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Oncolytic viruses represent a novel drug class in which native or modified viruses mediate tumor regression through selective replication within and lysis of tumor cells as well as induction of systemic antitumor immunity capable of eradicating tumor at distant, uninjected sites. Talimogene laherparepvec (TVEC) is a type I herpes simplex virus genetically modified to preferentially replicate in tumor cells, enhance antigen loading of MHC class I molecules and express granulocyte-macrophage colony-stimulating factor to increase tumor-antigen presentation by dendritic cells. It is presently the only oncolytic virus approved by the FDA with an indication for advanced melanoma based upon improved durable response rate in a randomized, phase III trial. Clinical trials are underway in melanoma investigating TVEC as neoadjuvant monotherapy and in combination with checkpoint inhibitors for unresectable disease as well as in an array of other malignancies. It is appropriate to review TVEC's biology mechanism of action, clinical indication and future directions as a prototype of the burgeoning class of oncolytic viruses.

The probabilistic inference model has been widely used in various areas, such as error-control coding, machine learning, speech recognition, artificial intelligence, and statistics. In this paper, we study both computation and communications power consumption of optical-based and electronic-based implementations of the probabilistic inference algorithm used in solving large scale problems. Our analysis indicates that the optical implementation provides substantial reduction for power and area compare to the electronic-based solutions as problems become large. For a network with 1 million nodes and 100 alphabet size, our proposed wavelength multiplexed all-optical implementation requires approximately 200 kilowatts (kW) of power as compared with 1.47 gigawatts (GW) and 1.7 megawatts (MW) using CPU-based and subthreshold VLSI-based systems, respectively. The optical-based solution is tolerant to shot noise and imperfections of optical modules used in the architecture as well. We also performed an all-optical experimental verification of a graphical inference as the proof of concept and have demonstrated the essential mathematical operations, multiplication, and normalization (division), in photonics operations using nonlinear bulk materials. The normalization and multiplication are shown optically through a pump-probe saturation process and a logarithm-summation-exponential (log-sum-exp) operation, respectively. We used single mode silicon waveguide and single-wall carbon nanotube (SWCNT) as nonlinear optical materials to implement logarithm and exponential operations, respectively. The SWCNT is also used as the nonlinear component in the pump-probe saturation experiment to implement the normalization function.

The use of assistance dogs for children with Autism Spectrum Disorder is an emerging field, with interventions varying from formal assistance dog programs aimed at increasing child safety in public, to incorporating assistance dogs into therapy sessions. Previous reviews have suggested mostly positive outcomes from participating in such programs, however cited a lack of high quality studies available. This systematic review aims to answer the question: what effect does participating in an assistance dog program have on the quality of life of children with Autism Spectrum Disorders and their caregivers? After analysis, ten studies were deemed to meet the inclusion and exclusion criteria, and were included in the review. Findings suggest that participating in various Autism assistance dog programs can: 1) increase child safety in public, which in turn decreases self-reported parental stress and increases self-reported parental confidence in managing their child; 2) increase positive behaviours and decrease negative behaviours; and 3) facilitate motor, communication and social development. However, disparities were found between studies, particularly between quantitative and qualitative results, and between the quality of the projects’ design. These factors indicate that further, high quality research is still needed to support emerging evidence.

The spaceflight environment is relevant to conditions encountered by pathogens during the course of infection and induces novel changes in microbial pathogenesis not observed using conventional methods. It is unclear how microbial cells sense spaceflight-associated changes to their growth environment and orchestrate corresponding changes in molecular and physiological phenotypes relevant to the infection process. Here we report that spaceflight-induced increases in Salmonella virulence are regulated by media ion composition, and that phosphate ion is sufficient to alter related pathogenesis responses in a spaceflight analogue model. Using whole genome microarray and proteomic analyses from two independent Space Shuttle missions, we identified evolutionarily conserved molecular pathways in Salmonella that respond to spaceflight under all media compositions tested. Identification of conserved regulatory paradigms opens new avenues to control microbial responses during the infection process and holds promise to provide an improved understanding of human health and disease on Earth.

Antibodies capable of activating the complement system (CS) when bound with antigen are referred to as “complement-fixing antibodies” and are involved in protection against Flaviviruses. A complement-fixing antibody test has been used in the past to measure the ability of dengue virus (DENV)-specific serum antibodies to activate the CS. As originally developed, the test is time-consuming, cumbersome, and has limited sensitivity for DENV diagnosis. Here, we developed and characterized a novel multiplex anti-DENV complement-fixing assay based on the Luminex platform to quantitate serum antibodies against all four serotypes (DENV1-4) that activate the CS based on their ability to fix the complement component 1q (C1q). The assay demonstrated good reproducibility and showed equivalent performance to a DENV microneutralization assay that has been used to determine DENV serostatus. In non-human primates, antibodies produced in response to primary DENV1-4 infection induced C1q fixation on homologous and heterologous serotypes. Inter-serotype cross-reactivity was associated with homology of the envelope protein. Interestingly, the antibodies produced following vaccination against Zika virus fixed C1q on DENV. The anti-DENV complement fixing antibody assay represents an alternative approach to determine the quality of functional antibodies produced following DENV natural infection or vaccination and a biomarker for dengue serostatus, while providing insights about immunological cross-reactivity among different Flaviviruses.

The death of a baby, stillborn or living only briefly after birth, is a moral affront to the cycle of life, leaving parents without the life stories and material objects that traditionally offer comfort to the bereaved, nor—in an increasingly secularized society—a religious framework for making sense of their loss. For the grieving mother, it is also a physical affront, as her body continues to rehearse its part in its symbiotic relationship with a baby whose own body is disintegrating. Attempting to forge continuing bonds with her child after death makes special demands upon the notion of embodied spirituality, as she attempts to make sense of this tragedy in an embodied way. This paper, which reconciles the distinct perspectives of bereaved mothers and children’s doctors, proposes that the thoughtful re-presentation of medical insight into pregnancy and fetal development may assuage parents’ grief by adding precious detail to their baby’s life course, and by offering the mother a material basis to conceptualize her own body as part of the distributed personhood of her baby.

Abstract Background Severe myocarditis associated with electrical conduction abnormalities and occasionally heart failure has been well documented following treatment with immune checkpoint blockade with an estimated incidence of less than 1%. However, the incidence, early detection, and management of less severe immune-related myocarditis are unknown since most immunotherapy trials have not included routine cardiac monitoring. Herein, we provide the first description of subclinical or smoldering myocarditis with minimal signs and symptoms following immune checkpoint blockade with a single dose of ipilimumab and nivolumab. Case presentation Our patient was diagnosed with immune checkpoint blockade-induced myocarditis based upon an acute rise in serum cardiac troponin I beginning 2 weeks after the initial dose of ipilimumab/nivolumab consistent with the reported median onset of clinical myocarditis at 17 days, as well as a lack of other causes despite extensive cardiac evaluation. The patient initially presented with intractable nausea with no known gastrointestinal etiology. High dose glucocorticoid therapy led to rapid resolution of nausea and a four-fold decrease in troponin I over 4 days. Serum troponin I spiked again following a steroid taper to 13 times the upper limit of normal with endomyocardial biopsy revealing collagen fibrosis and lymphocytic inflammation predominantly comprised of CD8+ T cells consistent with chronic smoldering myocarditis. Serum anti-striated muscle antibodies were also detected with no evidence of rhabdomyolysis. Serum cardiac troponin I levels as an indicator of ongoing myocyte damage gradually improved with chronic prednisone at 10 mg daily. Late addition of intravenous immunoglobulin was associated with rapid normalization of creatine kinase-myocardial band. Conclusions This case demonstrates that subclinical, smoldering myocarditis may occur following immune checkpoint blockade, with evidence of both humoral and cell-mediated immunity responsive to corticosteroid therapy. This experience supports early monitoring for myocarditis with serial electrocardiograms and serum troponin I determinations in large, prospective cohorts of patients receiving combination immune checkpoint blockade as early detection and initiation of immunosuppression may forestall fulminant presentation of this disease and limit myocardial damage.

Harmonic generation is a nonlinear optical process occurring in a variety of materials; the higher orders generation is generally less efficient than lower orders. Here, the authors report that the third-harmonic is thirty times stronger than the second-harmonic in monolayer MoS2.

Atomically thin transition metal dichalcogenides can be grown on large scale using chemical vapour deposition which, however, determines presence of grain boundaries. Here, the authors report that third-harmonic generation imaging provides excellent sensitivity and fast speed for grain boundary visualization in MoS2.

Abstract As a type of nonlinear system with complexity, mode-locked fiber lasers are known for their complex behaviour. It is a challenging task to understand the fundamental physics behind such complex behaviour, and a unified description for the nonlinear behaviour and the systematic and quantitative analysis of the underlying mechanisms of these lasers have not been developed. Here, we present a complexity science-based theoretical framework for understanding the behaviour of mode-locked fiber lasers by going beyond reductionism. This hierarchically structured framework provides a model with variable dimensionality, resulting in a simple view that can be used to systematically describe complex states. Moreover, research into the attractors’ basins reveals the origin of stochasticity, hysteresis and multistability in these systems and presents a new method for quantitative analysis of these nonlinear phenomena. These findings pave the way for dynamics analysis and system designs of mode-locked fiber lasers. We expect that this paradigm will also enable potential applications in diverse research fields related to complex nonlinear phenomena.

Current anti-epileptic drugs (AEDs) act on a limited set of neuronal targets, are ineffective in a third of patients with epilepsy, and do not show disease-modifying properties. MicroRNAs are small noncoding RNAs that regulate levels of proteins by post-transcriptional control of mRNA stability and translation. MicroRNA-134 is involved in controlling neuronal microstructure and brain excitability and previous studies showed that intracerebroventricular injections of locked nucleic acid (LNA), cholesterol-tagged antagomirs targeting microRNA-134 (Ant-134) reduced evoked and spontaneous seizures in mouse models of status epilepticus. Translation of these findings would benefit from evidence of efficacy in non-status epilepticus models and validation in another species. Here, we report that electrographic seizures and convulsive behavior are strongly reduced in adult mice pre-treated with Ant-134 in the pentylenetetrazol model. Pre-treatment with Ant-134 did not affect the severity of status epilepticus induced by perforant pathway stimulation in adult rats, a toxin-free model of acquired epilepsy. Nevertheless, Ant-134 post-treatment reduced the number of rats developing spontaneous seizures by 86% in the perforant pathway stimulation model and Ant-134 delayed epileptiform activity in a rat ex vivo hippocampal slice model. The potent anticonvulsant effects of Ant-134 in multiple models may encourage pre-clinical development of this approach to epilepsy therapy. Keywords: noncoding RNA, hippocampal sclerosis, epileptogenesis, chemoconvulsant, status epilepticus, anti-epileptic drug, temporal lobe epilepsy

Tandem pumping technique are traditionally adopted to develop >3-kW continuous-wave (cw) Yb3+-doped fiber lasers, which are usually pumped by other fiber lasers at shorter wavelengths (1018 nm e.g.,). Fiber lasers directly pumped by laser diodes have higher wall-plug efficiency and are more compact. Here we report two high brightness monolithic cw fiber laser sources at 1080 nm. Both lasers consist of a cw fiber laser oscillator and one laser-diode pumped double cladding fiber amplifier in the master oscillator-power amplifier configuration. One laser, using 30-μm-core Yb3+-doped fiber as the gain medium, can produce >5-kW average laser power with near diffraction-limited beam quality (M23+-doped fiber as the gain medium and produced >8-kW average laser power with high beam quality (M2: ∼ 4). The slope efficiency of the fiber amplifier with respect to the launched pump power reach 83%. To the best of our knowledge, this is the first detailed report for >5-kW near-diffraction-limited and >8-kW high-brightness monolithic fiber lasers directly pumped by laser diodes.

Background: Immune checkpoint inhibitors (ICI) eliminate cancer cells through release of inhibition of cytotoxic CD8+ lymphocytes. Potent systemic activation of immune cells provides unprecedented efficacy in some types of advanced cancer therapy, but also often induces serious immune related adverse events (irAEs) that can be devastating if not promptly identified and properly managed. Herein, we describe the case of multiple major irAEs manifesting after administration of combination ICI therapy in a patient with vaginal melanoma.Case:A 54-year-old, G2P0 woman with recurrent metastatic vaginal melanoma, following three doses of combination nivolumab-ipilimumab immunotherapy, presented for admission at our tertiary care center for the work-up of sudden-onset of colitis of unknown etiology. Prior to admission at our facility, the patient was diagnosed with a severe maculopapular rash, headaches and hyponatremia in the weeks immediately following initiation of therapy. During work up of the colitis, infectious etiologies were ruled out, and the patient was discharged on a steroid taper for treatment of presumed immune-related colitis. Consideration of salt-supplement resistant hyponatremia with new onset frontal headache in the setting of immune-related colitis indicated possible hypophysitis. With high suspicion for multiple high grade irAEs, ICI was discontinued, and the patient was given high dose intravenous steroids prior to discharge with a prednisone dose taper for outpatient management. After control of irAEs was achieved, ipilimumab therapy was subsequently discontinued to minimize the chance of recurrent irAEs, yet nivolumab monotherapy was resumed in an attempt to control disease progression that could occur in with iatrogenic immunosuppression. Conclusion: ICIs have demonstrated the ability to induce improved long-term survival in metastatic cutaneous or mucosal melanomas, including those of gynecologic origin. As ICI therapy becomes more widespread, healthcare providers across all fields of medicine need be vigilant to recognize the symptoms of irAEs that can often masquerade as common illnesses to prevent potentially dangerous irreversible immune toxicities. Keywords: Immunotherapy, Immune toxicity, Immune-related adverse events, Melanoma

In communities across North America, organiza­tions have launched local food system initiatives as a response to the depredations of the globalized agri-food economy; however, they increasingly find that they cannot achieve their desired impacts or sustain their ventures by operating solely within their home communities. Consequently, they embark on regional food system development initiatives. Drawing upon the experiences of 41 organizations—including Working Land­scapes, a grassroots nonprofit that two authors of this paper direct—this paper examines emerging regional food initiatives in the rural, economically distressed region of northeastern North Carolina. We eluci­date characteristics that differentiate regional initia­tives from the same organizations’ local activities. We find that regional initiatives are motivated by organizations’ strategic needs, which are highly variable in spatial scale, largely uncoordi­nated with each other, and not yet successful in fully achieving their goals. Drawing upon this analysis, we identify opportunities to increase the effectiveness of regional food system initiatives by increasing shared understandings of these initia­tives and advancing region-scale planning.

BackgroundParomomycin-based topical treatments were shown to be effective in curing cutaneous leishmaniasis (CL) lesions caused by Leishmania major in Tunisia. Cure rates of an index lesion were approximately 80%. As a follow on, we conducted a similar Phase 3 trial in Panama to demonstrate the efficacy of these treatments against New World species. The primary objective was to determine if a combination topical cream (paromomycin-gentamicin) resulted in statistically superior final clinical cure rates of an index lesion compared to a paromomycin alone topical cream for the treatment of CL, primarily caused by Leishmania panamensis.MethodsWe conducted a randomized, double blind, Phase 3 trial of topical creams for the treatment of CL caused by Leishmania spp. Three hundred ninety nine patients with one to ten CL lesions were treated by topical application once daily for 20 days. The primary efficacy endpoint was percentage of subjects with clinical cure of an index lesion confirmed to contain Leishmania with no relapse.ResultsThe clinical cure of the index lesion for paromomycin-gentamicin was 79% (95% CI; 72 to 84) and for paromomycin alone was 78% (95% CI; 74 to 87) (p = 0.84). The most common adverse events considered related to study cream application were mild to moderate dermatitis, pain, and pruritus.ConclusionsSuperiority of paromomycin-gentamicin was not demonstrated. However, the approximately 80% cure rates for both topical creams were similar to those demonstrated in Tunisia and previously reported with parenteral antimonials.

Cerebrospinal fluid (CSF) flows through the brain, transporting chemical signals and removing waste. CSF production in the brain is balanced by a constant outflow of CSF, the anatomical basis of which is poorly understood. Here, we characterized the anatomy and physiological function of the CSF outflow pathway along the olfactory sensory nerves through the cribriform plate, and into the nasal epithelia. Chemical ablation of olfactory sensory nerves greatly reduced outflow of CSF through the cribriform plate. The reduction in CSF outflow did not cause an increase in intracranial pressure (ICP), consistent with an alteration in the pattern of CSF drainage or production. Our results suggest that damage to olfactory sensory neurons (such as from air pollution) could contribute to altered CSF turnover and flow, providing a potential mechanism for neurological diseases.

Introduction: Elevated levels of mitochondrial reactive oxygen species (ROS) contribute to the development of numerous cardiovascular diseases. TERT, the catalytic subunit of telomerase, has been shown to translocate to mitochondria to suppress ROS while promoting ATP production. Acute overexpression of TERT increases survival and decreases infarct size in a mouse model of myocardial infarct, while decreased telomerase activity predisposes to mitochondrial defects and heart failure. In the present study, we examined the role of TERT on cardiac structure and function under basal conditions and conditions of acute or prolonged stress in a novel rat model of TERT deficiency.Methods: Cardiac structure and function were evaluated via transthoracic echocardiogram. Langendorff preparations were used to test the effects of acute global ischemia reperfusion injury on cardiac function and infarction. Coronary flow and left ventricular pressure were measured during and after ischemia/reperfusion (I/R). Mitochondrial DNA integrity was measured by PCR and mitochondrial respiration was assessed in isolated mitochondria using an Oxygraph. Angiotensin II infusion was used as an established model of systemic stress.Results: No structural changes (echocardiogram) or coronary flow/left ventricle pressure (isolated hearts) were observed in TERT−/− rats at baseline; however, after I/R, coronary flow was significantly reduced in TERT−/− compared to wild type (WT) rats, while diastolic Left Ventricle Pressure was significantly elevated (n = 6 in each group; p < 0.05) in the TERT−/−. Interestingly, infarct size was less in TERT−/− rats compared to WT rats, while mitochondrial respiratory control index decreased and mitochondrial DNA lesions increased in TERT−/− compared to WT. Angiotensin II treatment did not alter cardiac structure or function; however, it augmented the infarct size significantly more in TERT−/− compared to the WT.Conclusion: Absence of TERT activity increases susceptibility to stress like cardiac injury. These results suggest a critical role of telomerase in chronic heart disease.

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.

Nursing education focuses on nursing theory and the ability to perform tasks. There is a lack of education related to prioritization of nursing tasks. Therefore, new nurses transitioning into their roles sometimes struggle and, as a result, leave their units or, often enough, our facility. We developed a Professional Success Program that includes cognitive prioritization exercises and simulation scenarios to assist these nurses. After utilizing the program, our facility has seen an increase in nurse retention. [ABSTRACT FROM AUTHOR]

Abstract Background An important public health goal is to decrease the prevalence of key behavioural risk factors, such as tobacco use and obesity. Survey information is often available at the regional level, but heterogeneity within large geographic regions cannot be assessed. Advanced spatial analysis techniques are demonstrated to produce sensible micro area estimates of behavioural risk factors that enable identification of areas with high prevalence. Methods A spatial Bayesian hierarchical model was used to estimate the micro area prevalence of current smoking and excess bodyweight for the Erie-St. Clair region in southwestern Ontario. Estimates were mapped for male and female respondents of five cycles of the Canadian Community Health Survey (CCHS). The micro areas were 2006 Census Dissemination Areas, with an average population of 400–700 people. Two individual-level models were specified: one controlled for survey cycle and age group (model 1), and one controlled for survey cycle, age group and micro area median household income (model 2). Post-stratification was used to derive micro area behavioural risk factor estimates weighted to the population structure. SaTScan analyses were conducted on the granular, postal-code level CCHS data to corroborate findings of elevated prevalence. Results Current smoking was elevated in two urban areas for both sexes (Sarnia and Windsor), and an additional small community (Chatham) for males only. Areas of excess bodyweight were prevalent in an urban core (Windsor) among males, but not females. Precision of the posterior post-stratified current smoking estimates was improved in model 2, as indicated by narrower credible intervals and a lower coefficient of variation. For excess bodyweight, both models had similar precision. Aggregation of the micro area estimates to CCHS design-based estimates validated the findings. Conclusions This is among the first studies to apply a full Bayesian model to complex sample survey data to identify micro areas with variation in risk factor prevalence, accounting for spatial correlation and other covariates. Application of micro area analysis techniques helps define areas for public health planning, and may be informative to surveillance and research modeling of relevant chronic disease outcomes.

In the last decades of his life Seamus Heaney enjoyed phenomenal worldwide success, outselling, or so it was widely held, all other poets writing in English combined, a fact attesting to the existence of an international component in his work. A close study of the entire body of his poetry, as well as a study of the concurrent poetic interests he himself professed and which other critics have identified, reveals a subtle and gradual shift toward what may be referred to as the “international style”. The reader encounters such a style, prominently manifest, in the work of some of Heaney’s poetic influences, especially Eastern European poets like Czeslaw Milosz and Zbigniew Herbert. This article argues, however, that Heaney’s stylistic shift was too slight to account for the enormity of his international success and asserts instead that his far-ranging appeal is a matter of tone: Heaney’s attitude toward his material, but more so, deep characteristics of his personality – what Ted Hughes refers to as “the ultimate suffering and decision” in him –occupy space below the surface of his work and imbue it with a quality to which readers around the world are drawn.

Hypoxic–ischemic injury (HII) at birth has been found to relate to differences in development, including decreased memory performance. The current study assessed recognition memory in 6- and 12-month-old HII infants and typically developing (TD) infants using two eye-tracking paradigms well suited to explore explicit memory processes early in life: visual paired comparison (VPC) and relational memory (RM). During the VPC, infants were familiarized to a face and then tested for their novelty preference immediately and after a two-minute delay. At 6 months, neither HII nor TD showed a VPC novelty preference at immediate delay, but at 12 months, both groups did; after the two-minute delay, no group showed a novelty preference. During RM, infants were presented with blocks containing a learning phase with three different scene–face pairs, and a test phase with one of the three scenes and all three faces appearing simultaneously. When there was no interference from other scene–face pairs between learning and test, 6-month-old TD showed evidence of an early novelty preference, but when there was interference, they revealed an early familiarity preference. For 12-month-old TD, some evidence for a novelty preference during RM was seen regardless of interference. Although HII and TD showed similar recognition memory on the VPC, when looking at RM, HII infants showed subtle differences in their attention to the familiar and novel faces as compared to their TD peers, suggesting that there might be subtle differences in the underlying memory processing mechanisms between HII and TD. More work is needed to understand how these attentional patterns might be predictive of later memory outcomes.

Weight-loss diets are notorious for their low adherence, which is a barrier to efforts to reduce population rates of overweight and obesity. However, there is some evidence that adherence is better among people on other kinds of diets, such as vegan and gluten free. This study aimed to explore the predictors of dietary adherence across five restrictive dietary patterns (vegan, vegetarian, paleo, gluten free, and weight loss). This study used both qualitative and quantitative methods among 292 adult community members who were following a restrictive dietary pattern. Personality, mental health, and motivational predictors of adherence were examined. Substantial differences in adherence were found between dietary groups, with vegans and vegetarians being particularly high in adherence and gluten-free and weight-loss dieters being comparably low. Four consistent predictors of adherence across different dietary patterns were supported in both the quantitative and qualitative analyses. Self-efficacy and social identification with one’s dietary group positively predicted adherence. Conversely, being motivated in one’s dietary choices by mood or by weight control negatively predicted adherence. These findings speak to the importance of social and motivational factors in determining adherence. The results also illustrate the utility of looking beyond weight-loss dieters and virtuous individual traits for insights into how adherence may be improved.

This paper investigates the cost-effectiveness of operation strategies which can be used to abate CO 2 emissions in a local multi-energy system. A case study is carried out using data from a real energy system that integrates district heating, district cooling, and electricity networks at Chalmers University of Technology. Operation strategies are developed using a mixed integer linear programming multi-objective optimization model with a short foresight rolling horizon and a year of data. The cost-effectiveness of different strategies is evaluated across different carbon prices. The results provide insights into developing abatement strategies for local multi-energy systems that could be used by utilities, building owners, and authorities. The optimized abatement strategies include: increased usage of biomass boilers, substitution of district heating and absorption chillers with heat pumps, and higher utilization of storage units. The results show that, by utilizing all the strategies, a 20.8% emission reduction can be achieved with a 2.2% cost increase for the campus area. The emission abatement cost of all strategies is 36.6–100.2 (€/tCO 2 ), which is aligned with estimated carbon prices if the Paris agreement target is to be achieved. It is higher, however, than average European Emission Trading System prices and Sweden’s carbon tax in 2019.

The author shares his perspectives of teaching law for over forty years. In this article, he recalls his experiences with students, colleagues, and exams. Early in his career, he learned an important life lesson that he remembers nearly every day: if you love your job, it is not really work. He feels this is the most important perspective that he has to share. He considers teaching a wonderful life.

Introduction Geographic disparities in health indicators, such as premature mortality, may reveal area-level weaknesses in health system performance. Monitoring geographic trends can therefore have powerful implications for system evaluation and planning. However, attempts to understand patterns of population health can be complicated by underlying regional differences in demographics and behaviours. Objectives and Approach This study aimed to identify regional disparities in premature mortality (defined as death before age 75), and to investigate how fully these disparities can be explained by population-level characteristics. Ontario’s 76 administrative Local Health Integration Network (LHIN) sub-regions, which vary in geographic and population size, were analyzed using linked population-level data from the Institute for Clinical Evaluative Sciences and Cancer Care Ontario. Spatially structured, sex-stratified Bayesian hierarchical models were used to estimate standardized mortality ratios (SMRs) for each LHIN sub-region in the 2011-2015 period. Models were adjusted for key population-level demographic and behavioural risk factors. Results Large disparities in premature mortality presented at the sub-region level in males and females. Low premature mortality clustered around large, urban population centers in Ottawa and Toronto. Premature mortality was comparatively higher throughout the rest of the province, particularly in northern and southeast Ontario. Higher prevalence of material deprivation, overweight and obesity, sedentary behaviour, and smoking were all significantly (α=0.05) associated with elevated premature mortality risk, while increased alcohol consumption and immigrant population were associated with decreased risk. Adjusting for model covariates reduced variance of sub-region SMR estimates by 87% in males and 89% in females. Population-level characteristics thus explain a large proportion of geographic inequality in premature mortality. However, residual spatial variation suggests that systematic regional differences in premature mortality extend beyond population-level traits. Conclusion/Implications This study represents a novel application of small-area analytic techniques to Ontario mortality data, made possible by comprehensive linkage of vital statistics. The findings highlight the importance of population composition to geographic disparities in health. Future work should investigate the influence of system-level factors in areas with elevated premature mortality.