Integrated Community Care Delivered by Public Health-Care and Social-Care Systems: Results from a Realist Synthesis.

Introduction: Integrated community care (ICC) is defined as an interweaving of health-care and social-care interventions deployed in spatial and relational proximity using an interdisciplinary and cross-sectoral approach. Consideration of territory scale and time scale are at the center of ICC practices. Its deployment in public health and social care networks (HSCN) can be complex due to their broad mandate, the complexity of their management, and accountability. Therefore, we aimed to describe ICC delivered by public HSCN to determine how, why, for whom, and in what circumstances ICC works and produces outcomes. Methods: A realist synthesis was conducted consisting of five steps consistent with realist synthesis standards (RAMESES projects) to produce configurations of Context - Mechanism - Outcomes (CMOc) and development of a middle-range explanatory theory of why and how the identified outcomes may have occurred. Results: In total, 26 studies were selected and used, as evidence, to support-either partially or fully-the production of CMOc based on the initial program theory. Nine unique CMO configurations were identified based on the data analyses and team discussion. ICC middle-range theory is informed by the CMO configurations identified. Discussion: This realist synthesis allowed us to identify the central mechanisms of ICC delivered by public HSCN and to produce a middle range theory. ICC is based on a specific philosophy and deployed by a professional agency oriented toward a community agency within a local system of interdisciplinary and cross-sectoral action. Conclusion: Our middle-range theory will provide a solid analytical framework as a foundation for ICC implementation and future research.

Introduction: Les interventions en santé et services sociaux intégrées en proximité des communautés (IIPC) sont définies comme une imbrication d'interventions de soins de santé et de services sociaux à l'échelle du territoire et considérant la temporalité, déployées dans une proximité spatiale et relationnelle au moyen d'une approche interdisciplinaire et intersectorielle. Son déploiement dans les réseaux publics de santé et de soins sociaux (RSSS) peut s'avérer complexe en raison de l'étendue de leur mandat, de la complexité de leur gestion et de leur responsabilité. C'est pourquoi nous avons cherché à décrire les IIPC dispensées par les RSSS publics afin de déterminer comment, pourquoi, pour qui et dans quelles circonstances les IIPC fonctionnent et produisent des résultats. Méthodes utilisées: Une synthèse réaliste a été réalisée en cinq étapes conformes aux normes de synthèse réaliste (projet RAMESES) afin de produire des configurations Contexte ­ Mécanisme ­ Effets (CMOc) et de développer une théorie explicative de moyenne portée sur le pourquoi et le comment des résultats identifiés. Résultats: Au total, 26 études ont été sélectionnées et utilisées comme preuves pour étayer ­ partiellement ou totalement ­ la production de CMOc sur la base de la théorie initiale de programme. Neuf configurations uniques CMO ont été identifiées sur la base des analyses de données et des discussions de l'équipe. La théorie de moyenne portée des IIPC s'appuie sur les configurations CMO identifiées. Discussion: Cette synthèse réaliste nous a permis d'identifier les mécanismes centraux des IIPC déployées par les RSSS publics et de produire une théorie de moyenne portée. Les IIPC sont fondées sur une philosophie et le développement d'une capacité d'agir professionnelle mise en action vers le renforcement de la capacité d'agir de la communauté au sein d'un système local d'action interdisciplinaire et intersectoriel. Conclusion: L'utilisation de notre théorie de moyenne portée pour la mise en œuvre d'IIPC fournira un cadre analytique solide comme base pour des implantations ou des recherches futures.

Application of quasimetagenomics methods to define microbial diversity and subtype Listeria monocytogenes in dairy and seafood production facilities.

IMPORTANCE: In developed countries, the human diet is predominated by food commodities, which have been manufactured, processed, and stored in a food production facility. Little is known about the application of metagenomic sequencing approaches for detecting foodborne pathogens, such as L. monocytogenes, and characterizing microbial diversity in food production ecosystems. In this work, we investigated the utility of 16S rRNA amplicon and quasimetagenomic sequencing for the taxonomic and phylogenetic classification of Listeria culture enrichments of environmental swabs collected from dairy and seafood production facilities. We demonstrated that single-nucleotide polymorphism (SNP) analyses of L. monocytogenes metagenome-assembled genomes (MAGs) from quasimetagenomic data sets can achieve similar resolution as culture isolate whole-genome sequencing. To further understand the impact of genome coverage on MAG SNP cluster resolution, an in silico downsampling approach was employed to reduce the percentage of target pathogen sequence reads, providing an initial estimate of required MAG coverage for subtyping resolution of L. monocytogenes.

A continent-wide detailed geological map dataset of Antarctica.

A dataset to describe exposed bedrock and surficial geology of Antarctica has been constructed by the GeoMAP Action Group of the Scientific Committee on Antarctic Research (SCAR) and GNS Science. Our group captured existing geological map data into a geographic information system (GIS), refined its spatial reliability, harmonised classification, and improved representation of glacial sequences and geomorphology, thereby creating a comprehensive and coherent representation of Antarctic geology. A total of 99,080 polygons were unified for depicting geology at 1:250,000 scale, but locally there are some areas with higher spatial resolution. Geological unit definition is based on a mixed chronostratigraphic- and lithostratigraphic-based classification. Description of rock and moraine polygons employs the international Geoscience Markup Language (GeoSciML) data protocols to provide attribute-rich and queryable information, including bibliographic links to 589 source maps and scientific literature. GeoMAP is the first detailed geological map dataset covering all of Antarctica. It depicts 'known geology' of rock exposures rather than 'interpreted' sub-ice features and is suitable for continent-wide perspectives and cross-discipline interrogation.

Sub-continental-scale carbon stocks of individual trees in African drylands.

The distribution of dryland trees and their density, cover, size, mass and carbon content are not well known at sub-continental to continental scales1-14. This information is important for ecological protection, carbon accounting, climate mitigation and restoration efforts of dryland ecosystems15-18. We assessed more than 9.9 billion trees derived from more than 300,000 satellite images, covering semi-arid sub-Saharan Africa north of the Equator. We attributed wood, foliage and root carbon to every tree in the 0-1,000 mm year-1 rainfall zone by coupling field data19, machine learning20-22, satellite data and high-performance computing. Average carbon stocks of individual trees ranged from 0.54 Mg C ha-1 and 63 kg C tree-1 in the arid zone to 3.7 Mg C ha-1 and 98 kg tree-1 in the sub-humid zone. Overall, we estimated the total carbon for our study area to be 0.84 (±19.8%) Pg C. Comparisons with 14 previous TRENDY numerical simulation studies23 for our area found that the density and carbon stocks of scattered trees have been underestimated by three models and overestimated by 11 models, respectively. This benchmarking can help understand the carbon cycle and address concerns about land degradation24-29. We make available a linked database of wood mass, foliage mass, root mass and carbon stock of each tree for scientists, policymakers, dryland-restoration practitioners and farmers, who can use it to estimate farmland tree carbon stocks from tablets or laptops.

Application of Pharmacokinetic/Pharmacodynamic Modeling to Bridge Mouse Antitumor Efficacy and Monkey Toxicology Data for Determining the Therapeutic Index of an Interleukin-10 Fc Fusion Protein.

Pharmacokinetic/pharmacodynamic (PK/PD) modeling was performed to quantitatively integrate preclinical pharmacology and toxicology data for determining the therapeutic index (TI) of an interleukin-10 (IL-10) fragment crystallizable (Fc) fusion protein. Mouse Fc fused with mouse IL-10 (mFc-mIL-10) was studied in mice for antitumor efficacy, and the elevation of interleukin-18 (IL-18) was examined as a PD biomarker. The in vivo mFc-mIL-10 EC50 for the IL-18 induction was estimated to be 2.4 nM, similar to the in vitro receptor binding affinity (Kd) of 3.2 nM. The IL-18 induction was further evaluated in cynomolgus monkeys, where the in vivo induction EC50 by a human IL-10 human Fc-fusion protein (hFc-hIL-10) was 0.08 nM vs. 0.3 nM measured as the in vitro Kd. The extent of the IL-18 induction correlated with mouse antitumor efficacy and was used to connect mouse efficacy to that in monkeys. The PD-based efficacious dose projected in monkeys was comparable to the results obtained using a PK-based method in which mouse efficacious exposure was targeted and corrected for affinity differences between the species. Furthermore, PK/PD relationships were developed for anemia and thrombocytopenia in monkeys treated with hFc-hIL-10, with thrombocytopenia predicted to be dose-limiting toxicity. Using quantitative pharmacology and toxicology information obtained through modeling work in the same species, the TI of hFc-hIL-10 in monkeys was determined to be 2.4 (vs. PD-based efficacy) and 1.2-3 (vs. PK-based efficacy), indicating a narrow safety margin. The model-based approaches were proven valuable to the developability assessment of the IL-10 Fc-fusion protein.

Target-Mediated Drug Disposition Affects the Pharmacokinetics of Interleukin-10 Fragment Crystallizable Fusion Proteins at Pharmacologically Active Doses.

Fragment crystallizable (Fc) fusion is commonly used for extending the half-life of biotherapeutics such as cytokines. In this work, we studied the pharmacokinetics of Fc-fused interleukin-10 (IL-10) proteins that exhibited potent antitumor activity in mouse syngeneic tumor models. At pharmacologically active doses of ≥0.1 mg/kg, both mouse Fc-mouse IL-10 and human Fc-human IL-10, constructed as the C terminus of the Fc domain fused with IL-10 via a glycine-serine polypeptide linker, exhibited nonlinear pharmacokinetics after intravenous administration to mice at the doses of 0.05, 0.5, and 5 mg/kg. With a nominal dose ratio of 1:10:100; the ratio of the area under the curve for mouse Fc-mouse IL-10 and human Fc-human IL-10 was 1:181:1830 and 1:75:633, respectively. In contrast, recombinant mouse or human IL-10 proteins exhibited linear pharmacokinetics in mice. Compartmental analysis, using the Michaelis-Menten equation with the in vitro IL-10 receptor alpha binding affinity inputted as the Km, unified the pharmacokinetic data across the dose range. Additionally, nontarget-mediated clearance estimated for fusion proteins was ∼200-fold slower than that for cytokines, causing the manifestation of target-mediated drug disposition (TMDD) in the fusion protein pharmacokinetics. The experimental data generated with a mouse IL-10 receptor alpha-blocking antibody and a human Fc-human IL-10 mutant with a reduced receptor binding affinity showed significant improvements in pharmacokinetics, supporting TMDD as the cause of nonlinearity. Target expression and its effect on pharmacokinetics must be determined when considering using Fc as a half-life extension strategy, and pharmacokinetic evaluations need to be performed at a range of doses covering pharmacological activity. SIGNIFICANCE STATEMENT: Target-mediated drug disposition can manifest to affect the pharmacokinetics of a fragment crystallizable (Fc)-fused cytokine when the nontarget-mediated clearance of the cytokine is decreased due to neonatal Fc receptor-mediated recycling and molecular weight increases that reduce the renal clearance. The phenomenon was demonstrated with interleukin-10 Fc-fusion proteins in mice at pharmacologically active doses. Future drug designs using Fc as a half-life extension approach for cytokines need to consider target expression and its effect on pharmacokinetics at relevant doses.

Integrated Community Care Delivered by Public Health Care and Social Care Systems: Protocol for a Realist Synthesis.

INTRODUCTION: Integrated Community Care (ICC) is defined as an interweaving of territory scale and time scale health care and social care interventions implemented in proximity (spatial and relational) in an interdisciplinary and cross-sectoral manner. However, the deployment of in public health and social care networks can be complex owing to their broad mandate and the complexity of their management and accountability. Therefore, we aim to describe integrated community care in order to shed light on how they work, for whom and in what circumstances. THEORY AND METHODS: We will conduct a realist synthesis to design a flexible and scalable theory of the functioning of ICC deployed by public health and social care networks. To do so, a two-phase approach will be used: a systematic review on the topic of interest; and co-development and refinement of theory with local and international stakeholders. This data will be analyzed using both qualitative and quantitative methods. DISSEMINATION OF RESULTS: The results will be disseminated through peer-reviewed publications, academic presentations and a policy brief. This last document will include evidence on how ICC can be deployed by public health and social care networks to produce the impacts targeted.

A Conceptual Framework for Integrated Community Care.

INTRODUCTION: The various health and social care services provided in a given local area (i.e., place-based) must not only deliver primary care in proximity to the population, but act upstream on the social determinants of health. This type of care, when provided in a holistic and integrated manner, aims to improve the physical and mental health-but also the well-being and social capital-of individuals, families, groups and communities. This type of approach is known as Integrated Community Care (ICC). THEORY AND METHODS: This article was developed from a non-systematic review of scientific and grey literature followed by a qualitative analysis and researcher reflections on ICC. RESULTS: The article presents the core concepts of ICC, namely temporality, local area, health care, social care, proximity and integration. These concepts are unpacked and a conceptual diagram is set forth to put the dynamic links between the concepts into perspective. DISCUSSION AND CONCLUSION: The purpose of the article is to provide a conceptual clarification of ICC. Three examples of practise (from Switzerland, Quebec [Canada] and Italy) are used as illustrations to provide a better understanding of ICC and to open up horizons.

Synthesis and Preclinical Evaluation of a 68Ga-Labeled Adnectin, 68Ga-BMS-986192, as a PET Agent for Imaging PD-L1 Expression.

Blocking the interaction of the immune checkpoint molecule programmed cell death protein-1 and its ligand, PD-L1, using specific antibodies has been a major breakthrough for immune oncology. Whole-body PD-L1 expression PET imaging may potentially allow for a better prediction of response to programmed cell death protein-1-targeted therapies. Imaging of PD-L1 expression is feasible by PET with the adnectin protein 18F-BMS-986192. However, radiofluorination of proteins such as BMS-986192 remains complex and labeling yields are low. The goal of this study was therefore the development and preclinical evaluation of a 68Ga-labeled adnectin protein (68Ga-BMS-986192) to facilitate clinical trials. Methods:68Ga labeling of DOTA-conjugated adnectin (BXA-206362) was performed in NaOAc-buffer at pH 5.5 (50°C, 15 min). In vitro stability in human serum at 37°C was analyzed using radio-thin layer chromatography and radio-high-performance liquid chromatography. PD-L1 binding assays were performed using the transduced PD-L1-expressing lymphoma cell line U-698-M and wild-type U-698-M cells as a negative control. Immunohistochemical staining studies, biodistribution studies, and small-animal PET studies of 68Ga-BMS-986192 were performed using PD-L1-positive and PD-L1-negative U-698-M-bearing NSG mice. Results:68Ga-BMS-986192 was obtained with quantitative radiochemical yields of more than 97% and with high radiochemical purity. In vitro stability in human serum was at least 95% after 4 h of incubation. High and specific binding of 68Ga-BMS-986192 to human PD-L1-expressing cancer cells was confirmed, which closely correlates with the respective PD-L1 expression level determined by flow cytometry and immunohistochemistry staining. In vivo, 68Ga-BMS-986192 uptake was high at 1 h after injection in PD-L1-positive tumors (9.0 ± 2.1 percentage injected dose [%ID]/g) and kidneys (56.9 ± 9.2 %ID/g), with negligible uptake in other tissues. PD-L1-negative tumors demonstrated only background uptake of radioactivity (0.6 ± 0.1 %ID/g). Coinjection of an excess of unlabeled adnectin reduced tumor uptake of PD-L1 by more than 80%. Conclusion:68Ga-BMS-986192 enables easy radiosynthesis and shows excellent in vitro and in vivo PD-L1-targeting characteristics. The high tumor uptake combined with low background accumulation at early imaging time points demonstrates the feasibility of 68Ga-BMS-986192 for imaging of PD-L1 expression in tumors and is encouraging for further clinical applications of PD-L1 ligands.

[Visions of recovery in residential mental health services in a region of Quebec]. / Les visions du rétablissement dans des services résidentiels en santé mentale d'une région québécoise.

Objective Following a reorganization in the housing sector of mental health services in a region of Quebec, this descriptive study assessed the perceived integration of recovery principles according to service users (n=25), managers of residential facilities (n=19) and social and health care professionals (n=30). Method All participants completed the Recovery Self-Assessment. Service users also filled the Satisfaction with Life Domains Scale. Additional qualitative questions were asked in a written format. Results Most service users were satisfied overall with their current residence but noted that intervention options and addressing sexual needs could be improved. Clinicians perceived significantly less integration of the various dimensions of recovery than the two other groups (p < 0.001). All groups identified that persons with mental illness should be more involved in service planning in residences. Conclusion Integrating the perspectives of different key stakeholders highlighted the need to continue to work collaboratively to support a recovery process in housing facilities and involve more service users.

Application of the Gyrolab microfluidic platform to measure picomolar affinity of a PD-L1-binding Adnectin™ radioligand for positron emission tomography.

Advances in in vitro display and protein engineering yield therapeutics with affinities in the picomolar range. The Gyrolab® microfluidics platform uses the kinetic exclusion assay principle to measure subnanomolar solution affinities. This work describes application of the Gyrolab solution affinity module and the new multi-curve analysis feature to determine affinity of the PD-L1 Adnectin™ positron emission tomography radioligand, which was measured as 20 pM for human PD-L1. We also report key parameters that affect assay signal-to-background ratio and data quality, such as detection reagent concentration. Gyrolab offers the necessary throughput for rapid assay development with low sample consumption, as demonstrated in this study, which also provides helpful tips for assay optimization for solution affinity measurement.

Case Management in Primary Care for Frequent Users of Health Care Services: A Realist Synthesis.

PURPOSE: Case management (CM) is a promising intervention for frequent users of health care services. Our research question was how and under what circumstances does CM in primary care work to improve outcomes among frequent users with chronic conditions? METHODS: We conducted a realist synthesis, searching MEDLINE, CINAHL, Embase, and PsycINFO (1996 to September 2017) for articles meeting the following criteria: (1) population: adult frequent users with chronic disease, (2) intervention: CM in a primary care setting with a postintervention evaluation, and (3) primary outcomes: integration of services, health care system use, cost, and patient outcome measures. Academic and gray literature were evaluated for relevance and robustness. Independent reviewers extracted data to identify context, mechanism, and outcome (CMO) configurations. Analysis of CMO configurations allowed for the modification of an initial program theory toward a refined program theory. RESULTS: Of the 9,295 records retrieved, 21 peer-reviewed articles and an additional 89 documents were retained. We evaluated 19 CM interventions and identified 11 CMO configurations. The development of a trusting relationship fostering patient and clinician engagement in the CM intervention was recurrent in many CMO configurations. CONCLUSION: Our refined program theory proposes that in the context of easy access to an experienced and trusted case manager who provides comprehensive care while maintaining positive interactions with patients, the development of this relationship fosters the engagement of both individuals and yields positive outcomes when the following mechanisms are triggered: patients and clinicians feel supported, respected, accepted, engaged, and committed; and patients feel less anxious, more secure, and empowered to self-manage.

Case management in primary care for frequent users of healthcare services with chronic diseases and complex care needs: an implementation and realist evaluation protocol.

INTRODUCTION: Significant evidence in the literature supports case management (CM) as an effective intervention to improve care for patients with complex healthcare needs. However, there is still little evidence about the facilitators and barriers to CM implementation in primary care setting. The three specific objectives of this study are to: (1) identify the facilitators and barriers of CM implementation in primary care clinics across Canada; (2) explain and understand the relationships between the actors, contextual factors, mechanisms and outcomes of the CM intervention; (3) identify the next steps towards CM spread in primary care across Canada. METHODS AND ANALYSIS: We will conduct a multiple-case embedded mixed methods study. CM will be implemented in 10 primary care clinics in five Canadian provinces. Three different units of analysis will be embedded to obtain an in-depth understanding of each case: the healthcare system (macro level), the CM intervention in the clinics (meso level) and the individual/patient (micro level). For each objective, the following strategy will be performed: (1) an implementation analysis, (2) a realist evaluation and (3) consensus building among stakeholders using the Technique for Research of Information by Animation of a Group of Experts method. ETHICS AND DISSEMINATION: This study, which received ethics approval, will provide innovative knowledge about facilitators and barriers to implementation of CM in different primary care jurisdictions and will explain how and why different mechanisms operate in different contexts to generate different outcomes among frequent users. Consensual and prioritised statements about next steps for spread of CM in primary care from the perspectives of all stakeholders will be provided. Our results will offer context-sensitive explanations that can better inform local practices and policies and contribute to improve the health of patients with complex healthcare needs who frequently use healthcare services. Ultimately, this will increase the performance of healthcare systems and specifically mitigate ineffective use and costs.

Microbiomes Associated With Foods From Plant and Animal Sources.

Food microbiome composition impacts food safety and quality. The resident microbiota of many food products is influenced throughout the farm to fork continuum by farming practices, environmental factors, and food manufacturing and processing procedures. Currently, most food microbiology studies rely on culture-dependent methods to identify bacteria. However, advances in high-throughput DNA sequencing technologies have enabled the use of targeted 16S rRNA gene sequencing to profile complex microbial communities including non-culturable members. In this study we used 16S rRNA gene sequencing to assess the microbiome profiles of plant and animal derived foods collected at two points in the manufacturing process; post-harvest/pre-retail (cilantro) and retail (cilantro, masala spice mixes, cucumbers, mung bean sprouts, and smoked salmon). Our findings revealed microbiome profiles, unique to each food, that were influenced by the moisture content (dry spices, fresh produce), packaging methods, such as modified atmospheric packaging (mung bean sprouts and smoked salmon), and manufacturing stage (cilantro prior to retail and at retail). The masala spice mixes and cucumbers were comprised mainly of Proteobacteria, Firmicutes, and Actinobacteria. Cilantro microbiome profiles consisted mainly of Proteobacteria, followed by Bacteroidetes, and low levels of Firmicutes and Actinobacteria. The two brands of mung bean sprouts and the three smoked salmon samples differed from one another in their microbiome composition, each predominated by either by Firmicutes or Proteobacteria. These data demonstrate diverse and highly variable resident microbial communities across food products, which is informative in the context of food safety, and spoilage where indigenous bacteria could hamper pathogen detection, and limit shelf life.

Commissioning of a multi-beamline femtoslicing facility at SOLEIL.

The investigation of ultrafast dynamics, taking place on the few to sub-picosecond time scale, is today a very active research area pursued in a variety of scientific domains. With the recent advent of X-ray free-electron lasers (XFELs), providing very intense X-ray pulses of duration as short as a few femtoseconds, this research field has gained further momentum. As a consequence, the demand for access strongly exceeds the capacity of the very few XFEL facilities existing worldwide. This situation motivates the development of alternative sub-picosecond pulsed X-ray sources among which femtoslicing facilities at synchrotron radiation storage rings are standing out due to their tunability over an extended photon energy range and their high stability. Following the success of the femtoslicing installations at ALS, BESSY-II, SLS and UVSOR, SOLEIL decided to implement a femtoslicing facility. Several challenges were faced, including operation at the highest electron beam energy ever, and achievement of slice separation exclusively with the natural dispersion function of the storage ring. SOLEIL's setup also enables, for the first time, delivering sub-picosecond pulses simultaneously to several beamlines. This last feature enlarges the experimental capabilities of the facility, which covers the soft and hard X-ray photon energy range. In this paper, the commissioning of this original femtoslicing facility is reported. Furthermore, it is shown that the slicing-induced THz signal can be used to derive a quantitative estimate for the degree of energy exchange between the femtosecond infrared laser pulse and the circulating electron bunch.

Discovery of Clinical Candidate BMS-823778 as an Inhibitor of Human 11ß-Hydroxysteroid Dehydrogenase Type 1 (11ß-HSD-1).

BMS-823778 (2), a 1,2,4-triazolopyridinyl-methanol derived analog, was identified as a potent and selective inhibitor of human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1) enzyme (IC50 = 2.3 nM) with >10,000-fold selectivity over 11ß-HSD-2. Compound 2 exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED50 = 0.6 mg/kg) and in diet-induced obese (DIO) mice (ED50 = 34 mg/kg). Compound 2 also showed excellent inhibition in an ex vivo adipose DIO mouse model (ED50 = 5.2 mg/kg). Oral bioavailability ranges from 44% to 100% in preclinical species. Its favorable development properties, pharmacokinetics, high adipose-to-plasma concentration ratio, and preclinical pharmacology profile have prompted the evaluation of 2 for the treatment of type 2 diabetes and metabolic syndrome in phase 2 clinical trials.

Salmonella Serotyping Using Whole Genome Sequencing.

Until recently, traditional serology and the Kauffmann White Scheme (KWS) have been the gold standard for Salmonella serotyping. Whole Genome Sequencing (WGS) has now emerged as an alternative in this field. Serotype information remains a cornerstone in food safety and public health activities to reduce the burden of salmonellosis. At the same time, recent advances in WGS have improved the ability to perform advanced pathogen characterization while improving trace back investigations to determine the source of foodborne illness during outbreaks. Serovar prediction based on WGS can be performed using in silico data analysis tools. Three such tools have been developed: (a). Salmonella in silico Typing Resource (SISTR), (b). SeqSero, and (c). in silico 7-gene MLST ST (Multilocus Sequence Typing Sub-Typing) which was generated using the SISTR platform. Public health officials around the world are diligently working to validate these tools for replacing traditional surveillance methods to provide a more powerful approach for molecular epidemiology in support of public health investigations. In this study, we report a retrospective analysis of our laboratory inventory of 1,041 Salmonella isolates collected between 1999 and 2017. These isolates are of public health significance since they all came from either food, feed or environmental swabs. They were all serotyped by both traditional serology and WGS using an in silico SeqSero tool for serovar prediction. Both predicted identical Salmonella serotypes in 899 isolates (86.4% of the 1,041 Salmonella isolates). SeqSero assignments differed from traditional serological testing in 80 isolates (7.7%) and no serotype prediction was ascertained from 62 isolates (5.9%). This retrospective study is an excellent example of using WGS and SeqSero as a data analysis tool to predict Salmonella serotypes that can provide numerous advantages including molecular and genetic details regarding the characteristics of the Salmonella isolates compared to traditional KWS serotyping. In conclusion, it is evident that using WGS and in silico tools for Salmonella serotyping might someday replace traditional serotyping.

Synthesis and Biologic Evaluation of a Novel 18F-Labeled Adnectin as a PET Radioligand for Imaging PD-L1 Expression.

The programmed death protein (PD-1) and its ligand (PD-L1) play critical roles in a checkpoint pathway cancer cells exploit to evade the immune system. A same-day PET imaging agent for measuring PD-L1 status in primary and metastatic lesions could be important for optimizing drug therapy. Herein, we have evaluated the tumor targeting of an anti-PD-L1 adnectin after 18F-fluorine labeling. Methods: An anti-PD-L1 adnectin was labeled with 18F in 2 steps. This synthesis featured fluorination of a novel prosthetic group, followed by a copper-free click conjugation to a modified adnectin to generate 18F-BMS-986192. 18F-BMS-986192 was evaluated in tumors using in vitro autoradiography and PET with mice bearing bilateral PD-L1-negative (PD-L1(-)) and PD-L1-positive (PD-L1(+)) subcutaneous tumors. 18F-BMS-986192 was evaluated for distribution, binding, and radiation dosimetry in a healthy cynomolgus monkey. Results:18F-BMS-986192 bound to human and cynomolgus PD-L1 with a dissociation constant of less than 35 pM, as measured by surface plasmon resonance. This adnectin was labeled with 18F to yield a PET radioligand for assessing PD-L1 expression in vivo. 18F-BMS-986192 bound to tumor tissues as a function of PD-L1 expression determined by immunohistochemistry. Radioligand binding was blocked in a dose-dependent manner. In vivo PET imaging clearly visualized PD-L1 expression in mice implanted with PD-L1(+), L2987 xenograft tumors. Two hours after dosing, a 3.5-fold-higher uptake (2.41 ± 0.29 vs. 0.82 ± 0.11 percentage injected dose per gram, P < 0.0001) was observed in L2987 than in control HT-29 (PD-L1(-)) tumors. Coadministration of 3 mg/kg ADX_5322_A02 anti-PD-L1 adnectin reduced tumor uptake at 2 h after injection by approximately 70%, whereas HT-29 uptake remained unchanged, demonstrating PD-L1-specific binding. Biodistribution in a nonhuman primate showed binding in the PD-L1-rich spleen, with rapid blood clearance through the kidneys and bladder. Binding in the PD-L1(+) spleen was reduced by coadministration of BMS-986192. Dosimetry estimates indicate that the kidney is the dose-limiting organ, with an estimated human absorbed dose of 2.20E-01 mSv/MBq. Conclusion:18F-BMS-986192 demonstrated the feasibility of noninvasively imaging the PD-L1 status of tumors by small-animal PET studies. Clinical studies with 18F-BMS-986192 are under way to measure PD-L1 expression in human tumors.

An intervention strategy for improving residential environment and positive mental health among public housing tenants: rationale, design and methods of Flash on my neighborhood!

BACKGROUND: In Canada, public housing programs are an important part of governmental strategies to fight poverty and public exclusion. The Flash on my neighborhood! project is a four-year multiphase community-based participatory action research strategy currently implemented in six public housing developments (n = 1009 households) across the province of Québec, Canada. The goal is to reduce the mental health disparities faced by these public housing tenants compared to the general population, while identifying which environmental and policy changes are needed to turn public housing settings into healthier environments. METHODS: The protocol involves three successive, interconnected phases: 1) Strengths and needs assessment, including community outreach and recruitment of tenants to collaborate as peer researchers, an exploratory qualitative component (photovoice), a systematic neighborhood observation, and a household survey; 2) Action plan development, including a community forum and interactive capacity-building and discussion sessions; 3) Action plan implementation and monitoring. The entire intervention is evaluated using a mixed-method design, framed within a multiple case study perspective. Throughout the project and particularly in the evaluation phase, data will be collected to record a) contextual factors (tenants' previous experience of participation, history of public housing development, etc.); b) activities that took place and elements from the action plan that were implemented; and c) short- and medium-term outcomes (objective and perceived improvements in the quality of the residential setting, both physically and in terms of mental health and social capital). DISCUSSION: The study will provide unprecedented evidence-based information on the key ingredients of a collective intervention process associated with the increased collective empowerment and positive mental health of public housing tenants.

Case management in primary care among frequent users of healthcare services with chronic conditions: protocol of a realist synthesis.

INTRODUCTION: A common reason for frequent use of healthcare services is the complex healthcare needs of individuals suffering from multiple chronic conditions, especially in combination with mental health comorbidities and/or social vulnerability. Frequent users (FUs) of healthcare services are more at risk for disability, loss of quality of life and mortality. Case management (CM) is a promising intervention to improve care integration for FU and to reduce healthcare costs. This review aims to develop a middle-range theory explaining how CM in primary care improves outcomes among FU with chronic conditions, for what types of FU and in what circumstances. METHODS AND ANALYSIS: A realist synthesis (RS) will be conducted between March 2017 and March 2018 to explore the causal mechanisms that underlie CM and how contextual factors influence the link between these causal mechanisms and outcomes. According to RS methodology, five steps will be followed: (1) focusing the scope of the RS; (2) searching for the evidence; (3) appraising the quality of evidence; (4) extracting the data; and (5) synthesising the evidence. Patterns in context-mechanism-outcomes (CMOs) configurations will be identified, within and across identified studies. Analysis of CMO configurations will help confirm, refute, modify or add to the components of our initial rough theory and ultimately produce a refined theory explaining how and why CM interventions in primary care works, in which contexts and for which FU with chronic conditions. ETHICS AND DISSEMINATION: Research ethics is not required for this review, but publication guidelines on RS will be followed. Based on the review findings, we will develop and disseminate messages tailored to various relevant stakeholder groups. These messages will allow the development of material that provides guidance on the design and the implementation of CM in health organisations. TRIAL REGISTRATION NUMBER: Prospero CRD42017057753.