Identifying the Patterns of Pattern Recognition Receptors.

Intestinal homeostasis requires microbial recognition that results in appropriate responses to commensals and pathogens. In this issue of Immunity, Price et al. (2018) map the in vivo expression of five toll-like receptors (TLR) in intestinal epithelia, revealing distinct spatio-temporal expression patterns that shape responses to TLR ligands.

Critical Role for the Microbiota in CX3CR1+ Intestinal Mononuclear Phagocyte Regulation of Intestinal T Cell Responses.

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.

Thymic development of gut-microbiota-specific T cells.

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.

Using multi-level regression to determine associations and estimate causes and effects in clinical anesthesia due to patient, practitioner and hospital or health system practice variability.

In this research methods tutorial of clinical anesthesia, we will explore techniques to estimate the influence of a myriad of factors on patient outcomes. Big data that contain information on patients, treated by individual anesthesiologists and surgical teams, at different hospitals, have an inherent multi-level data structure (Fig. 1). While researchers often attempt to determine the association between patient factors and outcomes, that does not provide clinicians with the whole story. Patient care is clustered together according to clinicians and hospitals where they receive treatment. Therefore, multi-level regression models are needed to validly estimate the influence of each factor at each level. In addition, we will explore how to estimate the influence that variability-for example, one anesthesiologist deciding to do one thing, while another takes a different approach-has on outcomes for patients, using the intra-class correlation coefficient for continuous outcomes and the median odds ratio for binary outcomes. From this tutorial, you should acquire a clearer understanding of how to perform and interpret multi-level regression modeling and estimate the influence of variable clinical practices on patient outcomes in order to answer common but complex clinical questions. Fig. 1 Infographics.

Surgeon Postoperative Opioid Prescribing Intensity and Risk of Persistent Opioid Use Among Opioid-naive Adult Patients: A Population-based Cohort Study.

OBJECTIVE: The aim of this study was to determine the relationship between surgeon opioid prescribing intensity and subsequent persistent opioid use among patients undergoing surgery. SUMMARY BACKGROUND DATA: The extent to which different postoperative prescribing practices lead to persistent opioid use among surgical patients is poorly understood. METHODS: Retrospective population-based cohort study assessing opioid-naive adults who underwent 1 of 4 common surgeries. For each surgical procedure, the surgeons' opioid prescribing intensity was categorized into quartiles based on the median daily dose of morphine equivalents of opioids dispensed within 7 days of the surgical visit for all the surgeons' patients. The primary outcome was persistent opioid use in the year after surgery, defined as 180 days or more of opioids supplied within the year after the index date excluding prescriptions filled within 30 days of the index date. Secondary outcomes included a refill for an opioid within 30 days and emergency department visits and hospitalizations within 1 year. RESULTS: Among 112,744 surgical patients, patients with surgeons in the highest intensity quartile (Q4) were more likely to fill an opioid prescription within 7 days after surgery compared with those in the lowest quartile (Q1) (83.3% Q4 vs 65.4% Q1). In the primary analysis, the incidence of persistent opioid use in the year after surgery was rare in both highest and lowest quartiles (0.3% Q4 vs 0.3% Q1), adjusted odds ratio (AOR) of 1.18, 95% CI 0.83-1.66). However, multiple analyses using stricter definitions of persistent use that included the requirement of a prescription filled within 7 days of discharge after surgery showed a significant association with surgeon quartile (up to an AOR 1.36, 95% CI 1.25, 1.47). Patients in Q4 were more likely to refill a prescription within 30 days (4.8% Q4 vs 4.0% Q1, AOR 1.14, 95% CI 1.04-1.24). CONCLUSIONS: Surgeons' overall prescribing practices may contribute to persistent opioid use and represent a target for quality improvement. However, the association was highly sensitive to the definition of persistent use used.

Verbal fluency functional magnetic resonance imaging detects anti-seizure effects and affective side effects of perampanel in people with focal epilepsy.

Perampanel, a noncompetitive antagonist of the postsynaptic a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor, is effective for controlling focal to bilateral tonic-clonic seizures but is also known to increase feelings of anger. Using statistical parametric mapping-derived measures of activation and task-modulated functional connectivity (psychophysiologic interaction), we investigated 14 people with focal epilepsy who had verbal fluency functional magnetic resonance imaging (fMRI) twice, before and after the add-on treatment of perampanel. For comparison, we included 28 people with epilepsy, propensity-matched for clinical characteristics, who had two scans but no change in anti-seizure medication (ASM) regimen in-between. After commencing perampanel, individuals had higher task-related activations in left orbitofrontal cortex (OFC), fewer task-related activations in the subcortical regions including the left thalamus and left caudate, and lower task-related thalamocaudate and caudate-subtantial nigra connectivity. Decreased task-related connectivity is observed between the left OFC and precuneus and left medial frontal lobe. Our results highlight the brain regions associated with the beneficiary therapeutic effects on focal to bilateral tonic-clonic seizures (thalamus and caudate) but also the undesired affective side effects of perampanel with increased anger and aggression (OFC).

Nonopioid Analgesic Prescriptions Filled after Surgery among Older Adults in Ontario, Canada: A Population-based Cohort Study.

BACKGROUND: The objective was to assess changes over time in prescriptions filled for nonopioid analgesics for older postoperative patients in the immediate postdischarge period. The authors hypothesized that the number of patients who filled a nonopioid analgesic prescription increased during the study period. METHODS: The authors performed a population-based cohort study using linked health administrative data of 278,366 admissions aged 66 yr or older undergoing surgery between fiscal year 2013 and 2019 in Ontario, Canada. The primary outcome was the percentage of patients with new filled prescriptions for nonopioid analgesics within 7 days of discharge, and the secondary outcome was the analgesic class. The authors assessed whether patients filled prescriptions for a nonopioid only, an opioid only, both opioid and nonopioid prescriptions, or a combination opioid/nonopioid. RESULTS: Overall, 22% (n = 60,181) of patients filled no opioid prescription, 2% (n = 5,534) filled a nonopioid only, 21% (n = 59,608) filled an opioid only, and 55% (n = 153,043) filled some combination of opioid and nonopioid. The percentage of patients who filled a nonopioid prescription within 7 days postoperatively increased from 9% (n = 2,119) in 2013 to 28% (n = 13,090) in 2019, with the greatest increase for acetaminophen: 3% (n = 701) to 20% (n = 9,559). The percentage of patients who filled a combination analgesic prescription decreased from 53% (n = 12,939) in 2013 to 28% (n = 13,453) in 2019. However, the percentage who filled both an opioid and nonopioid prescription increased: 4% (n = 938) to 21% (n = 9,880) so that the overall percentage of patients who received both an opioid and a nonopioid remained constant over time 76% (n = 18,642) in 2013 to 75% (n = 35,391) in 2019. CONCLUSIONS: The proportion of postoperative patients who fill prescriptions for nonopioid analgesics has increased. However, rather than a move to use of nonopioids alone for analgesia, this represents a shift away from combination medications toward separate prescriptions for opioids and nonopioids.

Adolescent intermittent ethanol exposure induces sex-dependent divergent changes in ethanol drinking and motor activity in adulthood in C57BL/6J mice.

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.

Trends in postoperative opioid prescribing in Ontario between 2013 and 2019: a population-based cohort study.

PURPOSE: Many hospital and provincial-level recommendations now advise a tailored approach to postoperative opioid prescribing; recent trends in postoperative prescribing at the population level have not been well described. METHODS: This population-based cohort study included opioid-naïve patients ≥ 18 yr of age who underwent one of 16 surgical procedures with varying anticipated postoperative pain between July 2013 and March 2020. We evaluated the rate of filled opioid prescriptions within seven days postoperatively, the total morphine milligram equivalent (MME) dose, duration, and type of the first opioid prescription. We then compared the MMEs in initial opioid prescriptions with available procedure-specific recommendations. RESULTS: The sample included 900,989 opioid-naïve patients (mean [standard deviation (SD)] age of 50 [17] 31 yr; 66% women). The percentage of patients filling an opioid prescription within 7 days postoperatively increased from 65% in 2013 to 69% in 2016, and returned to the baseline (65%) in 2019. The mean (SD) MMEs dispensed increased until 2015/2016 and then declined (226 [176] MMEs in 2013, 240 [202] MMEs in 2016, and 175 [175] MMEs in 2019). The most frequently prescribed opioid in 2013 was oxycodone compared with hydromorphone in 2019. Among patients who filled an opioid prescription in 2013, 67% were prescribed an opioid dose higher than those in one set of available prescribing recommendations, while in 2019, 41% were prescribed doses above those stated in recommendations. CONCLUSION: While the proportion of patients filling an opioid prescription postoperatively remained s during the study period, MMEs decreased after 2016. Opioid prescribing remained significantly higher than available prescribing recommendations, particularly among low pain procedures. These findings highlight the need to identify strategies that improve adherence to surgery-specific prescribing guidelines in North America.

RéSUMé: OBJECTIF: De nombreuses recommandations à l'échelle hospitalière et provinciale préconisent aujourd'hui une approche personnalisée de la prescription d'opioïdes postopératoires; les tendances récentes de la prescription postopératoire au niveau de la population n'ont pas été bien décrites. MéTHODE: Cette étude de cohorte basée sur la population englobait des patients naïfs aux opioïdes et âgés de ≥ 18 ans ayant bénéficié de l'une de 16 interventions chirurgicales entraînant une douleur postopératoire anticipée variable entre juillet 2013 et mars 2020. Nous avons évalué le taux d'ordonnances d'opioïdes remplies dans les sept jours suivant l'opération, la dose totale d'équivalent en milligrammes de morphine (EMM), ainsi que la durée et le type de la première ordonnance d'opioïdes. Nous avons ensuite comparé les EMM des ordonnances initiales d'opioïdes avec les recommandations spécifiques à l'intervention disponibles. RéSULTATS: L'échantillon comprenait 900 989 patients naïfs aux opioïdes (âge moyen [écart type (ET)] de 50 [17] ans; 66 % de femmes). La proportion de patients remplissant une ordonnance d'opioïdes dans les 7 jours suivant l'opération est passée de 65 % en 2013 à 69 % en 2016, et est revenue à la valeur de référence (65 %) en 2019. Les EMM moyens (ET) administrés ont augmenté jusqu'en 2015-2016, puis ont diminué (226 [176] EMM en 2013, 240 [202] EMM en 2016 et 175 [175] EMM en 2019). L'opioïde le plus fréquemment prescrit en 2013 était l'oxycodone par rapport à l'hydromorphone en 2019. Parmi les patients qui ont rempli une ordonnance d'opioïdes en 2013, 67 % se sont vu prescrire une dose d'opioïdes supérieure à celle d'un ensemble de recommandations de prescription disponibles, tandis qu'en 2019, 41 % se sont vu prescrire des doses supérieures à celles indiquées dans les recommandations. CONCLUSION: Alors que la proportion de patients remplissant une ordonnance d'opioïdes en période postopératoire est restée stable au cours de la période d'étude, les EMM ont diminué après 2016. La prescription d'opioïdes est demeurée beaucoup plus élevée que les recommandations de prescription disponibles, en particulier dans le cas d'interventions à faible douleur. Ces résultats soulignent la nécessité d'identifier des stratégies pour améliorer l'adhérence aux recommandations de prescription spécifiques au type de chirurgie en Amérique du Nord.

New Opioid Use after Invasive Mechanical Ventilation and Hospital Discharge.

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.

Determining Associations and Estimating Effects with Regression Models in Clinical Anesthesia.

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.

Early experience with medical assistance in dying in Ontario, Canada: a cohort study.

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.

Evaluation of opioid discontinuation after non-orthopaedic surgery among chronic opioid users: a population-based cohort study.

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.

Age and postoperative opioid prescriptions: a population-based cohort study of opioid-naïve adults.

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-naïve 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-naïve 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 < 0.001 for trend), and there was a small shift in the type of opioid (more codeine or tramadol and less oxycodone; P < 0.001 for trend). However, the total MME dose of the initial prescription(s) filled showed minimal age-related trends. CONCLUSIONS: The proportion of opioid-naïve patients filling postoperative opioid prescriptions decreases with age. However, postoperative opioid prescription dosage is not typically different in older adults.

Association between mothers' postoperative opioid prescriptions and opioid-related events in their children: A population-based cohort study.

BACKGROUND: Postoperative opioid prescriptions may be associated with risks of unintentional poisoning and drug diversion in other household members. The objective of this study was to explore the association between mothers' postoperative opioid prescriptions and incidence of opioid-related events in their children (aged 1 to 24 years). DATA AND METHODS: This retrospective cohort study used individually linked administrative health data from Ontario, Canada. A population-based sample of 170,156 opioid-naïve mothers (aged 15 to 64) (see Figure 1) who underwent surgery between 2013 and 2017 in Ontario was linked through birth records to create a cohort of their 283,550 opioid-naïve children (aged 1 to 24). The association between postoperative opioid analgesic prescriptions filled by mothers within seven days of discharge after surgery and opioid-related events (emergency department presentations or inpatient admissions for opioid poisoning, or mental and behavioural disorders attributable to opioid use) in their children within one year of their mother's discharge was assessed. RESULTS: Overall, 60.4% of the children in the cohort had a mother who filled a postoperative opioid prescription. The incidence of opioid-related events in children in the year after a mother's surgery was low overall (n=36/283,550, 0.01%), but higher among children whose mother filled a postoperative opioid prescription (n=29/171,139, 0.02%, vs. n=7/112,411, 0.01%, p=0.02), including in an analysis adjusting for child's age, mother's age, rural residence, neighbourhood income quintile and mother's Charlson comorbidity index score (adjusted odds ratio, 2.42 [95% confidence interval (CI), 1.05 to 5.54], p=0.04). DISCUSSION: Postoperative opioid prescriptions for mothers may contribute to opioid-related events in their children. These findings further underscore the importance of safe, effective opioid prescribing, as well as of patient and public education about the use, storage and disposal of these medications.

Investigating the Product Profiles and Structural Relationships of New Levansucrases with Conventional and Non-Conventional Substrates.

The synthesis of complex oligosaccharides is desired for their potential as prebiotics, and their role in the pharmaceutical and food industry. Levansucrase (LS, EC 2.4.1.10), a fructosyl-transferase, can catalyze the synthesis of these compounds. LS acquires a fructosyl residue from a donor molecule and performs a non-Lenoir transfer to an acceptor molecule, via ß-(2→6)-glycosidic linkages. Genome mining was used to uncover new LS enzymes with increased transfructosylating activity and wider acceptor promiscuity, with an initial screening revealing five LS enzymes. The product profiles and activities of these enzymes were examined after their incubation with sucrose. Alternate acceptor molecules were also incubated with the enzymes to study their consumption. LSs from Gluconobacter oxydans and Novosphingobium aromaticivorans synthesized fructooligosaccharides (FOSs) with up to 13 units in length. Alignment of their amino acid sequences and substrate docking with homology models identified structural elements causing differences in their product spectra. Raffinose, over sucrose, was the preferred donor molecule for the LS from Vibrio natriegens, N. aromaticivorans, and Paraburkolderia graminis. The LSs examined were found to have wide acceptor promiscuity, utilizing monosaccharides, disaccharides, and two alcohols to a high degree.

Variability in intensive care unit admission among pregnant and postpartum women in Canada: a nationwide population-based observational study.

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.

Rates of Mechanical Ventilation for Patients With Dementia in Ontario: A Population-Based Cohort Study.

The number of elderly patients with dementia receiving invasive mechanical ventilation is increasing over time in the United States, while the balance of potential benefits and harms of intensive care interventions in this population is unclear. In this report, we describe trends in use of invasive mechanical ventilation in elderly individuals with and without dementia in Ontario, Canada, and provide projections of the use of invasive mechanical ventilation through 2025. We show that rates of invasive mechanical ventilation for elderly patients with dementia are increasing faster than for the rest of the elderly (nondementia) population.

Temporal Variations in Incidence andOutcomes of Critical Illness Among Pregnant and Postpartum Women inCanada: A Population-Based Observational Study.

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.