uptake of water vapour, with one of the frameworks showing water uptake at very low relative humidity.

Culturally adapted motivational interviewing's effects on drinking in response to immigration and acculturation stressors among Latinx adults with heavy drinking problems.

INTRODUCTION: Culturally adapted motivational interviewing (CAMI) is a form of motivational interviewing that was adapted to address immigration- and acculturation-related stressors among Latinx adults who met criteria for hazardous drinking. This study hypothesized that (1) receiving CAMI was associated with reduced immigration/acculturation stress and related drinking and that (2) these associations differed by participants' acculturation and perceived discrimination levels. METHODS: This study employed a single group pre-post study design using data from a randomized controlled trial. Participants were Latinx adults who received CAMI (N = 149). The study assessed immigration/acculturation stress with the Measure of Immigration and Acculturation Stressors (MIAS) and measured related drinking with the Measure of Drinking Related to Immigration and Acculturation Stressors (MDRIAS). The study team conducted linear mixed modeling for repeated measures to examine outcome changes between the baseline and the 6-month and 12-month follow-ups and moderation effects. RESULTS: Compared to baseline, the study found significant decreases in the total MIAS and MDRIAS scores and subscale scores at 6- and 12-month follow-ups. Moderation analysis results showed that lower acculturation levels and higher levels of perceived discrimination were significantly associated with larger decreases at follow-up in total MIAS and MDRIAS scores and several subscale scores. CONCLUSIONS: Findings provide preliminary support for CAMI's efficacy in reducing immigration and acculturation stress and related drinking among Latinx adults with heavy drinking problems. The study observed more improvements among the less acculturated and more discriminated participants. Larger studies with more rigorous designs are needed.

Association of Nutritional Status with New-Onset Delirium in Elderly, Acute Care, Orthopaedic Trauma Patients: A Single-Center Observational Study.

OBJECTIVE: To determine whether nutritional status at hospital admission is independently associated with new-onset delirium (NOD) in elderly, orthopaedic trauma patients. DESIGN: Single-center, retrospective, cross-sectional study. SETTING: Data from patients at a large teaching hospital in Boston, MA, were analyzed. PATIENTS: All patients were ≥65 years and hospitalized for acute surgical management of their major fractures after trauma. INTERVENTION: None. MAIN OUTCOME MEASUREMENT: 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. RESULTS: 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). CONCLUSIONS: 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. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Association of nutrition status and hospital-acquired infections in older adult orthopedic trauma patients.

BACKGROUND: Malnutrition is linked to suboptimal outcomes following elective surgery. Trauma patients do not typically have an opportunity for preoperative nutrition optimization and may be at risk for malnutrition. Our goal was to investigate whether nutrition status is associated with development of hospital-acquired infections (HAIs) in older adult, orthopedic trauma patients. METHODS: We performed a retrospective analysis of data between January 1, 2017, and August 30, 2018, from the Massachusetts General Hospital Geriatric Inpatient Fracture Trauma Service. Admission nutrition 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 nutrition status is associated with HAIs, we performed a multivariable logistic regression analysis controlling for age, sex, Charlson Comorbidity Index, glomerular filtration rate, and type of anesthesia. RESULTS: Four hundred sixty-one patients comprised the analytic cohort. Multivariable regression analysis demonstrated that each unit increment in MNA score was associated with a 13% reduction in risk of HAI (odds ratio, 0.87; 95% CI, 0.79-0.97). Furthermore, adjusting for timing of perioperative antibiotics, perioperative transfusions, or development of pressure injury during hospitalization did not materially change these results. CONCLUSION: Our results demonstrate that malnutrition is highly prevalent in older adult, orthopedic trauma patients and that nutrition status may influence the risk of developing HAIs in this cohort of patients. Further studies are needed to determine whether optimizing perioperative nutrition in older adult, orthopedic trauma patients can reduce infectious complications and improve overall health outcomes.