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Purpose To provide population-level estimates of the association of frailty with one-year outcomes after critical illness. Materials and methods Retrospective cohort study of patients who survived an ICU admission between April 2002 and March 2015. Pre-existing frailty was classified using the Johns Hopkins Adjusted Clinical Groups frailty indicator. Multivariable Cox regression and Fine and Gray models were used to examine the association between frailty and mortality and hospital readmission. Results Of 534,991 patients, 19.3% had pre-existing frailty. Compared to non-frail survivors, at one-year frail patients had higher mortality (18.3% vs 9.5%, adjusted HR 1.17 95% CI: 1.15–1.19) and hospital readmission (44.4% vs 36.6%, adjusted HR 1.10 95% CI: 1.08–1.11) and a CAN$19,628 (95% CI: $19,279–$19,997) greater increase in healthcare costs compared to the year prior to hospitalization. The association between frailty and mortality was stronger among older individuals, but the risk of readmission among frail patients decreased with age. Conclusion Patients with pre-existing frailty who develop critical illness have higher rates of hospital readmission and death than patients without frailty, and age modifies these associations. These data highlight the importance of considering both frailty and age when seeking to identify at-risk patients who might benefit from closer follow-up after discharge.

Background Many patients use opioids chronically before surgery; it is unclear if surgery alters the likelihood of ongoing opioid consumption in these patients. Methods We performed a population-based matched cohort study of adults in Ontario, Canada undergoing one of 16 non-orthopaedic surgical procedures and who were chronically using opioids, defined as (1) an opioid prescription that overlapped the index date and (2) either a total of 120 or more cumulative calendar days of filled opioid prescriptions, or 10 or more prescriptions filled in the prior year. Each surgical patient was matched based on age, sex, Charlson comorbidity index, and daily preoperative opioid dose to three non-surgical patients who were also chronic opioid users. The primary outcome was time to opioid discontinuation. Results The cohort included 4755 surgical and 14 265 matched non-surgical patients. After adjustment for sociodemographic characteristics and comorbidities, surgery was associated with an increased likelihood of opioid discontinuation (adjusted hazard ratio: 1.34, 95% confidence interval [CI]: 1.27, 1.42). Among surgical patients, factors associated with a reduced odds of discontinuation included a mean preoperative opioid dose above 90 morphine milligram equivalents (adjusted odds ratio [aOR]: 0.39; 95% CI: 0.32, 0.49) or filling a prescription for oxycodone (aOR: 0.73; 95% CI: 0.56, 0.98). Receipt of an in-patient Acute Pain Service consultation (aOR: 1.34; 95% CI: 1.06, 1.69) or residing in the highest neighbourhood income quintile (aOR: 1.35; 95% CI: 1.04, 1.79) were associated with a greater odds of opioid discontinuation. Conclusions For chronic opioid users, surgery was associated with an increased likelihood of discontinuation of opioids in the following year compared with non-surgical chronic opioid users.

BACKGROUND: Medical assistance in dying (MAiD) was legalized across Canada in June 2016. Some have expressed concern that patient requests for MAiD might be driven by poor access to palliative care and that social and economic vulnerability of patients may influence access to or receipt of MAiD. To examine these concerns, we describe Ontario’s early experience with MAiD and compare MAiD decedents with the general population of decedents in Ontario. METHODS: We conducted a retrospective cohort study comparing all MAiD-related deaths with all deaths in Ontario, Canada, between June 7, 2016, and Oct. 31, 2018. Clinical and demographic characteristics were collected for all MAiD decedents and compared with those of all Ontario decedents when possible. We used logistic regression analyses to describe the association of demographic and clinical factors with receipt of MAiD. RESULTS: A total of 2241 patients (50.2% women) were included in the MAiD cohort, and 186 814 in the general Ontario decedent cohort. Recipients of MAiD reported both physical (99.5%) and psychologic suffering (96.4%) before the procedure. In 74.4% of cases, palliative care providers were involved in the patient’s care at the time of the MAiD request. The statutory 10-day reflection period was shortened for 26.6% of people. Compared with all Ontario decedents, MAiD recipients were younger (mean 74.4 v. 77.0 yr, standardized difference 0.18);, more likely to be from a higher income quintile (24.9% v. 15.6%, standardized difference across quintiles 0.31); less likely to reside in an institution (6.3% v. 28.0%, standardized difference 0.6); more likely to be married (48.5% v. 40.6%) and less likely to be widowed (25.7% v. 35.8%, standardized difference 0.34); and more likely to have a cancer diagnosis (64.4% v. 27.6%, standardized difference 0.88 for diagnoses comparisons). INTERPRETATION: Recipients of MAiD were younger, had higher income, were substantially less likely to reside in an institution and were more likely to be married than decedents from the general population, suggesting that MAiD is unlikely to be driven by social or economic vulnerability. Given the high prevalence of physical and psychologic suffering, despite involvement of palliative care providers in caring for patients who request MAiD, future studies should aim to improve our understanding and treatment of the specific types of suffering that lead to a MAiD request.

Background Pregnancy-related critical illness results in approximately 300,000 deaths globally each year. The objective was to describe the variation in ICU admission and the contribution of patient- and hospital-based factors in ICU admission among acute care hospitals for pregnant and postpartum women in Canada. Methods A nationwide cohort study between 2004 and 2015, comprising all pregnant or postpartum women admitted to Canadian hospitals. The primary outcome was ICU admission. Secondary outcomes were severe maternal morbidity (a potentially life-threatening condition) and maternal death (during and within 6 weeks after pregnancy). The proportion of total variability in ICU admission rates due to the differences among hospitals was described using the median odds ratio from multi-level logistic regression models, adjusting for individual hospital clusters. Results There were 3,157,248 identifiable pregnancies among women admitted to 342 Canadian hospitals. The overall ICU admission rate was 3.2 per 1000 pregnancies. The rate of severe maternal morbidity was 15.8 per 1000 pregnancies, of which 10% of women were admitted to an ICU. The most common severe maternal morbidity events included postpartum hemorrhage (n = 16,364, 0.52%) and sepsis (n = 11,557, 0.37%). Of the 195 maternal deaths (6.2 per 100,000 pregnancies), only 130 (67%) were admitted to ICUs. Patients dying in hospital, without admission to ICU, included those with cardiovascular compromise, hemorrhage, and sepsis. For 2 pregnant women with similar characteristics at different hospitals, the average (median) odds of being admitted to ICU was 1.92 in 1 hospital compared to another. Hospitals admitting the fewest number of pregnant patients had the highest incidence of severe maternal morbidity and mortality. Patient-level factors associated with ICU admission were maternal comorbidity index (OR 1.88 per 1 unit increase, 95%CI 1.86–1.99), urban residence (OR 1.09, 95%CI 1.02–1.16), and residing at the lowest income quintile (OR 1.44, 95%CI 1.34–1.55). Conclusions Most women who experience severe maternal morbidity are not admitted to an ICU. There exists a wide hospital-level variability in ICU admission, with patients living in urban locations and patients of lowest income levels most likely to be admitted to ICU. Cardiovascular compromise, hemorrhage, and sepsis represent an opportunity for improved patient care and outcomes.

Objective Pregnancy-associated morbidity results in hundreds of thousands of deaths annually worldwide. Reducing maternal mortality is a key United Nations Millennium Development Goal. Although maternal mortality has declined in high-income countries, contemporary estimates of maternal morbidity and mortality trends in Canada are lacking. Methods This population-based study investigated all antepartum, peripartum, and postpartum women presenting to an acute care hospital in Canada from April 1, 2004 to March 31, 2015. The primary outcome was the change in rates of severe maternal morbidity over time. Secondary outcomes included severe maternal mortality and intensive care unit admission, including by province and territory (level of evidence: II2). Results The cohort comprised 2 035 453 mothers with 3 162 303 pregnancies. There were 17.7 per 1000 episodes of severe maternal morbidity, with annual increases of 1.3% (95% confidence interval [CI] 0.60–2.0) for severe maternal morbidity. The maternal mortality rate was 6.2 per 100 000 deliveries and stable over time (estimated percentage of annual change of −0.46%; 95% CI −5.0 to 4.3). The most common causes of severe maternal morbidity were postpartum hemorrhage (5.5 per 1000 deliveries), sepsis (3.8 per 1,000 deliveries), and cardiac failure (1.5 per 1000 deliveries). Severe maternal morbidity varied across Canadian regions but was highest in the Territories at 22.8 per 1000 deliveries. Conclusion Although maternal mortality has been stable in Canada over time, rates of severe maternal morbidity are increasing and are associated with substantial regional variation, with the highest rates experienced by women in the northern Territories.

With alcohol readily accessible to adolescents, its consumption leads to many adverse effects, including impaired learning, attention, and behavior. Adolescents report higher rates of binge drinking compared to adults. They are also more prone to substance use disorder in adulthood due to physiological changes during the adolescent developmental period. We used C57BL/6J male and female mice to investigate the long-lasting impact of binge ethanol exposure during adolescence on voluntary ethanol intake and open field behavior during later adolescence (Experiment 1) and during emerging adulthood (Experiment 2). The present set of experiments were divided into four stages: (1) adolescent intermittent vapor inhalation exposure, (2) abstinence, (3) voluntary ethanol intake, and (4) open field behavioral testing. During adolescence, male and female mice were exposed to air or ethanol using intermittent vapor inhalation from postnatal day (PND) 28-42. Following this, mice underwent short-term abstinence from PND 43-49 (Experiment 1) or protracted abstinence from PND 43-69 (Experiment 2). Beginning on PND 50-76 or PND 70-97, mice were assessed for intermittent voluntary ethanol consumption using a two-bottle choice drinking procedure over 28 days. Male adolescent ethanol-exposed mice showed increased ethanol consumption following short-term abstinence and following protracted abstinence. In contrast, female mice showed no changes in ethanol consumption following short-term abstinence and decreased ethanol consumption following protracted abstinence. There were modest changes in open field behavior following voluntary ethanol consumption in both experiments. These data demonstrate a sexually divergent shift in ethanol consumption following binge ethanol exposure during adolescence and differences in open field behavior. These results highlight sex-dependent vulnerability to developing substance use disorders in adulthood.

Background Patients with chronic disease prefer an adequately supported death at home, but often die in the hospital. We assessed temporal trends and sex differences in healthcare intensity and location of death among decedents with heart failure. Methods and Results This was a retrospective cohort study of adults with heart failure who died between April 1, 2004 and March 31, 2017 in Ontario, Canada. We used population‐based administrative databases to assess healthcare utilization during the last 6 months of life and applied multilevel multivariable logistic regression to assess whether sex was independently associated with location of death. Among 396 024 decedents with heart failure, mean (SD) age was 81.8 (10.7) years, 51.5% were women, and 53.4% had in‐hospital deaths. From 2004 to 2016, there was an increase in patients receiving mechanical ventilation (15.1%–19.6%), hemodialysis (5.2%–6.8%), and cardiac revascularization (1.7%–2.3%). Relative to men, women spent fewer days in a hospital (mean, 16.4 versus 18.3; mean difference, 1.9; 95% CI, 1.7–2.0; P P P P P Conclusions Among decedents with heart failure, invasive care in the last 6 months increased in prevalence over time but was less common in women, who had lower odds of dying in a hospital.

Rationale: Patients who receive invasive mechanical ventilation (IMV) are usually exposed to opioids as part of their sedation regimen. The rates of posthospital prescribing of opioids are unknown. Objectives: To determine the frequency of persistent posthospital opioid use among patients who received IMV. Methods: We assessed opioid-naive adults who were admitted to an ICU, received IMV, and survived at least 7 days after hospital discharge in Ontario, Canada over a 26-month period (February, 2013 through March, 2015). The primary outcome was new, persistent opioid use during the year after discharge. We assessed factors associated with persistent use by multivariable logistic regression. Patients receiving IMV were also compared with matched hospitalized patients who did not receive intensive care (non-ICU). Measurements and Main Results: Among 25,085 opioid-naive patients on IMV, 5,007 (20.0%; 95% confidence interval [CI], 19.5–20.5) filled a prescription for opioids in the 7 days after hospital discharge. During the next year, 648 (2.6%; 95% CI, 2.4–2.8) of the IMV cohort met criteria for new, persistent opioid use. The patient characteristic most strongly associated with persistent use in the IMV cohort was being a surgical (vs. medical) patient (adjusted odds ratio, 3.29; 95% CI, 2.72–3.97). The rate of persistent use was slightly higher than for matched non-ICU patients (2.6% vs. 1.5%; adjusted odds ratio, 1.37 [95% CI, 1.19–1.58]). Conclusions: A total of 20% of IMV patients received a prescription for opioids after hospital discharge, and 2.6% met criteria for persistent use, an average of 300 new persistent users per year in a population of 14 million. Receipt of surgery was the factor most strongly associated with persistent use.

There are an increasing number of “big data” studies in anesthesia that seek to answer clinical questions by observing the care and outcomes of many patients across a variety of care settings. This Readers’ Toolbox will explain how to estimate the influence of patient factors on clinical outcome, addressing bias and confounding. One approach to limit the influence of confounding is to perform a clinical trial. When such a trial is infeasible, observational studies using robust regression techniques may be able to advance knowledge. Logistic regression is used when the outcome is binary (e.g., intracranial hemorrhage: yes or no), by modeling the natural log for the odds of an outcome. Because outcomes are influenced by many factors, we commonly use multivariable logistic regression to estimate the unique influence of each factor. From this tutorial, one should acquire a clearer understanding of how to perform and assess multivariable logistic regression.

Intestinal damage driven by unrestricted immune responses against the intestinal microbiota can lead to the development of inflammatory diseases including inflammatory bowel disease. How such breakdown in tolerance occurs alongside the mechanisms to reinforce homeostasis with the microbiota are a focus of many studies. Our recent work demonstrates coordinated interactions between intact microbiota and CX(3)CR1 expressing intestinal antigen presenting cells (APCs) that limits T helper 1 cell responses and promotes differentiation of regulatory T cells (Treg) against intestinal antigens including pathogens, soluble proteins and the microbiota itself. We find a microbial attachment to intestinal epithelial cells is necessary to support these anti-inflammatory immune functions. In this addendum, we discuss how our findings enhance understanding of microbiota-directed homeostatic functions of the intestinal immune system and implications of modulating this interaction in ameliorating inflammatory disease.

PURPOSE Opioids are commonly prescribed for acute pain after surgery. However, it is unclear whether these prescriptions are usually modified to account for patient age and, in particular, opioid-related risks among older adults. We therefore sought to describe postoperative opioid prescriptions filled by opioid-naive adults undergoing four common surgical procedures. METHODS This retrospective cohort study used individually linked surgery and prescription opioid dispensing data from Ontario, Canada to create a population-based sample of 135 659 opioid-naive adults who underwent one of four surgical procedures (laparoscopic cholecystectomy, laparoscopic appendectomy, knee meniscectomy, or breast excision) between 2013 and 2017. Patient age, in years, was categorized as 18 to 64, 65 to 69, 70 to 74, and 75 and over. Postoperative opioid prescriptions were identified as those filled on or within 6 days of surgical discharge date. For those who filled a prescription, we assessed the total morphine milligram equivalent (MME) dose, types of opioids, and any subsequent opioid prescriptions filled within 30 days of surgical discharge date. Results were presented stratified by surgical procedure. RESULTS For three of the four surgical procedures we assessed, the proportion of patients who filled a postoperative opioid prescription decreased with age (P

Humans and their microbiota have coevolved a mutually beneficial relationship in which the human host provides a hospitable environment for the microorganisms and the microbiota provides many advantages for the host, including nutritional benefits and protection from pathogen infection1. Maintaining this relationship requires a careful immune balance to contain commensal microorganisms within the lumen while limiting inflammatory anti-commensal responses1,2. Antigen-specific recognition of intestinal microorganisms by T cells has previously been described3,4. Although the local environment shapes the differentiation of effector cells3–5 it is unclear how microbiota-specific T cells are educated in the thymus. Here we show that intestinal colonization in early life leads to the trafficking of microbial antigens from the intestine to the thymus by intestinal dendritic cells, which then induce the expansion of microbiota-specific T cells. Once in the periphery, microbiota-specific T cells have pathogenic potential or can protect against related pathogens. In this way, the developing microbiota shapes and expands the thymic and peripheral T cell repertoire, allowing for enhanced recognition of intestinal microorganisms and pathogens. In young mice, antigens from the gut microbiota are trafficked by CX3CR1+ dendritic cells from the gut to the thymus, where they induce the expansion of T cells that are specific to commensal microorganisms.

Signaling by Toll-like receptors (TLRs) on intestinal epithelial cells (IECs) is critical for intestinal homeostasis. To visualize epithelial expression of individual TLRs in vivo, we generated five strains of reporter mice. These mice revealed that TLR expression varied dramatically along the length of the intestine. Indeed, small intestine (SI) IECs expressed low levels of multiple TLRs that were highly expressed by colonic IECs. TLR5 expression was restricted to Paneth cells in the SI epithelium. Intestinal organoid experiments revealed that TLR signaling in Paneth cells or colonic IECs induced a core set of host defense genes, but this set did not include antimicrobial peptides, which instead were induced indirectly by inflammatory cytokines. This comprehensive blueprint of TLR expression and function in IECs reveals unexpected diversity in the responsiveness of IECs to microbial stimuli, and together with the associated reporter strains, provides a resource for further study of innate immunity.

Objective To evaluate whether the male predominance of older people admitted to intensive care units (ICUs) is due to gender differences in the presence of spouses, partners, or children; rates of gender-specific disease; or triage decisions made by health system personnel. Data sources and collection Three population-based datasets, 2004-2012, of Canadians ≥65 years: provincial health care data from Manitoba (n = 250 190) and national data of nursing home residents (n = 133 982) and community-based homecare recipients (n = 210 090). Study design Retrospective observational study, using multivariable Cox proportional hazards and logistic regression. Principal findings Males predominated in ICU admissions: from Manitoba (hazard ratio [HR] = 1.87, 95% CI = 1.80-1.95), nursing homes (HR = 1.47, 1.35-1.60), and homecare (odds ratio = 1.14, 1.11-1.17). Adjustment for spouses, partners, and children did not attenuate this effect. The HR for gender was lower by 13.5 percent, relative, after excluding ICU care for cardiac causes. Male predominance was not present during a second ICU admission among survivors of a first ICU-containing hospitalization (HR = 1.07, 0.96-1.20). Conclusions In three older cohorts, the male predominance of ICU admission was not explained by gender differences in the presence of a spouse, partner, or children, or cardiac disease rates. The third finding suggests that triage bias is unlikely to be responsible for the male predominance.

Defective tissue repair is a hallmark of many inflammatory disorders including, inflammatory bowel disease (IBD). While it is clear that high fat diets (HFD) can exacerbate inflammatory disease by increasing inflammation, the direct effect of lipids on tissue homeostasis and repair remains undefined. We show here that short term exposure to HFD directly impairs barrier repair after intestinal epithelial damage by interfering with recognition and uptake of apoptotic neutrophils by intestinal macrophages. Apoptotic neutrophil uptake induces macrophage IL-10 production, which is lacking after intestinal damage in the context of HFD. Overexpression of IL-10 rescues repair defects after HFD treatment, but not if epithelial cells lack the IL-10 receptor, highlighting the key role of IL-10 in barrier repair. These findings demonstrate a previously unidentified mechanism by which dietary lipids directly interfere with homeostatic processes required to maintain tissue integrity.

Key Points Question Is maternal age associated with severe maternal morbidity and with maternal death in Canada? Findings In this nationwide population-based cohort study of 3.1 million pregnancies in Canada, severe maternal morbidity has increased over the past decade, and this trend coincided with an increase over time in maternal age and in the proportion of pregnancies to older mothers. Extremes of maternal age, especially those 45 years or older compared with those aged 20 to 24 years, were associated with severe maternal morbidity and with maternal mortality. Meaning Increasing maternal age was an independent characteristic associated with severe maternal morbidity and mortality., This nationwide population-based cohort study investigates the association of maternal age, adjusting for patient-level and hospital-level factors, with severe maternal morbidity and maternal death in Canada., Importance Over the past 2 decades, there has been a trend toward increasing maternal age in many high-income countries. Maternal age may lead to greater attendant morbidity and mortality for Canadian mothers. Objective To investigate the association of maternal age, adjusting for patient-level and hospital-level factors, with severe maternal morbidity (SMM) and maternal death in Canada. Design, Setting, and Participants A nationwide population-based cohort study of all antepartum, peripartum, and postpartum women and adolescents seen at Canadian acute care hospitals from April 1, 2004, to March 31, 2015. All analyses were completed on September 13, 2018. Exposures Maternal age at the index delivery. Main Outcomes and Measures Severe maternal morbidity and maternal death during pregnancy and within 6 weeks after termination of pregnancy. Results During the study period, there were 3 162 303 new pregnancies (mean [SD] maternal age, 29.5 [5.6] years) and 3 533 259 related hospital admissions. There were 54 219 episodes of SMM (17.7 cases per 1000 deliveries) in the entire study period, with a 9.8% relative increase from 2004-2005 to 2014-2015, in addition to an increasing proportion of pregnancies to older mothers. Independent patient-level factors associated with SMM included increasing Maternal Comorbidity Index; maternal age 19 years or younger and 30 years or older, with the greatest risk experienced by women 45 years or older (odds ratio [OR], 2.69; 95% CI, 2.34-3.06 compared with maternal age 20-24 years); and lowest income quintile (OR, 1.19; 95% CI, 1.14-1.22 compared with highest income quintile). Hospital-level factors associated with SMM included specific provinces. Independent patient-level factors associated with maternal mortality included increasing Maternal Comorbidity Index, age 40 to 44 years (OR, 3.39; 95% CI, 1.68-6.82 compared with age 20-24 years), age 45 years or older (OR, 4.39; 95% CI, 1.01-19.10 compared with age 20-24 years), and lowest income quintile (OR, 4.14; 95% CI, 2.03-8.50 compared with highest income quintile). Hospital-level factors associated with maternal mortality included lowest hospital pregnancy volume. Conclusions and Relevance In Canada, maternal age and SMM have increased over the past decade. Results of this study suggest that province of residence, maternal comorbidity, residence income quintile, and extremes of maternal age, especially those 45 years or older, were associated with SMM and mortality. These findings are relevant to prospective parents, their health care team, and public health planning.

To assess temporal trends in pre-existing opioid exposure prior to hospitalization among elderly intensive care unit (ICU) patients and its association with adverse outcomes.We performed a population-based retrospective cohort study using health administrative data from the province of Ontario, Canada. We included all older adult (65 years) admissions to an ICU between April 2002 and March 2015. The exposure was opioid use before admission categorized as chronic use, intermittent use, and non-use.The cohort included 711,312 elderly patient admissions to an ICU. Of these, 6.8% (n = 48,363) were chronic opioid users, 28.1% (n = 200,149) intermittent users, and 65.0% (n = 462,800) non-users. Compared with non-users, chronic opioid users and intermittent users had higher in-hospital mortality (adjusted odds ratio: 1.12, 95% CI, 1.09-1.15, p 0.0001 for chronic users; adjusted odds ratio: 1.09, 95% CI, 1.07-1.11, p 0.0001 for intermittent users), and a lower subdistribution hazard of time to hospital discharge, translating to a longer hospital length of stay (adjusted hazard ratio: 0.87, 95% CI, 0.85-0.88, p 0.0001 for chronic users; adjusted hazard ratio: 0.93, 95% CI, 0.92-0.94, p 0.0001 for intermittent users).Among elderly ICU patients, opioid exposure prior to admission is prevalent and use is associated with higher in-hospital mortality.

Epidemiological evidence finds cigarette smoking is a common risk factor for a number of diseases, not only in the lung but also in other tissues, such as the gastrointestinal tract. While it is well-documented that smoking directly drives lung inflammatory disease, how it promotes disease in peripheral tissues is incompletely understood. In this study, we utilized a mouse model of short-term smoke exposure and found increased Th17 cells and neutrophilia in the lung as well as in the circulation. Following intestinal inflammatory challenge, smoke exposed mice showed increased pathology which corresponds to enhanced intestinal Th17 cells, ILC3 and neutrophils within intestinal tissue. Using cellular depletion and genetic deficiencies, we define a cellular loop by which IL-17A and downstream neutrophils drive cigarette smoke-enhanced intestinal inflammation. Collectively, cigarette smoke induced local lung Th17 responses lead to increased systemic susceptibility to inflammatory insult through enhanced circulating neutrophils. These data demonstrate a cellular pathway by which inflammatory challenge in the lung can sensitize the intestine to enhanced pathological innate and adaptive immune responses.

Objective Macrophage accumulation in adipose tissue (AT) during obesity contributes to inflammation and insulin resistance. Recruitment of monocytes to obese AT has been the most studied mechanism explaining this accumulation. However, recent evidence suggests that recruitment-independent mechanisms may also regulate pro-inflammatory AT macrophage (ATM) numbers. The role of increased ATM survival during obesity has yet to be explored. Results We demonstrate that activation of apoptotic pathways is significantly reduced in ATMs from diet-induced and genetically obese mice. Concurrently, pro-survival Bcl-2 family member protein levels and localization to the mitochondria is elevated in ATMs from obese mice. This increased pro-survival signaling was associated with elevated activation of the transcription factor, NF-κB, and increased expression of its pro-survival target genes. Finally, an obesogenic milieu increased ATM viability only when NF-κB signaling pathways were functional. Conclusions Our data demonstrate that obesity promotes survival of inflammatory ATMs, possibly through an NF-κB-regulated mechanism., Graphical abstract, Highlights • Macrophage apoptosis is decreased in obese adipose tissue. • ATMs from obese mice display increased mitochondrial localization of Bcl-2. • The pro-survival targets of NF-κB are increased in ATMs from obese mice. • NF-κB activation in ATMs during metabolic stimulation increases their survival. • Decreased ATM apoptosis contributes to macrophage accumulation in obesity.

Rationale: Mechanically ventilated patients require complex care and are at high risk for rehospitalization, but different systems of care may result in different hospital discharge practices and rates of rehospitalization. Objectives: To compare lengths of hospitalization, discharge patterns, and rehospitalization rates in New York in the United States and Ontario in Canada. Methods: We conducted a retrospective cohort study of mechanically ventilated patients who survived an acute care hospitalization in New York or Ontario from 2010 to 2012, using linkable administrative healthcare data. Results: The primary outcome was the cumulative incidence of first rehospitalization within 30 days of discharge, accounting for the competing risk of death. Of 71,063 mechanically ventilated patients in New York, and 41,875 in Ontario who survived to hospital discharge, median length of initial hospital stay was similar in New York and Ontario (15 d, interquartile range = 8–28 vs. 16 d [9–30]), but was systematically shorter in New York when stratified by patient subgroups of different illness severity. Fewer patients in New York were discharged directly home (53.6% vs. 71.4%). Of patients in New York, 15,527 (cumulative incidence 21.9%) had a first rehospitalization within 30 days versus 5,580 (cumulative incidence 13.3%) in Ontario (P

Purpose Pregnancy-related critical illness leads to death for 3–14% of affected women. Although identifying patients at risk could facilitate preventive strategies, guide therapy, and help in clinical research, no prior systematic review of this literature exploring the validity of risk prediction models for maternal mortality exists. Therefore, we have systematically reviewed and meta-analyzed risk prediction models for maternal mortality. Methods Search strategy: MEDLINE, EMBASE and Scopus, from inception to May 2017. Selection criteria: Trials or observational studies evaluating risk prediction models for maternal mortality. Data collection and analysis: Two reviewers independently assessed studies for eligibility and methodological quality, and extracted data on prediction performance. Results Thirty-eight studies that evaluated 12 different mortality prediction models were included. Mortality varied across the studies, with an average rate 10.4%, ranging from 0 to 41.7%. The Collaborative Integrated Pregnancy High-dependency Estimate of Risk (CIPHER) model and the Maternal Severity Index had the best performance, were developed and validated from studies of obstetric population with a low risk of bias. The CIPHER applies to critically ill obstetric patients (discrimination: area under the receiver operating characteristic curve (AUC) 0.823 (0.811–0.835), calibration: graphic plot [intercept—0.09, slope 0.92]). The Maternal Severity Index applies to hospitalized obstetric patients (discrimination: AUC 0.826 [0.802–0.851], calibration: standardized mortality ratio 1.02 [0.86–1.20]). Conclusions Despite the high heterogeneity of the study populations and the limited number of studies validating the finally eligible prediction models, the CIPHER and the Maternal Severity Index are recommended for use among critically ill and hospitalized pregnant and postpartum women for risk adjustment in clinical research and quality improvement studies. Neither index has sufficient discrimination to be applicable for clinical decision making at the individual patient level.

Key Points Question What are the patterns of care at the end of life for physicians compared with nonphysicians? Findings In this cohort study of 2507 physicians and 7513 nonphysicians who died in Ontario, Canada, physicians were no more likely to die at home than nonphysicians. Overall, they did not consistently opt for less-aggressive care but instead used both intensive and palliative care more than nonphysicians. Meaning These findings highlight a more nuanced perspective of what physicians may perceive to be optimal care at the end of life., This cohort study compares the location of death and measures of health care use in the last 6 months of life for physicians vs nonphysicians in Canada., Importance The idea that physicians as patients choose less-aggressive care at the end of life for themselves is an often-cited rationale to advocate for less technology-laden end-of-life care. Objective To assess end-of-life care received by physicians compared with nonphysicians in a system with universal health care. Design, Setting, and Participants In this population-level decedent cohort study of data from April 1, 2004, through March 31, 2015 (fiscal years 2004-2014), in Ontario, Canada, 2507 physicians were matched approximately 1:3 to 7513 nonphysicians (ie, individuals who never were registered as a physician with the College of Physicians and Surgeons of Ontario) according to age, sex, income quintile, and location of residence. Main Outcomes and Measures The primary outcome was location of death. Other outcomes included measures of health care use in the last 6 months of life. Differences were assessed using Poisson regression with robust error variances, adjusting for the Charlson Comorbidity Index. Results In total, 2516 physicians and 954 836 nonphysicians died between April 1, 2004, and March 31, 2015, in Ontario; 2247 physicians (89.3%) and 474 182 nonphysicians (49.7%) were men. The median (interquartile range) age at death was 82 (74-87) years for the physicians and 80 (68-87) years for the nonphysicians. After matching, data for 2507 physicians and 7513 nonphysicians were analyzed. For physicians, the risk of death at home was no different from that for nonphysicians (42.8% vs 39.0%; adjusted relative risk [aRR], 1.04; 95% CI, 0.99-1.09), but the risk of death in an intensive care unit was increased (11.9% vs 10.0%; aRR, 1.22; 95% CI, 1.08-1.39). In the prior 6 months, physicians had a decreased risk of an emergency department visit (73.0% vs 78.4%; aRR, 0.96; 95% CI, 0.94-0.98) but increased risks of an intensive care unit admission (20.8% vs 19.1%; aRR, 1.14; 95% CI, 1.05-1.24) and of receipt of palliative care services (52.9% vs 47.4%; aRR, 1.18; 95% CI, 1.13-1.23). Among a subgroup of 457 physicians and 1347 nonphysicians with cancer, the risk of death at home or intensive care unit was increased (37.6% vs 28.6%; aRR, 1.30; 95% CI, 1.13-1.50), as was the risk of receiving chemotherapy in the last 6 months of life. Conclusions and Relevance There was no difference overall for physicians compared with nonphysicians in terms of the likelihood of dying at home; physicians were more likely to die in an intensive care unit and to receive chemotherapy, but also to receive palliative care services. These findings suggest that physicians do not consistently opt for less-aggressive care but instead receive end-of-life care that includes both intensive and palliative care. These findings inform a more nuanced perspective of what physicians may perceive to be optimal care at the end of life.

Limited data are available to characterize the long-term outcomes and associated costs for patients who require prolonged mechanical ventilation (PMV; defined here as mechanical ventilation for longer than 21 d).To examine the association between PMV and mortality, health care utilization, and costs after critical illness.Population-based cohort study of adults who received mechanical ventilation in an intensive care unit (ICU) in Ontario, Canada between 2002 and 2013.We used linked administrative databases to determine discharge disposition, and ascertain 1-year mortality (primary outcome), readmissions to hospital and ICU, and health care costs for hospital survivors. Overall, 11,594 (5.4%) patients underwent PMV, with 42.4% of patients dying in the hospital (vs. 27.6% of patients who did not undergo prolonged ventilation; P 0.0001). Patients on prolonged ventilation were more frequently discharged to other facilities or home with health care support (84.8 vs. 43.5%, P 0.0001). Among hospital survivors, estimated mortality was higher for patients who underwent PMV: 16.6 versus 11% at 1 year and 42.0 versus 30.4% at 5 years. At 1 year after hospital discharge, patients on prolonged ventilation had higher rates of hospital readmission (47.2 vs. 37.7%; adjusted odds ratio = 1.20; 95% confidence interval = 1.14-1.26), ICU readmission (19.0 vs. 11.6%; adjusted odds ratio = 1.49; 95% confidence interval: 1.39, 1.60), and total health care costs: median (interquartile range) Can $32,526 ($20,821-$56,102) versus Can $13,657 ($5,946-$38,022). Increasing duration of mechanical ventilation was associated with higher mortality and health care utilization.Critically ill patients who undergo mechanical ventilation in an ICU for longer than 21 days have high in-hospital mortality and greater postdischarge mortality, health care utilization, and health care costs compared with patients who undergo mechanical ventilation for a shorter period of time.

Background The purpose of this study was to examine hospital mortality, long-term mortality, and health service utilization among critically ill patients. We also determined whether these outcomes differed according to demographic and clinical characteristics. Methods We conducted a retrospective cohort study of adults (age ≥18 years) who survived admission to an intensive care unit (ICU) in Ontario, Canada, between 1 April 2002 and 31 March 2012, excluding isolated admissions to step-down or intermediate ICUs, coronary care ICUs, or cardiac surgery ICUs. Adults (age ≥18 years) who survived an acute hospitalization that did not include an ICU stay formed the comparator group. The primary outcome was mortality following hospital discharge. Secondary outcomes were healthcare utilization, including emergency room admissions and hospital readmissions during follow-up. Results Over the study interval, 500,124 patients were admitted to ICUs and 420,187 (84 %) survived to hospital discharge. Median follow-up for survivors was 5.3 (interquartile range 2.5, 8.2) years. Patients admitted to an ICU were more likely to subsequently visit the emergency department, be readmitted to the hospital and ICU, receive home care support, require rehabilitation, and be admitted for long-term care. Those requiring more resources within the ICU required more resources after discharge. One-third of patients admitted to the ICU died during long-term follow-up, with overall probabilities of death of 11 % and 29 % at 1 year and 5 years, respectively. In the adjusted analysis, there was an increasing hazard of death with increasing age, reaching a hazard ratio of 18.08 (95 % confidence interval 16.60–19.68) for those ≥85 years of age compared with those aged 18–24 years. Conclusions Healthcare utilization after hospital discharge was higher among ICU patients, and also among those requiring more healthcare resources during their ICU admission, than among all hospitalized patients as a group. One-third of ICU patients died within the 5 years following discharge, and age was the most influential determinant of outcome. These findings should help target post–ICU discharge services for high-risk groups and better inform goals-of-care discussions for elderly critically ill patients. Electronic supplementary material The online version of this article (doi:10.1186/s13054-016-1248-y) contains supplementary material, which is available to authorized users.

The intestinal barrier is vulnerable to damage by microbiota-induced inflammation that is normally restrained through mechanisms promoting homeostasis. Such disruptions contribute to autoimmune and inflammatory diseases including inflammatory bowel disease. We identified a regulatory loop whereby, in the presence of the normal microbiota, intestinal antigen-presenting cells (APCs) expressing the chemokine receptor CX3CR1 reduced expansion of intestinal microbe-specific T helper 1 (Th1) cells and promoted generation of regulatory T cells responsive to food antigens and the microbiota itself. We identified that disruption of the microbiota resulted in CX3CR1+ APC-dependent inflammatory Th1 cell responses with increased pathology after pathogen infection. Colonization with microbes that can adhere to the epithelium was able to compensate for intestinal microbiota loss, indicating that although microbial interactions with the epithelium can be pathogenic, they can also activate homeostatic regulatory mechanisms. Our results identify a cellular mechanism by which the microbiota limits intestinal inflammation and promotes tissue homeostasis.

Introduction Intensive Care Units (ICUs) provide life-supporting treatment; however, resources are limited, so demand may exceed supply in the event of pandemics, environmental disasters, or in the context of an aging population. We hypothesized that comprehensive national data on ICU resources would permit a better understanding of regional differences in system capacity. Methods After the 2009–2010 Influenza A (H1N1) pandemic, the Canadian Critical Care Trials Group surveyed all acute care hospitals in Canada to assess ICU capacity. Using a structured survey tool administered to physicians, respiratory therapists and nurses, we determined the number of ICU beds, ventilators, and the ability to provide specialized support for respiratory failure. Results We identified 286 hospitals with 3170 ICU beds and 4982 mechanical ventilators for critically ill patients. Twenty-two hospitals had an ICU that routinely cared for children; 15 had dedicated pediatric ICUs. Per 100,000 population, there was substantial variability in provincial capacity, with a mean of 0.9 hospitals with ICUs (provincial range 0.4-2.8), 10 ICU beds capable of providing mechanical ventilation (provincial range 6–19), and 15 invasive mechanical ventilators (provincial range 10–24). There was only moderate correlation between ventilation capacity and population size (coefficient of determination (R2) = 0.771). Conclusion ICU resources vary widely across Canadian provinces, and during times of increased demand, may result in geographic differences in the ability to care for critically ill patients. These results highlight the need to evolve inter-jurisdictional resource sharing during periods of substantial increase in demand, and provide background data for the development of appropriate critical care capacity benchmarks.

The mechanism by which macrophages and other immune cells accumulate in adipose tissue (AT) has been an area of intense investigation over the past decade. Several different chemokines and their cognate receptors have been studied for their role as chemoattractants in promoting recruitment of immune cells to AT. However, it is also possible that chemoattractants known to promote clearance of immune cells from tissues to regional lymph nodes might be a critical component to overall AT immune homeostasis. In this study, we evaluated whether CCR7 influences AT macrophage (ATM) or T‐cell (ATT) accumulation. CCR7 −/− and littermate wild‐type (WT) mice were placed on low‐fat diet (LFD) or high‐fat diet (HFD) for 16 weeks. CCR7 deficiency did not impact HFD‐induced weight gain, hepatic steatosis, or glucose intolerance. Although lean CCR7 −/− mice had an increased proportion of alternatively activated ATMs, there were no differences in ATM accumulation or polarization between HFD‐fed CCR7 −/− mice and their WT counterparts. However, CCR7 deficiency did lead to the preferential accumulation of CD8 + ATT cells, which was further exacerbated by HFD feeding. Finally, expression of inflammatory cytokines/chemokines, such as Tnf , Il6 , Il1β , Ccl2 , and Ccl3 , was equally elevated in AT by HFD feeding in CCR7 −/− and WT mice, while Ifng and Il18 were elevated by HFD feeding in CCR7 −/− but not in WT mice. Together, these data suggest that CCR7 plays a role in CD8 + ATT cell egress, but does not influence ATM accumulation or the metabolic impact of diet‐induced obesity.