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Immediate early genes are rapidly transcribed in response to neuronal activity, but the underlying mechanism is unclear. The authors show that this rapid transcription is mediated by a stalled RNA polymerase II, poised just downstream of the transcription start site. RNAi-depletion of negative elongation factor compromises the rapid transcription. Transcription of immediate early genes (IEGs) in neurons is highly sensitive to neuronal activity, but the mechanism underlying these early transcription events is largely unknown. We found that several IEGs, such as Arc (also known as Arg3.1 ), are poised for near-instantaneous transcription by the stalling of RNA polymerase II (Pol II) just downstream of the transcription start site in rat neurons. Depletion through RNA interference of negative elongation factor, a mediator of Pol II stalling, reduced the Pol II occupancy of the Arc promoter and compromised the rapid induction of Arc and other IEGs. In contrast, reduction of Pol II stalling did not prevent transcription of IEGs that were expressed later and largely lacked promoter-proximal Pol II stalling. Together, our data strongly indicate that the rapid induction of neuronal IEGs requires poised Pol II and suggest a role for this mechanism in a wide variety of transcription-dependent processes, including learning and memory.

Background In the critically ill, energy delivery from enteral nutrition (EN) is often less than the estimated energy requirement. Parenteral nutrition (PN) as a supplement to EN may increase energy delivery. We aimed to determine if an individually titrated supplemental PN strategy commenced 48–72 hours following ICU admission and continued for up to 7 days would increase energy delivery to critically ill adults compared to usual care EN delivery. Methods This study was a prospective, parallel group, phase II pilot trial conducted in six intensive care units in Australia and New Zealand. Mechanically ventilated adults with at least one organ failure and EN delivery below 80% of estimated energy requirement in the previous 24 hours received either a supplemental PN strategy (intervention group) or usual care EN delivery. EN in the usual care group could be supplemented with PN if EN remained insufficient after usual methods to optimise delivery were attempted. Results There were 100 patients included in the study and 99 analysed. Overall, 71% of the study population were male, with a mean (SD) age of 59 (17) years, Acute Physiology and Chronic Health Evaluation II score of 18.2 (6.7) and body mass index of 29.6 (5.8) kg/m 2 . Significantly greater energy (mean (SD) 1712 (511) calories vs. 1130 (601) calories, p  < 0.0001) and proportion of estimated energy requirement (mean (SD) 83 (25) % vs. 53 (29) %, p  < 0.0001) from EN and/or PN was delivered to the intervention group compared to usual care. Delivery of protein and proportion of estimated protein requirements were also greater in the intervention group (mean (SD) 86 (25) g, 86 (23) %) compared to usual care (mean (SD) 53 (29) g, 51 (25) %, p  < 0.0001). Antibiotic use, ICU and hospital length of stay, mortality and functional outcomes were similar between the two groups. Conclusions This individually titrated supplemental PN strategy applied over 7 days significantly increased energy delivery when compared to usual care delivery. Clinical and functional outcomes were similar between the two patient groups. Trial registration Clinical Trial registry details: NCT01847534 (First registered 22 April 2013, last updated 31 July 2016)

A wealth of research demonstrates that harm reduction interventions for substance use (SU) save lives and reduce risk for serious infectious diseases such as HIV, hepatitis C, and other SU-related health conditions. The U.S. has adopted several harm reduction interventions at federal and state levels to combat SU-related harm. While several policy changes on the federal and state levels decriminalized interventions and further support their use, other policies limit the reach of these interventions by delaying or restricting care, leaving access to life-saving interventions inconsistent across the U.S. Federal and state policies in the U.S. that restrict access to medications for opioid use disorder (MOUD), criminalize possession of drug paraphernalia, prevent syringe service programs and overdose prevention centers from operating, and limit prescribing of pre-exposure prophylaxis (PrEP) pose significant barriers to harm reduction access and implementation. This paper aims to bridge publications and reports on current state and federal harm reduction intervention policies and discuss policy recommendations. Federally, the DEA and SAMHSA should expand certification for methadone dispensing to settings beyond dedicated opioid treatment programs and non-OTP prescribers. Congress can decriminalize items currently categorized as paraphernalia, permit purchasing of syringes and all drug checking equipment using federal funds, amend the Controlled Substances Act to allow for expansion of overdose prevention centers, protect Medicaid coverage of PrEP, and expand Medicaid to cover residential SU treatment. At the state level, states can reduce regulations for prescribing MOUD and PrEP, decriminalize drug paraphernalia, codify Good Samaritan laws, and remove restrictions for syringe service program and overdose prevention center implementation. Lastly, states should expand Medicaid to allow broader access to treatment for SU and oppose Medicaid lock-outs based on current SU. These changes are needed as overdose deaths and serious infectious disease rates from SU continue to climb and impact American lives.

Background Rheumatic heart disease (RHD) is highly prevalent and under-detected in remote First Nations Australian communities. Rural communities face severe health workforce shortages that impact negatively on health outcomes. Task-sharing using local healthcare workers, trained to screen for active RHD cases (using handheld ultrasound with remote support from experts), has been proposed as a means of improving early detection whilst also strengthening referral pathways. Implementing new models of care within remote communities, however, requires local knowledge, cultural and operational adaptation, whilst ensuring consistency and quality assurance across multiple sites. This study aimed to co-design local implementation strategies for an RHD active case finding program with five remote communities and explain how and why the task-sharing program might lead to improved health outcomes. Methods A qualitative study using a Theory of Change approach and ‘yarning’ methods, was conducted with five remote First Nations Australian communities. We used a combination of participant observation, extensive field notes over sequential visits to each site, supplemented with document analysis to inform co-design of Theories of Change for each community. Data were curated using NVivo software and analysed using Powell’s refined compilation of implementation strategies framework. Results Through the co-design process, a total of 24 locally tailored implementation strategies were identified. All sites identified the need for a positive implementation environment, including recognition of local healthcare workers through positive messaging and celebratory events for achieving key training milestones. Other key themes included the importance of opportunistic RHD screening, and the integration of local languages during both training and screening. Five locally adapted versions of the Theory of Change were co-designed to include planned outcomes, assumptions, causal mechanisms, and indicators for the program at each community. Conclusions Our study identified implementation strategies and Theories of Change for the training and screening aspects of a new model of care for RHD screening in five remote First Nation Australian communities. These findings will be used to support future program evaluation and exploration the mechanisms by which the RHD screening program achieves its outcomes.

Intensive care unit (ICU)-acquired weakness often develops in patients who are undergoing invasive mechanical ventilation. Early active mobilization may mitigate ICU-acquired weakness, increase survival, and reduce disability. We randomly assigned 750 adult patients in the ICU who were undergoing invasive mechanical ventilation to receive increased early mobilization (sedation minimization and daily physiotherapy) or usual care (the level of mobilization that was normally provided in each ICU). The primary outcome was the number of days that the patients were alive and out of the hospital at 180 days after randomization. The median number of days that patients were alive and out of the hospital was 143 (interquartile range, 21 to 161) in the early-mobilization group and 145 days (interquartile range, 51 to 164) in the usual-care group (absolute difference, -2.0 days; 95% confidence interval [CI], -10 to 6; P = 0.62). The mean (±SD) daily duration of active mobilization was 20.8±14.6 minutes and 8.8±9.0 minutes in the two groups, respectively (difference, 12.0 minutes per day; 95% CI, 10.4 to 13.6). A total of 77% of the patients in both groups were able to stand by a median interval of 3 days and 5 days, respectively (difference, -2 days; 95% CI, -3.4 to -0.6). By day 180, death had occurred in 22.5% of the patients in the early-mobilization group and in 19.5% of those in the usual-care group (odds ratio, 1.15; 95% CI, 0.81 to 1.65). Among survivors, quality of life, activities of daily living, disability, cognitive function, and psychological function were similar in the two groups. Serious adverse events were reported in 7 patients in the early-mobilization group and in 1 patient in the usual-care group. Adverse events that were potentially due to mobilization (arrhythmias, altered blood pressure, and desaturation) were reported in 34 of 371 patients (9.2%) in the early-mobilization group and in 15 of 370 patients (4.1%) in the usual-care group (P = 0.005). Among adults undergoing mechanical ventilation in the ICU, an increase in early active mobilization did not result in a significantly greater number of days that patients were alive and out of the hospital than did the usual level of mobilization in the ICU. The intervention was associated with increased adverse events. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; TEAM ClinicalTrials.gov number, NCT03133377.).

Trachoma, caused by ocular infection with Chlamydia trachomatis, is hyperendemic on the Bijagós Archipelago of Guinea Bissau. An understanding of the risk factors associated with active trachoma and infection on these remote and isolated islands, which are atypical of trachoma-endemic environments described elsewhere, is crucial to the implementation of trachoma elimination strategies. A cross-sectional population-based trachoma prevalence survey was conducted on four islands. We conducted a questionnaire-based risk factor survey, examined participants for trachoma using the World Health Organization (WHO) simplified grading system and collected conjunctival swab samples for 1507 participants from 293 randomly selected households. DNA extracted from conjunctival swabs was tested using the Roche Amplicor CT/NG PCR assay. The prevalence of active (follicular and/or inflammatory) trachoma was 11% (167/1508) overall and 22% (136/618) in 1-9 year olds. The prevalence of C. trachomatis infection was 18% overall and 25% in 1-9 year olds. There were strong independent associations of active trachoma with ocular and nasal discharge, C. trachomatis infection, young age, male gender and type of household water source. C. trachomatis infection was independently associated with young age, ocular discharge, type of household water source and the presence of flies around a latrine. In this remote island environment, household-level risk factors relating to fly populations, hygiene behaviours and water usage are likely to be important in the transmission of ocular C. trachomatis infection and the prevalence of active trachoma. This may be important in the implementation of environmental measures in trachoma control.

The role of cytochrome P450-derived epoxy-oxylipins and their metabolites in human inflammation and resolution is unknown. We report that epoxy-oxylipins are present in blood of healthy, male volunteers at baseline and following intradermal injection of UV-killed Escherichia coli , an experimental model of acute resolving inflammation. At the site of inflammation, cytochrome P450s and epoxide hydrolase (EH) isoforms, which catabolise oxylipins to corresponding diols, are differentially upregulated throughout the inflammatory response, as is the biosynthesis of epoxy-oxylipins. GSK2256294, a selective sEH inhibitor specifically elevates 12,13-EpOME and 14,15-EET. While inhibition of sEH hastens pain resolution, it has no effect on tissue heat, redness and swelling. GSK2256294, however, significantly reduces numbers of circulating intermediate monocytes that expand during inflammation. We find that 12,13-EpOME blocks the transition of classical to intermediate monocytes in a p38 MAPK-dependent manner, results that are recapitulated when blocking p38 MAPK in vitro and when administering the p38 MAPK inhibitor losmapimod in vivo to healthy volunteers. Furthermore, fewer intermediate monocytes are observed at the site of inflammation, accompanied by reduced tissue CD4 T cells. Hence, we have mapped the expression, activity and function of epoxy-oxylipins in human inflammation revealing new mechanisms of monocyte differentiation and resolution biology. Here they demonstrate a therapeutic intervention elevating levels of CYP450-derived lipids to control the expansion of intermediate monocytes in tissue and peripheral blood, presenting a first in class therapeutic approach for treating chronic inflammatory disease.

Fabry disease is a rare X-linked deficiency of lysosomal alpha-galactosidase that causes glycolipid accumulation in tissues, including the brain. The most common neurologic sequelae of Fabry are cognitive decline and white matter lesions (WMLs) on brain magnetic resonance imaging (MRI). In the at-large population, however, WMLs are non-specific, highly prevalent, and most are clinically silent. Thus, we compared Fabry to typical brain aging to identify factors unique to Fabry-related cognitive decline. Twenty adult Fabry patients (75% female; median age 36.4 yrs, range: 19.8–63.2 yrs; 95% on enzyme replacement therapy) without a history of stroke or other neurologic diseases and 20 age/sex-matched healthy controls were enrolled in a case-control study. All participants underwent a neurocognitive assessment and a 3.0 T MRI study of the brain that used structural MRI (e.g., fluid-attenuated inversion recovery, FLAIR), semi-quantitative MRI (e.g., normalized FLAIR signal intensity), and quantitative MRI (diffusion tensor imaging, bound-pool fraction imaging). During a blinded review of structural MRIs, a neuroradiologist’s categorization of case-control status did not correspond to disease status (Fisher’s test, P  > 0.99) but rather to age ( P  = 0.004), indicating qualitative changes associated with Fabry were similar to normal age-related brain alterations. Using quantitative MRI, however, we detected evidence of microstructural damage in the white matter of younger Fabry adults (<40 yrs). With age, WML severity increased and the corpus callosum atrophied in Fabry, phenomena absent in controls and consistent with progressive tissue damage. Neurocognitive assessments identified trends for lower verbal intelligence quotient and executive function in the younger Fabry participants, which became statistically significant in the older Fabry patients. Our data suggest that the early onset of microstructural damage in Fabry drives the insidious degeneration of white matter, leading to impaired cognition. Aging Fabry patients may benefit from serial cognitive assessments to identify unmet therapeutic needs.

Flexible multielectrode arrays with glassy carbon (GC) electrodes and metal interconnection (hybrid MEAs) have shown promising performance in multi-channel neurochemical sensing. A primary challenge faced by hybrid MEAs fabrication is the adhesion of the metal traces with the GC electrodes, as prolonged electrical and mechanical stimulation can lead to adhesion failure. Previous devices with GC electrodes and interconnects made of a homogeneous material (all GC) demonstrated exceptional electrochemical stability but required miniaturization for enhanced tissue integration and chronic electrochemical sensing. In this study, we used two different methods for the fabrication of all GC-MEAs on thin flexible substrates with miniaturized features. The first method, like that previously reported, involves a double pattern-transfer photolithographic process, including transfer-bonding on temporary polymeric support. The second method requires a double-etching process, which uses a 2 µm-thick low stress silicon nitride coating of the Si wafer as the bottom insulator layer for the MEAs, bypassing the pattern-transfer and demonstrating a novel technique with potential advantages. We confirmed the feasibility of the two fabrication processes by verifying the practical conductivity of 3 µm-wide 2 µm-thick GC traces, the GC microelectrode functionality, and their sensing capability for the detection of serotonin using fast scan cyclic voltammetry. Through the exchange and discussion of insights regarding the strengths and limitations of these microfabrication methods, our goal is to propel the advancement of GC-based MEAs for the next generation of neural interface devices.