Practical considerations including appropriate timing and optimal local delivery of immune stimulatory agents play an important role in safety and efficacy of this approach. Here we discuss promising approaches in drug delivery technologies and opportunity for combining intratumoral immunotherapy with other cancer treatments and summarize the recent preclinical and clinical evidences that highlighted its promise as a part of routine oncologic care. Copyright ©2020, American Association for Cancer Research.PURPOSE Prostate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. We investigated whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, likely rendering those sensitive to HR-directed therapies. EXPERIMENTAL DESIGN HRD levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach on whole genome (n=311) and whole exome sequencing data (n=498) of both primary and metastatic prostate adenocarcinomas (PRAD) to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. RESULTS Known BRCA-deficient samples showed all previously described HR-deficiency associated mutational signatures in the whole genome sequencing data. HRD-associated mutational signatures were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR-related genes. Similar results, albeit with lower sensitivity and accuracy, were also obtained from whole exome sequencing data. CONCLUSIONS These findings may expand the number of cases likely to respond to PARP inhibitor treatment. Based on the HR-associated mutational signatures, 5-8 % of localized prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations). Copyright ©2020, American Association for Cancer Research.OBJECTIVES To identify and summarise existing indices for measuring multimorbidity beyond disease counts, to establish which indices include mental health comorbidities or outcomes, and to develop recommendations based on applicability, performance, and usage. DESIGN Systematic review. DATA SOURCES Seven medical research databases (Medline, Web of Science Core Collection, Cochrane Library, Embase, PsycINFO, Scopus, and CINAHL Plus) from inception to October 2018 and bibliographies and citations of relevant papers. Searches were limited to English language publications. ELIGIBILITY CRITERIA FOR STUDY SELECTION Original articles describing a new multimorbidity index including more information than disease counts and not focusing on comorbidity associated with one specific disease. Studies were of adults based in the community or at population level. RESULTS Among 7128 search results, 5560 unique titles were identified. After screening against eligibility criteria the review finally included 35 papers. As index components, 25 indices used conditions (weighted or in combination with other parameters), five used diagnostic categories, four used drug use, and one used physiological measures. Predicted outcomes included mortality (18 indices), healthcare use or costs (13), hospital admission (13), and health related quality of life (7). 29 indices considered some aspect of mental health, with most including it as a comorbidity. 12 indices are recommended for use. CONCLUSIONS 35 multimorbidity indices are available, with differing components and outcomes. Researchers and clinicians should examine existing indices for suitability before creating new ones. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42017074211. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http//group.bmj.com/group/rights-licensing/permissions.BACKGROUND Comprehensive longitudinal studies are important for understanding the complex risk factors, pathways, exposures and interactions that lead to the development and persistence of asthma. We aimed to examine associations between use of household cleaning products in early life and childhood respiratory and allergic disease using data from the Canadian Healthy Infant Longitudinal Development (CHILD) Cohort Study. METHODS We summed responses from parental questionnaires that indicated the frequency of use of 26 household cleaning products in the homes of 2022 children from this birth cohort when they were 3-4 months of age to create a cumulative Frequency of Use Score (FUS). We used multivariable logistic regression models to assess whether frequent compared with less frequent use was associated with recurrent wheeze, atopy or asthma diagnosis, as defined by the questionnaire and clinical assessments at age 3 years. Data were collected between 2008 and 2015. RESULTS Children in homes with a higher freqgic airway disease and help to identify household behaviours as a potential area for intervention. © 2020 Joule Inc. or its licensors.Congenital toxoplasmosis occurs following transplacental transfer of Toxoplasma gondii Irrespective of symptom status at birth, infants with congenital infection may develop serious long-term sequelae, including learning disability, seizures, hydrocephalus, motor and hearing deficits, chorioretinitis and retinal scarring with impaired vision. Timely diagnosis facilitates early initiation of therapy, aimed at prevention or amelioration of adverse clinical consequences. Diagnosis can be difficult, however, since acutely infected mothers are often asymptomatic and laboratory testing can be complex. Moreover, any decision to start treatment in the newborn must include careful consideration of the benefits and risks. This paper outlines a structured approach for managing an infant born to a woman with possible or confirmed T. gondii infection during pregnancy, including key aspects of the antenatal history, interpretation and timing of investigations, treatment and appropriate follow-up. Our recommendations are based on current evidence in the literature, consensus from two UK paediatric infectious disease centres and the UK specialist Toxoplasma Reference Unit. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Decreased release of palmitic acid methyl ester (PAME), a vasodilator, from perivascular adipose tissue (PVAT) might contribute to hypertension pathogenesis. However, the PAME biosynthetic pathway remains unclear. In this study, we hypothesized that PAME is biosynthesized from palmitic acid (PA) via human catechol-O-methyltransferase (COMT) catalysis and that decreased PAME biosynthesis plays a role in hypertension pathogenesis. We compared PAME biosynthesis between age-matched normotensive Wistar Kyoto (WKY) rats and hypertensive spontaneously hypertensive rats (SHRs) and investigated the effects of losartan treatment on PAME biosynthesis. Computational molecular modeling indicated that PA binds well at the active site of COMT. Furthermore, in in vitro enzymatic assays in the presence of Comt and S-5′-adenosyl-L-methionine (AdoMet), the stable isotope [13C16]-PA was methylated to form [13C16]-PAME in incubation medium or the Krebs-Henseleit solution containing 3T3-L1 adipocytes, or rat PVAT. The adipocytes apathway. Moreover, we confirmed PVAT dysfunction in the hypertensive state. COMT-dependent PAME biosynthesis is involved in AT-1 receptor-mediated blood pressure regulation, as evidenced by the reversal of decreased PAME biosynthesis in PVAT by losartan in hypertensive rats. This finding might help in developing novel therapeutic or preventive strategies against hypertension. The American Society for Pharmacology and Experimental Therapeutics.Dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for treatment of T2D and obesity due to their beneficial effects on body weight, blood glucose and insulin sensitivity. DACRAs activate the receptors for a prolonged time period resulting in metabolic effects superior to those of amylin. Pharmacological amylin receptor activation leads to body weight loss and reduced food intake as well as improved food preference, at least short-term. Due to the prolonged receptor activation, different dosing intervals and hence less frequent receptor activation might change the efficacy of DACRA treatment in terms of weight loss and food preference. In this study, we compared daily dosing (q.d.) to dosing every other day (q.a.d.) with the aim of understanding the optimal balance between efficacy and tolerability. Obese and lean male Sprague-Dawley rats were treated with the DACRA, KBP-088, applying two different dosing intervals 1.5 nmol/kg q.d. and 3 nmol/kg q.a.d, in order to assess the effects on le in the treatment of obesity. The American Society for Pharmacology and Experimental Therapeutics.Classifying microorganisms as „obligate” aerobes has colloquially implied death without air, leading to the erroneous assumption that without oxygen they are unable to survive. However, over the past few decades, more than a few obligate aerobes have been found to possess anaerobic energy conservation strategies that sustain metabolic activity in the absence of growth or at very slow growth rates. Similarly, studies emphasizing the aerobic prowess of certain facultative aerobes have sometimes led to under-recognition of their anaerobic capabilities. Yet an inescapable consequence of the affinity both obligate and facultative aerobes have for oxygen is that the metabolism of these organisms may drive this substrate to scarcity, making anoxic survival an essential skill. To illustrate this, we highlight the importance of anaerobic survival strategies for Pseudomonas aeruginosa and Streptomyces coelicolor, representative facultative and obligate aerobes, respectively. Included amongst these strategies we describe a role for redox-active secondary metabolites (RAMs), such as phenazines made by P. aeruginosa, in enhancing substrate-level phosphorylation. Importantly, RAMs are made by diverse bacteria, often during stationary phase in the absence of oxygen, and can sustain anoxic survival. We present a hypothesis for how RAMs may enhance or even unlock energy conservation pathways that facilitate the anaerobic survival of both RAM-producers and non-producers. Copyright © 2020 American Society for Microbiology.Bacterial microcompartments (MCPs) are widespread protein-based organelles composed of metabolic enzymes encapsulated within a protein shell. The function of MCPs is to optimize metabolic pathways by confining toxic and/or volatile pathway intermediates. A major class of MCPs, known as glycyl radical MCPs has only been partially characterized. Here, we show that uropathogenic Escherichia coli CFT073 uses a glycyl radical MCP for 1,2-propanediol (1,2-PD) fermentation. Bioinformatic analyses identified a large gene cluster (named grp for [underln]g[/underln]lycyl [underln]r[/underln]adical [underln]p[/underln]ropanediol) that encodes homologs of a glycyl radical diol dehydratase, other 1,2-PD catabolic enzymes and MCP shell proteins. Growth studies showed that E. coli CFT073 grows on 1,2-PD under anaerobic conditions but not under aerobic conditions. All nineteen grp genes were individually deleted and 8/19 were required for 1,2-PD fermentation. Electron microscopy and genetic studies showed that a bacterial MCP is involved.