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ABSTRACT IMPACT: This work may provide new targets for vaccine and immunotherapeutic development against MRSA infections. OBJECTIVES/GOALS: Staphylococcus aureus is the leading cause of skin and skin structure infection (SSSI), a primary portal of entry for invasive infection. Patients with SA SSSI have a high 1-year recurrence. We have shown innate memory protects mice against SA SSSI. The goal of this project is to determine epigenetic mechanisms of protective memory against SA SSSI. METHODS/STUDY POPULATION: We have shown macrophages (Mf) afford protective memory against recurrent SA SSSI in mice. Priming by prior infection reduced skin lesion size and MRSA burden, which correlated with increased Mf in abscesses and lymph nodes. Priming potentiated the opsonophagocytic killing of SA by bone-marrow derived Mf (BMDM) in vitro, and their adoptive transfer into naive skin afforded protective efficacy in vivo. Here, we investigated epigenetic mechanisms of anti-SA efficacy in BMDMs. BMDM from naive (uninfected) or primed (SA SSSI) wild-type C57Bl/6 mice were cultured ex vivo. DNA from BMDM groups were isolated and analyzed for methylation changes using reduced representation bisulfite sequencing (RRBS). Pathway analyses of methylation changes were determined with Panther. RESULTS/ANTICIPATED RESULTS: Present findings indicate the protective memory afforded by BMDM was mediated by epigenetic modifications of the DNA. Using RRBS, we profiled differentially methylated regions (DMR) in DNA from naive vs. primed BMDM. Primed BMDM exhibited significantly different DMRs as compared to naive BMDM. Proximity to known genes were mapped using GREAT. Pathway analyses revealed DMRs predominant in genes integral to immune modulation, such as integrin signaling, cytokine/chemokine networks, and growth regulation. For example, SA-primed BMDM were hypermethylated proximate to GIMAP8 versus naive BMDM, suggesting repression of this protein. Gimap family ligands are small GTPase immune-associated proteins expressed in immune cells known to regulate macrophage lysosomal fusion during parasite infection. DISCUSSION/SIGNIFICANCE OF FINDINGS: These findings reveal epigenetic mechanisms of macrophage innate memory against recurrent MRSA infection. Functional testing of these genes in response to SA infection is needed to confirm their protective role. These insights may provide new targets for vaccine and immunotherapeutic development against MRSA.
To conduct a pilot study implementing combined genomic and epidemiologic surveillance for hospital-acquired multidrug-resistant organisms (MDROs) to predict transmission between patients and to estimate the local burden of MDRO transmission.
Pilot prospective multicenter surveillance study.
The study was conducted in 8 university hospitals (2,800 beds total) in Melbourne, Australia (population 4.8 million), including 4 acute-care, 1 specialist cancer care, and 3 subacute-care hospitals.
All clinical and screening isolates from hospital inpatients (April 24 to June 18, 2017) were collected for 6 MDROs: vanA VRE, MRSA, ESBL Escherichia coli (ESBL-Ec) and Klebsiella pneumoniae (ESBL-Kp), and carbapenem-resistant Pseudomonas aeruginosa (CRPa) and Acinetobacter baumannii (CRAb). Isolates were analyzed and reported as routine by hospital laboratories, underwent whole-genome sequencing at the central laboratory, and were analyzed using open-source bioinformatic tools. MDRO burden and transmission were assessed using combined genomic and epidemiologic data.
In total, 408 isolates were collected from 358 patients; 47.5% were screening isolates. ESBL-Ec was most common (52.5%), then MRSA (21.6%), vanA VRE (15.7%), and ESBL-Kp (7.6%). Most MDROs (88.3%) were isolated from patients with recent healthcare exposure.
Combining genomics and epidemiology identified that at least 27.1% of MDROs were likely acquired in a hospital; most of these transmission events would not have been detected without genomics. The highest proportion of transmission occurred with vanA VRE (88.4% of patients).
Genomic and epidemiologic data from multiple institutions can feasibly be combined prospectively, providing substantial insights into the burden and distribution of MDROs, including in-hospital transmission. This analysis enables infection control teams to target interventions more effectively.
Shortages of personal protective equipment during the coronavirus disease 2019 (COVID-19) pandemic have led to the extended use or reuse of single-use respirators and surgical masks by frontline healthcare workers. The evidence base underpinning such practices warrants examination.
To synthesize current guidance and systematic review evidence on extended use, reuse, or reprocessing of single-use surgical masks or filtering face-piece respirators.
We used the World Health Organization, the European Centre for Disease Prevention and Control, the US Centers for Disease Control and Prevention, and Public Health England websites to identify guidance. We used Medline, PubMed, Epistemonikos, Cochrane Database, and preprint servers for systematic reviews.
Two reviewers conducted screening and data extraction. The quality of included systematic reviews was appraised using AMSTAR-2. Findings were narratively synthesized.
In total, 6 guidance documents were identified. Levels of detail and consistency across documents varied. They included 4 high-quality systematic reviews: 3 focused on reprocessing (decontamination) of N95 respirators and 1 focused on reprocessing of surgical masks. Vaporized hydrogen peroxide and ultraviolet germicidal irradiation were highlighted as the most promising reprocessing methods, but evidence on the relative efficacy and safety of different methods was limited. We found no well-established methods for reprocessing respirators at scale.
Evidence on the impact of extended use and reuse of surgical masks and respirators is limited, and gaps and inconsistencies exist in current guidance. Where extended use or reuse is being practiced, healthcare organizations should ensure that policies and systems are in place to ensure these practices are carried out safely and in line with available guidance.
Fifty to ninety percent of individuals with Major Neurocognitive Disorder (MNCD) have Neuropsychiatric Symptoms (NPS)1. Agitation and aggression are amongst the most persistent and treatment-refractory symptom clusters. Patients with these NPS are associated with increased risk of institutionalization, psychotropic medication use, caregiver burden, and mortality2.
Safe and effective treatments for NPS are lacking. Consensus guidelines emphasize the initial use of non-pharmacologic approaches though supportive evidence is limited3.
Extensive research has established the safety and efficacy of ECT in elderly patients with depression and other psychiatric conditions6. Clinical experience suggests that ECT is a valuable treatment option in MNCD-related treatment refractory NPS cases7-10. However, data supporting the efficacy and safety of this practice is scant.
Materials and Method:
Patients admitted to the geriatric psychiatry inpatient units who meet the inclusion criteria, were recruited from 2 Vancouver sites and 3 unit at Ontario Shores. These patients had an anesthesia consultation to evaluate their safety of going through ECT. Consent was obtained from their substitute decision makers. All patients enrolled are already on psychotropic medications.
Little is known about methylphenidate (MPH) use and mortality outcomes.
To investigate the association between MPH use and mortality among children with an attention-deficit hyperactivity disorder (ADHD) diagnosis.
This population-based cohort study analysed data from Taiwan's National Health Insurance Research Database (NHIRD). A total of 68 096 children and adolescents aged 4–17 years with an ADHD diagnosis and prescribed MPH between 2000 and 2010 were compared with 68 096 without an MPH prescription, matched on age, gender and year of first ADHD diagnosis. All participants were followed to death, migration, withdrawal from the National Health Insurance programme or 31 December 2013. MPH prescriptions were measured on a yearly basis during the study period, and the association between MPH use and mortality was analysed using a repeated-measures time-dependent Cox regression model. The outcome measures included all-cause, unnatural-cause (including suicide, accident and homicide) and natural-cause mortality, obtained from linkage to the National Mortality Register in Taiwan.
The MPH group had lower unadjusted all-cause, natural-, unnatural- and accident-cause mortality than the comparison group. After controlling for potential confounders, MPH use was associated with a significantly lower all-cause mortality (adjusted hazard ratio AHR = 0.81, 95% CI 0.67–0.98, P = 0.027), delayed use of MPH was associated with higher mortality (AHR = 1.05, 95% CI 1.01–1.09) and longer MPH use was associated with lower mortality (AHR = 0.83, 95% CI 0.70–0.98).
MPH use is associated with a reduced overall mortality in children with ADHD in this cohort study, but unmeasured confounding cannot be excluded absolutely.
The legal profession is facing a convergence of forces, most notably significant advances in the capabilities of technology, economic pressures challenging existing business models, and globalisation, that together herald a momentous change in the practice of law. From at least the 1970s the practice of law has experienced a number of changes which have impacted on the types of roles that lawyers play and the economics of lawyering, but they were more gradual as compared to the increased pace of change which is currently in play.
Around the world the legal profession has started to focus on these forces of‘disruption‘ and what they mean for lawyers, in their various roles, and the users of law, corporations, government, but especially the disadvantaged. For example in June 2013 the German Bar Association contracted with consulting firm PROGNOS to produce‘Der Rechtsdienstleistungsmarkt 2030‘ (‘The Legal Services Market 2030‘) which outlines how the legal services market is expected to function in 2030. The Law Society of England and Wales published its‘Future of Legal Services Report‘ in January 2016. The American Bar Association (ABA) established a Commission on the Future of Legal Services which reported in August 2016 and has continued providing resources for the profession. In Australia the lead in seeking to understand these developments and formulate responses has been taken by the Law Society of New South Wales and its report on the Future of Law and Innovation in the Profession (FLIP). Academic attention has also been directed at these changes. A significant literature contributed to by both the profession and academics has developed on the changing legal profession and the impact of the various changes. Richard Susskind has predicted an increase in the use of technology, including without lawyers, commoditisation of legal work and a reconfiguration of the profession. Arguments about how the role of lawyers has changed and may change in the future have included both pessimistic accounts such as Susskind‘s, as well as more optimistic ones such as Trotter‘s, or Kronman‘s aspirational view of the lawyer-statesman.