Distal Immunization and Systemic Cytokines Establish a Transient Immune Alert State in the Intestine.

Conventionally, immune responses are studied in the context of inflamed tissues and their corresponding draining lymph nodes (LNs). However, little is known about the effects of systemic inflammatory signals generated during local inflammation on distal tissues and nondraining LNs. Using a mouse model of cutaneous immunization, we found that systemic inflammatory stimuli triggered a rapid and selective distal response in the small intestine and the mesenteric LN (mesLN). This consisted of increased permeability of intestinal blood vessels and lymphatic drainage of bloodborne solutes into the mesLN, enhanced activation and migration of intestinal dendritic cells, as well as amplified T cell responses in the mesLNs to systemic but not orally derived Ags. Mechanistically, we found that the small intestine endothelial cells preferentially expressed molecules involved in TNF-α signaling and that TNF-α blockade markedly diminished distal intestinal responses to cutaneous immunization. Together, these findings reveal that the intestinal immune system is rapidly and selectively activated in response to inflammatory cues regardless of their origin, thus identifying an additional layer of defense and enhanced surveillance of a key barrier organ at constant risk of pathogen encounter.

Mortality and risk factors associated with misdiagnosis of acute aortic syndrome in Ontario, Canada: a population-based study.

INTRODUCTION: Acute aortic syndrome (AAS) is a life-threatening aortic emergency. It describes three diagnoses: acute aortic dissection, acute intramural haematoma and penetrating atherosclerotic ulcer. Unfortunately, there are no accurate estimates of the miss rate for AAS, risk factors for missed diagnosis or its effect on outcomes. METHODS: A population-based retrospective cohort study of anonymously linked data for residents of Ontario, Canada, was carried out. Incident cases of AAS were identified between 2003 and 2018 using a validated algorithm based on ICD codes and death. Before multivariate modelling, all categorical variables were analysed for an association with missed AAS diagnosis using χ2 tests. These preliminary analyses were unadjusted for clustering or any covariates. Finally, we performed multilevel logistic regression analysis using a generalised linear mixed model approach to model the probability of a missed case occurring. RESULTS: There were 1299 cases of AAS (age mean (SD) 68.03±14.70, woman 500 (38.5%), rural areas (n=111, 8.55%)) over the study period. Missed cases accounted for 163 (12.5%) of the cohort. Mortality (non-missed AAS 59.7% vs missed AAS 54.6%) and surgical intervention (non-missed AAS 31% vs missed AAS 30.7%) were similar in missed and non-missed cases. However, lower acuity (Canadian triage acuity scale >2 (OR 2.45 95% CI 1.71 to 3.52) (the scale is from 1 to 5, with 1 indicating high acuity) had a higher odds of being a missed case and non-ambulatory presentation (OR 0.47 95% CI 0.33 to 0.67) and presenting to a teaching (OR 0.60 95% CI 0.40 to 0.90)) or cardiac centre (OR 0.41 95% CI 0.27 to 0.62) were associated with a lower odds of being a missed case. CONCLUSIONS: The high rate of misdiagnosis has remained stable for over a decade. Non-teaching and non-cardiac hospitals had a higher incidence of missed cases. Mortality and rates of surgery were not associated with a missed diagnosis of AAS. Educational interventions should be prioritised in non-teaching hospitals and non-cardiac centres.

Amphetamine-Related Emergency Department Visits in Ontario, Canada, 2003-2020.

OBJECTIVES: Despite unregulated amphetamine use increasing, there are limited data on related emergency department (ED) visits in Canada. Our primary objective was to examine trends in amphetamine-related ED visits over time in Ontario, including by age and sex. Secondary objectives were to examine whether patient characteristics were associated with ED revisit within 6 months. METHODS: Using administrative claims and census data, we calculated annual patient- and encounter-based rates of amphetamine-related ED visits from 2003 to 2020 among individuals 18+ years of age. We also performed a retrospective cohort study of individuals with amphetamine-related ED visits between 2019 and 2020 to determine whether select factors were associated with ED revisit within 6 months. Multivariable logistic regression modelling was used to measure associations. RESULTS: The population-based rate of amphetamine-related ED visits increased nearly 15-fold between 2003 (1.9/100,000 Ontarians) and 2020 (27.9/100,000 Ontarians). Seventy-five percent of individuals returned to the ED for any reason within 6 months. Psychosis and use of other substances were both independently associated with ED revisit for any reason within 6 months (psychosis: AOR = 1.54, 95% CI = 1.30-1.83; other substances: AOR = 1.84, 95% CI = 1.57-2.15), whereas having a primary care physician was negatively associated with ED revisit (AOR = 0.77, 95% CI = 0.60-0.98). CONCLUSIONS: Increasing rates of amphetamine-related ED visits in Ontario are cause for concern. Diagnoses of psychosis and the use of other substances may serve to identify individuals who are most likely to benefit from both primary and substance-specific care.

Epidemiology, mortality and miss rate of acute aortic syndrome in Ontario, Canada: a population-based study.

INTRODUCTION: Acute aortic syndrome (AAS) is a life-threatening emergency. It describes three distinct diagnoses: acute aortic dissection, acute intramural hematoma and penetrating atherosclerotic ulcer. There are currently no accurate estimates for incidence, mortality or misdiagnosis. Our objectives were to determine the incidence, mortality and miss rate of acute aortic syndrome in the emergency department (ED). METHODS: A population-based retrospective cohort study of anonymously linked data for residents of Ontario, Canada, was carried out. Incident cases of acute aortic syndrome were identified between 2003 and 2018 using a validated algorithm based on ICD-10 codes and death. Incidence (number of cases/population of Ontario), mortality, and miss rate were calculated. Miss rate was defined as when a patient was seen in the ED within 14 days prior to an acute aortic syndrome diagnosis with a presenting complaint consistent with acute aortic syndrome. RESULTS: There were 1299 cases of acute aortic syndrome over the study period [age mean (SD) 68.03 ± 14.70; female (n = 500, 38.5%); rural areas (n = 111, 8.6%)]. The overall annual incidence for acute aortic syndrome was 0.61 per 100,000. One year mortality decreased from 47.4 to 29.1%. ED mortality was 14.9%. In the 14 days prior to diagnosis 12.5% of patients were seen in the ED with a presentation consistent with acute aortic syndrome. CONCLUSIONS: Annual incidence of acute aortic syndrome was found to be lower than other population-based studies. Also, the burden of mortality is seen in the ED. Education initiatives should focus on the identification of acute aortic syndrome in the ED to address mortality and miss rate.

RéSUMé: INTRODUCTION: Le syndrome aortique aigu (SAA) est une urgence qui met la vie en danger. Il décrit trois diagnostics distincts: dissection aortique aiguë, hématome intramural aigu et ulcère athéroscléreux pénétrant. Il n'existe actuellement aucune estimation précise de l'incidence, de la mortalité ou des diagnostics erronés. Nos objectifs étaient de déterminer l'incidence, la mortalité et le taux d'échec du syndrome aortique aigu dans le service des urgences (SU). MéTHODES: Une étude de cohorte rétrospective basée sur la population a été réalisée à partir de données liées anonymement pour les résidents de l'Ontario, Canada. Les cas incidents de syndrome aortique aigu ont été identifiés entre 2003-2018 à l'aide d'un algorithme validé basé sur les codes CIM-10 et les décès. L'incidence (nombre de cas/population de l'Ontario), la mortalité et le taux d'absence ont été calculés. Le taux d'omission a été défini comme le cas où un patient a été vu à l'urgence dans les 14 jours précédant un diagnostic de syndrome aortique aigu et que la plainte était conforme au syndrome aortique aigu. RéSULTATS: Il y a eu 1 299 cas de syndrome aortique aigu pendant la période d'étude (âge moyen (ET) 68,03 ±14,70 ; femmes (n = 500, 38,5 %) ; zones rurales (n = 111, 8,6%)). L'incidence annuelle globale du syndrome aortique aigu était de 0,61 pour 100 000. La mortalité à un an a diminué de 47,4 % à 29,1 %. La mortalité aux urgences était de 14,9 %. Au cours des 14 jours précédant le diagnostic, 12,5 % des patients ont été vus aux urgences avec une présentation compatible avec le syndrome aortique aigu. CONCLUSIONS: L'incidence annuelle de syndrome aortique aigu s'est avérée inférieure à celle d'autres études basées sur la population. En outre, le poids de la mortalité est observé aux urgences. Les initiatives de formation devraient se concentrer sur l'identification des syndrome aortique aigu aux urgences afin de réduire la mortalité et le taux d'échec.

The Prebiotic Effect of Australian Seaweeds on Commensal Bacteria and Short Chain Fatty Acid Production in a Simulated Gut Model.

Diet is known to affect the composition and metabolite production of the human gut microbial community, which in turn is linked with the health and immune status of the host. Whole seaweeds (WH) and their extracts contain prebiotic components such as polysaccharides (PS) and polyphenols (PP). In this study, the Australian seaweeds, Phyllospora comosa, Ecklonia radiata, Ulva ohnoi, and their PS and PP extracts were assessed for potential prebiotic activities using an in vitro gut model that included fresh human faecal inoculum. 16S rRNA sequencing post gut simulation treatment revealed that the abundance of several taxa of commensal bacteria within the phylum Firmicutes linked with short chain fatty acid (SCFA) production, and gut and immune function, including the lactic acid producing order Lactobacillales and the chief butyrate-producing genera Faecalibacteria, Roseburia, Blautia, and Butyricicoccus were significantly enhanced by the inclusion of WH, PS and PP extracts. After 24 h fermentation, the abundance of total Firmicutes ranged from 57.35−81.55% in the WH, PS and PP samples, which was significantly greater (p ≤ 0.01) than the inulin (INU) polysaccharide control (32.50%) and the epigallocatechingallate (EGCG) polyphenol control (67.13%); with the exception of P. comosa PP (57.35%), which was significantly greater than INU only. However, all WH, PS and PP samples also increased the abundance of the phylum Proteobacteria; while the abundance of the phylum Actinobacteria was decreased by WH and PS samples. After 24 h incubation, the total and individual SCFAs present, including butyric, acetic and propionic acids produced by bacteria fermented with E. radiata and U. ohnoi, were significantly greater than the SCFAs identified in the INU and EGCG controls. Most notably, total SCFAs in the E. radiata PS and U. ohnoi WH samples were 227.53 and 208.68 µmol/mL, respectively, compared to only 71.05 µmol/mL in INU and 7.76 µmol/mL in the EGCG samples. This study demonstrates that whole seaweeds and their extracts have potential as functional food ingredients to support normal gut and immune function.

Rates of Smoking Cessation at 6 and 12 Months after a Clinical Tobacco Smoking Cessation Intervention in Head and Neck Cancer Patients in Northern Ontario, Canada.

Smoking during cancer treatment is associated with reduced treatment response and cancer recurrence in patients with tobacco-related cancers. The purpose of this study was to examine smoking characteristics in head and neck cancer patients (n = 503) with a history of smoking and examine the impact of an intensive clinical tobacco intervention to patients who were currently smoking. All participants completed an interviewer-administered questionnaire at study enrollment which examined smoking behaviours, motivations to quit, and strategies used to cessate smoking. Follow-up assessments were completed at 6- and 12-months which monitored whether patients had quit smoking, remained cessated, or continued to smoke since study recruitment. For those who were currently smoking (n = 186, 37.0%), an intensive clinical tobacco intervention that utilized the 3A's-Ask, Advise, Arrange-and the Opt-Out approach was offered to assist with smoking cessation at their new patient visit and followed-up weekly during their head and neck radiation therapy for 7 weeks. At 6 months, 23.7% (n = 41) of those who were smoking successfully quit; 51.2% quit 'cold turkey' (defined as using no smoking cessation assistance, aids or pharmacotherapy to quit), while 34.9% used pharmacotherapy (varenicline (Champix)) to quit. On average, it took those who were smoking 1-5 attempts to quit, but once they quit they remained cessated for the duration of the study. Although the head and neck cancer patients in this study reported high levels of nicotine dependence, many were able to successfully cessate.

Impact of Co-Delivery of EGCG and Tuna Oil within a Broccoli Matrix on Human Gut Microbiota, Phenolic Metabolites and Short Chain Fatty Acids In Vitro.

(-)-Epigallocatechin gallate (EGCG) and tuna oil (TO) are beneficial bioactive compounds. EGCG, TO or a combination of, delivered by broccoli by-products (BBP), were added to an in vitro anaerobic fermentation system containing human fecal inocula to examine their ability to generate short-chain fatty acids (SCFA), metabolize EGCG and change the gut microbiota population (assessed by 16 S gene sequencing). Following 24 h fermentation, EGCG was hydrolyzed to (-)-epigallocatechin and gallic acid. EGCG significantly inhibited the production of SCFA (p < 0.05). Total SCFA in facal slurries with BBP or TO-BBP (48-49 µmol/mL) were significantly higher (p < 0.05) than the negative control with cellulose (21 µmol/mL). EGCG-BBP and TO-EGCG-BBP treatment increased the relative abundance of Gluconacetobacter, Klebsiella and Trabulsiella. BBP and TO-BBP showed the greatest potential for improving gut health with the growth promotion of high butyrate producers, including Collinsella aerofaciens, Bacillus coagulans and Lactobacillus reuteri.

Discovery of Selective Inhibitors for In Vitro and In Vivo Interrogation of Skeletal Myosin II.

Myosin IIs, actin-based motors that utilize the chemical energy of adenosine 5'-triphosphate (ATP) to generate force, have potential as therapeutic targets. Their heavy chains differentiate the family into muscle (skeletal [SkMII], cardiac, smooth) and nonmuscle myosin IIs. Despite the therapeutic potential for muscle disorders, SkMII-specific inhibitors have not been reported and characterized. Here, we present the discovery, synthesis, and characterization of "skeletostatins," novel derivatives of the pan-myosin II inhibitor blebbistatin, with selectivity 40- to 170-fold for SkMII over all other myosin II family members. In addition, the skeletostatins bear improved potency, solubility, and photostability, without cytotoxicity. Based on its optimal in vitro profile, MT-134's in vivo tolerability, efficacy, and pharmacokinetics were determined. MT-134 was well-tolerated in mice, impaired motor performance, and had excellent exposure in muscles. Skeletostatins are useful probes for basic research and a strong starting point for drug development.

Seaweed Components as Potential Modulators of the Gut Microbiota.

Macroalgae, or seaweeds, are a rich source of components which may exert beneficial effects on the mammalian gut microbiota through the enhancement of bacterial diversity and abundance. An imbalance of gut bacteria has been linked to the development of disorders such as inflammatory bowel disease, immunodeficiency, hypertension, type-2-diabetes, obesity, and cancer. This review outlines current knowledge from in vitro and in vivo studies concerning the potential therapeutic application of seaweed-derived polysaccharides, polyphenols and peptides to modulate the gut microbiota through diet. Polysaccharides such as fucoidan, laminarin, alginate, ulvan and porphyran are unique to seaweeds. Several studies have shown their potential to act as prebiotics and to positively modulate the gut microbiota. Prebiotics enhance bacterial populations and often their production of short chain fatty acids, which are the energy source for gastrointestinal epithelial cells, provide protection against pathogens, influence immunomodulation, and induce apoptosis of colon cancer cells. The oral bioaccessibility and bioavailability of seaweed components is also discussed, including the advantages and limitations of static and dynamic in vitro gastrointestinal models versus ex vivo and in vivo methods. Seaweed bioactives show potential for use in prevention and, in some instances, treatment of human disease. However, it is also necessary to confirm these potential, therapeutic effects in large-scale clinical trials. Where possible, we have cited information concerning these trials.

Maternal prenatal gut microbiota composition predicts child behaviour.

BACKGROUND: Murine studies demonstrate that maternal prenatal gut microbiota influences brain development and behaviour of offspring. No human study has related maternal gut microbiota to behavioural outcomes during early life. This study aimed to evaluate relationships between the prenatal faecal microbiota, prenatal diet and childhood behaviour. METHODS: A sub-cohort of 213 mothers and 215 children were selected from a longitudinal pre-birth cohort. Maternal prenatal exposure measures collected during the third trimester included the faecal microbiota (generated using 16S rRNA amplicon sequencing), and dietary intake. The behavioural outcome used the Childhood Behaviour Checklist at age two. Models were adjusted for prenatal diet, smoking, perceived stress, maternal age and sample batch. FINDINGS: We found evidence that the alpha diversity of the maternal faecal microbiota during the third trimester of pregnancy predicts child internalising behaviour at two years of age (-2·74, (-4·71, -0·78), p = 0·01 (Wald test), R2=0·07). Taxa from butyrate-producing families, Lachnospiraceae and Ruminococcaceae, were more abundant in mothers of children with normative behaviour. A healthy prenatal diet indirectly related to decreased child internalising behaviours via higher alpha diversity of maternal faecal microbiota. INTERPRETATION: These findings support animal studies showing that the composition of maternal prenatal gut microbiota is related to offspring brain development and behaviour. Our findings highlight the need to evaluate potential impacts of the prenatal gut microbiota on early life brain development. FUNDING: This study was funded by the National Health and Medical Research Council of Australia (1082307, 1147980), Murdoch Children's Research Institute, Barwon Health and Deakin University.

Prescribing of two potentially interacting cardiovascular medications in atrial fibrillation patients on direct oral anticoagulants.

BACKGROUND: Amiodarone and diltiazem are commonly recommended cardiovascular medications for use in atrial fibrillation (AF) patients. They are known to have drug-drug interactions (DDIs) with direct oral anticoagulants (DOACs). We aimed to evaluate frequency of use of amiodarone or diltiazem among continuous users of DOACs in AF patients and to determine factors associated with their co-use. METHODS: The study population included all AF patients with continuous DOAC use in Ontario, Canada, ≥66 years, from April 1, 2017 to March 31, 2018. Concurrent use of amiodarone or diltiazem was determined by identifying the presence of an overlapping prescription. Multivariable logistic regression models were used to identify predictors of amiodarone or diltiazem use. RESULTS: In total, 5,390 AF patients, ≥66 years, with continuous DOAC use were identified. Amiodarone was co-prescribed in 6.4% patients and diltiazem was co-prescribed in 11.2% patients. Prior percutaneous coronary intervention (PCI) and coronary artery bypass surgery (CABG) were associated with significantly increased odds of amiodarone co-use (OR 2.51 [95% CI 1.54, 4.09], p = 0.0002 and OR 5.28 [95% CI 3.52, 7.93], p= <0.001, respectively). Patients with a heart failure (HF) history also had increased co-use of amiodarone (OR 2.05 [95% CI 1.57, 2.67], p < 0.001). The presence of chronic obstructive pulmonary disease (COPD) was associated with significantly increased odds of diltiazem co-use (OR 1.58 [95% CI 1.31, 1.9], p=<0.001). CONCLUSIONS: Among AF patients with continuous DOAC use, amiodarone was co-prescribed in 1 in 16 patients and diltiazem was co-prescribed in 1 in 9 patients. Predictors such as history of HF, PCI, CABG or COPD help identify vulnerable populations at increased risk of DDIs.

The Operation of Canada's Only Virtually Operated Radiation Oncology Service During the COVID-19 Pandemic.

PURPOSE: Our institution operates a remote radiation oncology service in Northern Ontario, Canada. Since the start of the coronavirus disease 2019 pandemic, this center has operated without radiation oncologists on site owing to safety precautions, and this study seeks to understand the effect of this shift. METHODS AND MATERIALS: Departmental level data reports were used to investigate differences in metrics between April to May of 2019 and April to May 2020. These metrics include the total number of referrals received, average wait time from referral to consult, the number of cases that underwent peer review before beginning treatment, the total number of fractions given over each period, patient-reported outcomes, and patient satisfaction. We also examined the importance of physical examinations and the use of SABR treatment. RESULTS: There was an observed decrease in the number of referrals received, total number of fractions administered, and number of patients providing patient-reported outcomes. We observed no change in patient wait times, cases undergoing peer review before commencing treatment, or overall patient satisfaction. Challenges were identified in the collection of patient- reported outcomes and the conduction of physical examinations. CONCLUSIONS: This paper provides proof of concept that a radiation clinic can function entirely virtually in the short term without sacrificing patient satisfaction, efficiency, or safety.

Rationale and design of the Women's Ischemia Trial to Reduce Events in Nonobstructive CAD (WARRIOR) trial.

BACKGROUND: Approximately half of all women with anginal symptoms and/or signs of ischemia and no obstructive coronary artery disease (INOCA) referred for coronary angiography have elevated risk for major adverse cardiac events (MACE), poor quality of life and resource consumption. Yet, guidelines focus on symptom management while clinical practice typically advocates only reassurance. Pilot studies of INOCA subjects suggest benefit with intensive medical therapy (IMT) that includes high-intensity statins and angiotensin converting enzyme inhibitors (ACE-I) or receptor blockers (ARB) to provide the rationale for a randomized pragmatic trial to limit MACE. METHODS: The Women's IschemiA TRial to Reduce Events In Non-ObstRuctive CAD is a multicenter, prospective, randomized, blinded outcome evaluation (PROBE design) of a pragmatic strategy of IMT vs usual care (UC) in 4,422 symptomatic women with INOCA (NCT03417388) in approximately 70 United States sites. The hypothesis is that IMT will reduce the primary outcome of first occurrence of MACE by 20% vs. UC at ∼2.5 year followup. Secondary outcomes include quality of life, time to return to "duty"/work, healthcare utilization, angina, cardiovascular death and individual primary outcome components over 3 years follow-up. The study utilizes web-based data capture, e-consents, single IRB and centralized pharmacy distribution of strategy medications directly to patients' homes to reduce site and patient burden. A biorepository will collect blood samples to assess potential mechanisms. CONCLUSIONS: The results of this trial will provide important data necessary to inform guidelines regarding how best to manage this growing and challenging population of women with INOCA.

Maternal carriage of Prevotella during pregnancy associates with protection against food allergy in the offspring.

In mice, the maternal microbiome influences fetal immune development and postnatal allergic outcomes. Westernized populations have high rates of allergic disease and low rates of gastrointestinal carriage of Prevotella, a commensal bacterial genus that produces short chain fatty acids and endotoxins, each of which may promote the development of fetal immune tolerance. In this study, we use a prebirth cohort (n = 1064 mothers) to conduct a nested case-cohort study comparing 58 mothers of babies with clinically proven food IgE mediated food allergy with 258 randomly selected mothers. Analysis of the V4 region of the 16S rRNA gene in fecal samples shows maternal carriage of Prevotella copri during pregnancy strongly predicts the absence of food allergy in the offspring. This association was confirmed using targeted qPCR and was independent of infant carriage of P. copri. Larger household size, which is a well-established protective factor for allergic disease, strongly predicts maternal carriage of P. copri.

Consumption of an Oil Palm Fruit Extract Promotes Large Bowel Health in Rats.

Oil palm fruit is widely used for edible oils, but the health benefits of other components are relatively unknown. We examined if consuming a polyphenol-rich extract of the fruit, from a vegetation by-product of oil processing, which also contains fibre, has gastro-intestinal benefits in rats on a Western-type diet (WD). The oil palm preparation (OPP) was added to food (OPP-F) or drinking water (OPP-D) to provide 50 mg of gallic acid equivalents (GAE)/d and compared to effects of high amylose maize starch (HAMS; 30%) in the diet or green tea extract (GT; 50 mg GAE/d) in drinking water over 4 wk. OPP treatments induced some significant effects (P < 0.05) compared to WD. OPP-D increased caecal digesta mass, caecal digesta concentrations of total SCFA, acetate and propionate (OPP-F increased caecal butyrate concentration), the numbers of mucus-producing goblet cells per colonic crypt, and caecal digesta abundance of some bacteria which may provide benefit to the host (Faecalibacterium prausnitzii, Akkermansia muciniphila and Ruminococcus gnavus). HAMS induced similar effects but with greater potency and had a broader impact on microbe populations, whereas GT had minimal impacts. These results suggest dietary OPP may benefit the large bowel.

Frequency of Immune Cell Subtypes in Peripheral Blood Correlates With Outcome for Patients With Metastatic Breast Cancer Treated With High-Dose Chemotherapy.

BACKGROUND: The frequency of circulating leukocytes has been shown to be a prognostic factor in patients being treated for different types of cancer. In breast cancer, tumor-infiltrating leukocytes may predict patient outcome, but few studies have investigated such associations for circulating leukocytes. PATIENTS AND METHODS: Multiparametric flow cytometry was used to examine the immunophenotypes of circulating peripheral blood mononuclear cells for 88 patients with metastatic breast cancer, which was then correlated to breast cancer-specific survival. Patients had been treated either with high-dose cyclophosphamide-containing regimens (group 1, n = 51 patients) or high-dose paclitaxel-containing regimens (group 2, n = 37 patients). RESULTS: The frequency of peripheral blood CD14+ monocytes indicated prognosis for patients in group 1 (but not group 2), while higher levels of CD11c+ dendritic cells indicated a better prognosis for patients in group 2 (but not group 1). The frequency of a number of different CD4+ or CD8+ T cell subtypes also predicted prognosis for patients in group 2. For example, patients in group 2 with a higher frequency of circulating CD4+ or CD8+ naive T cells (CD45RA+CD95-CD27+CD28+) showed a poorer prognosis. In contrast, T cells were not associated with prognosis for patients in group 1. CONCLUSION: Circulating leukocytes can predict clinical outcome for patients with breast cancer. Prediction of clinical outcome in this cohort of metastatic breast cancer patients was specific to the type of chemotherapy, and this finding is likely to apply to other therapies.

Design, Synthesis, and Preclinical Efficacy of Novel Nonretinoid Antagonists of Retinol-Binding Protein 4 in the Mouse Model of Hepatic Steatosis.

Retinol-binding protein 4 (RBP4) serves as a transporter for all- trans-retinol (1) in the blood, and it has been proposed to act as an adipokine. Elevated plasma levels of the protein have been linked to diabetes, obesity, cardiovascular diseases, and nonalcoholic fatty liver disease (NAFLD). Recently, adipocyte-specific overexpression of RBP4 was reported to cause hepatic steatosis in mice. We previously identified an orally bioavailable RBP4 antagonist that significantly lowered RBP4 serum levels in Abca4-/- knockout mice with concomitant normalization of complement system protein expression and reduction of bisretinoid formation within the retinal pigment epithelium. We describe herein the discovery of novel RBP4 antagonists 48 and 59, which reduce serum RBP4 levels by >80% in mice upon acute oral dosing. Furthermore, 59 demonstrated efficacy in the transgenic adi-hRBP4 murine model of hepatic steatosis, suggesting that RBP4 antagonists may also have therapeutic utility for the treatment of NAFLD.

Impact of comprehensive hospice palliative care on end-of-life care: a propensity-score-matched retrospective observational study.

BACKGROUND: Access to hospice palliative care may improve quality of life, reduce the use of potentially aggressive end-of-life care and allow for death to occur outside of an acute care hospital. The aim of this study was to examine the impact of an ambulatory hospice palliative care program on end-of-life care compared to care received by a matched control group of deceased patients. METHODS: This retrospective study included patients who received hospice palliative care through the Symptom Management Program in Sudbury, Ontario, during 2012-2015. Using linked administrative health records, we defined a propensity-matched control group and derived 4 previously defined variables associated with aggressive end-of-life care (chemotherapy received in the last 2 wk of life, > 1 emergency department visit within 30 d of death, > 1 hospital admission within 30 d of death and at least 1 intensive care unit admission within 30 d of death). We also examined place of death. We measured family/caregiver satisfaction with care 3 months after the patient's death using the FAMCARE questionnaire. RESULTS: Of 914 eligible decedents enrolled in the Symptom Management Program, 754 (82.5%) were matched. Receiving care through the program was protective for most measures of aggressive end-of-life care (absolute risk reduction [ARR] 12.73, 95% confidence interval [CI] 12.65-12.81 for any end-of-life care outcome) and death in an acute care setting (ARR 19.89, 95% CI 19.78-20.00). Of the 450 family caregivers invited to complete the FAMCARE questionnaire, 190 (42.2%) returned completed surveys; following data linkage and matching, 96 (21.3%) were available for analysis. Satisfaction with care received within the program appeared high (mean total score 85.72/100). INTERPRETATION: Provision of hospice palliative care through this ambulatory program was associated with lower use of aggressive end-of-life care and death outside of an acute care hospital. Improving access could be expected to provide positive benefits at the individual and system level.