Argonaute-bound small RNAs from promoter-proximal RNA polymerase II.

Argonaute (Ago) proteins mediate posttranscriptional gene repression by binding guide miRNAs to regulate targeted RNAs. To confidently assess Ago-bound small RNAs, we adapted a mouse embryonic stem cell system to express a single epitope-tagged Ago protein family member in an inducible manner. Here, we report the small RNA profile of Ago-deficient cells and show that Ago-dependent stability is a common feature of mammalian miRNAs. Using this criteria and immunopurification, we identified an Ago-dependent class of noncanonical miRNAs derived from protein-coding gene promoters, which we name transcriptional start site miRNAs (TSS-miRNAs). A subset of promoter-proximal RNA polymerase II (RNAPII) complexes produces hairpin RNAs that are processed in a DiGeorge syndrome critical region gene 8 (Dgcr8)/Drosha-independent but Dicer-dependent manner. TSS-miRNA activity is detectable from endogenous levels and following overexpression of mRNA constructs. Finally, we present evidence of differential expression and conservation in humans, suggesting important roles in gene regulation.

Sequestration of microRNA-mediated target repression by the Ago2-associated RNA-binding protein FAM120A.

Argonaute (Ago) proteins interact with various binding partners and play a pivotal role in microRNA (miRNA)-mediated silencing pathways. By utilizing immunoprecipitation followed by mass spectrometry to determine cytoplasmic Ago2 protein complexes in mouse embryonic stem cells (mESCs), we identified a putative RNA-binding protein FAM120A (also known as OSSA/C9ORF10) as an Ago2 interacting protein. Individual nucleotide resolution cross-linking and immunoprecipitation (iCLIP) analysis revealed that FAM120A binds to homopolymeric tracts in 3'-UTRs of about 2000 mRNAs, particularly poly(G) sequences. Comparison of FAM120A iCLIP and Ago2 iCLIP reveals that greater than one-third of mRNAs bound by Ago2 in mESCs are co-bound by FAM120A. Furthermore, such FAM120A-bound Ago2 target genes are not subject to Ago2-mediated target degradation. Reporter assays suggest that the 3'-UTRs of several FAM120A-bound miRNA target genes are less sensitive to Ago2-mediated target repression than those of FAM120A-unbound miRNA targets and FAM120A modulates them via its G-rich target sites. These findings suggest that Ago2 may exist in multiple protein complexes with varying degrees of functionality.

'Gun shop projects' for suicide prevention in the USA: current state and future directions.

OBJECTIVES: To describe community-driven suicide prevention partnerships between firearm retailers and public health officials ('gun shop projects'), including common elements and challenges. METHODS: We conducted qualitative interviews with leaders from state-level and national-level partnerships to determine common features, challenges and strategies used by these groups. Data were coded via theme analysis; two independent coders followed a shared codebook developed in an iterative fashion and with high inter-rater reliability. RESULTS: Across 10 interviews, data revealed four main themes: (1) community building was a cornerstone of these efforts; (2) appropriate messaging and language were vital to successes; (3) groups employed various educational and outreach campaigns and (4) groups identified common challenges and obstacles. CONCLUSIONS: Gun shop project partnerships between firearm retailers and public health officials show promise, with thematic data demonstrating common trends and steps towards successful programme implementation. Evaluative data are needed to determine the impact of these efforts on suicide prevention in local communities.

A novel social work approach to emergency department buprenorphine induction and warm hand-off to community providers.

STUDY OBJECTIVE: Medications for opioid use disorder (MOUD) is considered gold standard treatment for persons with an opioid use disorder and can be successfully initiated in emergency departments (EDBUP). Perceived provider barriers to EDBUP adoption include increased provider work, lack of provider knowledge about outpatient MOUD resources, and a lack of viable MOUD treatment options within health systems. We evaluated the feasibility of a novel EDBUP institutional design that utilizes the social work team to drive ED care for patients with OUD and coordinate MOUD referral to existing community resources. METHODS: This is a retrospective, cohort, single-center study describing patient outcomes in a social work driven EDBUP program with referral to community MOUD providers. ED patients with OUD were identified via patient request, standardized nurse screening, or ED provider concern. All identified patients received an urgent social work consult to explore willingness to seek treatment for OUD. Social workers developed individualized follow up plans with participating patients. Clinical data was abstracted from the Electronic Health Record. Social workers tracked continuity with outpatient MOUD services in a clinical care database. RESULTS: From June 1, 2018 through August 31, 2019, 120 patients opted for ED buprenorphine induction. 61% presented to initial outpatient intake appointment and 39% remained engaged in treatment after 30 days. CONCLUSIONS: EDs can effectively utilize the expertise of social workers to drive EDBUP and coordinate outpatient MOUD referrals. Our interdisciplinary EDBUP program structure is feasible and has the potential to yield meaningful reductions in physician workload and ED cost.

Recent Advances in Isoindigo-Inspired Organic Semiconductors.

Over the past decade, isoindigo has become a widely used electron-deficient subunit in donor-acceptor organic semiconductors, and these isoindigo-based materials have been widely used in both organic photovoltaic (OPV) devices and organic field effect transistors (OFETs). Shortly after the development of isoindigo-based semiconductors, researchers began to modify the isoindigo structure in order to change the optoelectronic properties of the resulting materials. This led to the development of many new isoindigo-inspired compounds; since 2012, the Kelly Research Group has synthesized a number of these isoindigo analogues and produced a variety of new donor-acceptor semiconductors. In this Personal Account, recent progress in the field is reviewed. We describe how the field has evolved from relatively simple donor-acceptor small molecules to structurally complex, highly planarized polymer systems. The relevance of these materials in OPV and OFET applications is highlighted, with particular emphasis on structure-property relationships.

Multiple and multidimensional life transitions in the context of life-limiting health conditions: longitudinal study focussing on perspectives of young adults, families and professionals.

BACKGROUND: There is a dearth of literature that investigates life transitions of young adults (YAs) with life-limiting conditions, families and professionals. The scant literature that is available has methodological limitations, including not listening to the voice of YAs, collecting data retrospectively, at one time point, from one group's perspective and single case studies. The aim of this study was to address the gaps found in our literature review and provide a clearer understanding of the multiple and multi-dimensional life transitions experienced by YAs and significant others, over a period of time. METHODS: This qualitative study used a longitudinal design and data were collected using semi-structured interviews over a 6-month period at 3 time points. Participants included 12 YAs with life-limiting conditions and their nominated significant others (10 family members and 11 professionals). Data were analysed using a thematic analysis approach. RESULTS: Life transitions of YA and significant others are complex; they experience multiple and multi-dimensional transitions across several domains. The findings challenge the notion that all life transitions are triggered by health transitions of YAs, and has highlighted environmental factors (attitudinal and systemic) that can be changed to facilitate smoother transitions in various aspects of their lives. CONCLUSIONS: This study makes a unique and significant contribution to literature. It provides evidence and rich narratives for policy makers and service providers to change policies and practices that are in line with the needs of YAs with life-limiting conditions as they transition to adulthood. Families and professionals have specific training needs that have not yet been met fully.

Decomposition and Cell Failure Mechanisms in Lead Halide Perovskite Solar Cells.

Perovskite solar cells have experienced a remarkably rapid rise in power conversion efficiencies, with state-of-the-art devices now competing with multicrystalline silicon and thin-film cadmium telluride in terms of efficiency. Unfortunately, the lead halide perovskite absorbers suffer from a lack of chemical stability and decompose in response to a variety of environmental stimuli. In this Forum Article, we provide a brief overview of the decomposition mechanisms in lead halide perovskite thin films, as well as the processes contributing to cell failure in finished devices. We finish by briefly surveying recent efforts to extend the device lifetime. Ultimately, if perovskite solar cells can be made stable, they will be an exciting, highly complementary addition to existing photovoltaic technologies.

School-based child sexual abuse prevention programs: moving toward resiliency-informed evaluation.

Although recent years have seen an increase in the range of child sexual abuse prevention programs delivered in schools, there have been relatively few efficacy studies. Those conducted have focused primarily on intrinsic child factors and have often lacked an explicit theoretical framework. We offer resiliency theory as a useful and apposite theoretical framework for program evaluation. Resiliency theory suggests that a wider range of factors should be considered, including intrinsic (personal characteristics) and extrinsic (environmental) factors. Such factors may increase risk or, alternatively, protect children from the negative effects of adversity. We argue that a resiliency perspective to efficacy studies should recognize a long-term view on children's capacity to cope and can employ both standardized and contextual resiliency-informed measures.

Compact layer free perovskite solar cells with 13.5% efficiency.

The recent breakthrough of organometal halide perovskites as the light harvesting layer in photovoltaic devices has led to power conversion efficiencies of over 16%. To date, most perovskite solar cells have adopted a structure in which the perovskite light absorber is placed between carrier-selective electron- and hole-transport layers (ETLs and HTLs). Here we report a new type of compact layer free bilayer perovskite solar cell and conclusively demonstrate that the ETL is not a prerequisite for obtaining excellent device efficiencies. We obtained power conversion efficiencies of up to 11.6% and 13.5% when using poly(3-hexylthiophene) and 2,2',7,7'-tetrakis(N,N-di(4-methoxyphenyl)amino)-9,9'-spirobifluorene, respectively, as the hole-transport material. This performance is very comparable to that obtained with the use of a ZnO ETL. Impedance spectroscopy suggests that while eliminating the ZnO leads to an increase in contact resistance, this is offset by a substantial decrease in surface recombination.

Panchromatic enhancement of light-harvesting efficiency in dye-sensitized solar cells using thermally annealed Au@SiO2 triangular nanoprisms.

Plasmonic enhancement is an attractive method for improving the efficiency of dye-sensitized solar cells (DSSCs). Plasmonic materials with sharp features, such as triangular metal nanoparticles, show stronger plasmonic effects than their spherical analogues; however, these nanoparticles are also often thermally unstable. In this work, we investigated the thermal stability of Au@SiO2 triangular nanoprisms by annealing at different temperatures. Morphological changes were observed at temperatures greater than 250 °C, which resulted in a blue shift of the localized surface plasmon resonance (LSPR). Annealing at 450 °C led to a further blue shift; however, this resulted in better overlap of the LSPR with the absorption spectrum of black dye. By introducing 0.05% (w/w) Au@SiO2 nanoprisms into DSSCs, we were able to achieve a panchromatic enhancement of the light-harvesting efficiency. This led to a 15% increase in the power conversion efficiency from 3.9 ± 0.6% to 4.4 ± 0.4%.

Chemical stability and degradation mechanisms of triangular Ag, Ag@Au, and Au nanoprisms.

Anisotropic metal nanoparticles have found use in a variety of plasmonic applications because of the large near-field enhancements associated with them; however, the very features that give rise to these enhancements (e.g., sharply curved edges and tips) often have high surface energies and are easily degraded. This paper describes the stability and degradation mechanisms of triangular silver, gold-coated silver, and gold nanoprisms upon exposure to a wide variety of adverse conditions, including halide ions, thiols, amines and elevated temperatures. The silver nanoprisms were immediately and irreversibly degraded under all of the conditions studied. In contrast, the core-shell Ag@Au nanoprisms were less susceptible to etching by chlorides and bromides, but were rapidly degraded by iodides, amines and thiols by a different degradation pathway. Only the pure gold nanoprisms were stable to all of the conditions tested. These results have important implications for the suitability of triangular nanoprisms in many applications; this is particularly true in biological or environmental fields, where the nanoparticles would inevitably be exposed to a wide variety of chemical stimuli.

Binge alcohol drinking is associated with GABAA alpha2-regulated Toll-like receptor 4 (TLR4) expression in the central amygdala.

Binge drinking (blood-alcohol levels ≥ 0.08 g% in a 2-h period), is a significant public health burden in need of improved treatment. Gene therapy may offer beneficial alternatives to current psychosocial and pharmacotherapeutic interventions, but identification of the target genes is a clinical challenge. We report that a GABA(A) α2 siRNA vector (pHSVsiLA2) infused into the central nucleus of the amygdala (CeA) of alcohol-preferring (P) rats caused profound and selective reduction of binge drinking associated with inhibition of α2 expression, decreased GABA(A) receptor density, and inhibition of Toll-like receptor 4 (TLR4). CeA infusion of a TLR4 siRNA vector (pHSVsiLTLR4a) also inhibited binge drinking, but neither vector functioned when infused into the ventral pallidum. Binge drinking was inhibited by a GABA(A) α1 siRNA vector (pHSVsiLA1) infused into the ventral pallidum, unrelated to TLR4. The vectors did not alter sucrose intake and a scrambled siRNA vector was negative. The data indicate that GABA(A) α2-regulated TLR4 expression in the CeA contributes to binge drinking and may be a key early neuroadaptation in excessive drinking.

Peripartum Cardiac Arrest with Terminal QRS Distortion: A Case Report.

Introduction: Peripartum cardiac arrest is increasing in incidence. While pulmonary embolism (PE) remains an important cause of peripartum morbidity and mortality, other cardiovascular emergencies such as myocardial infarction (MI) are now the leading cause of pregnancy-related death. Emergency physicians (EP) need to be well versed in subtle electrocardiographic (ECG) signs of coronary ischemia to better care for peripartum patients in cardiac arrest. Case Report: A 38-year-old gravida 2 parity1 female three days post-partum presented in cardiac arrest. After approximately 12 minutes of Advanced Cardiac Life Support including electric defibrillation, the patient experienced sustained return of spontaneous circulation. The physician team was primarily concerned for PE based on an initial ECG demonstrating terminal QRS distortion in V2 but no ST-segment elevation myocardial infarction (STEMI). Computed tomography angiography (CTA) of the chest did not reveal PE. Repeat ECG after CTA demonstrated STEMI criteria, and the patient was emergently taken to the cardiac catheterization laboratory where she was found to have 99% occlusion of the left anterior descending artery. Conclusion: Emergency physicians should have a high index of suspicion for MI when managing peripartum patients in cardiac arrest. The ECG findings specific for coronary-occlusive acute MI but not included in the classic STEMI criteria increase accuracy and prevent delays in diagnosis; however, the clinical uptake of this paradigm has been slow. Early recognition of terminal QRS distortion can help EPs more rapidly diagnose the etiology of cardiac arrest.

Catheter-associated urinary tract infections (CAUTIs) and non-CAUTI hospital-onset urinary tract infections: Relative burden, cost, outcomes and related hospital-onset bacteremia and fungemia infections.

OBJECTIVE: To describe the relative burden of catheter-associated urinary tract infections (CAUTIs) and non-CAUTI hospital-onset urinary tract infections (HOUTIs). METHODS: A retrospective observational study of patients from 43 acute-care hospitals was conducted. CAUTI cases were defined as those reported to the National Healthcare Safety Network. Non-CAUTI HOUTI was defined as a positive, non-contaminated, non-commensal culture collected on day 3 or later. All HOUTIs were required to have a new antimicrobial prescribed within 2 days of the first positive urine culture. Outcomes included secondary hospital-onset bacteremia and fungemia (HOB), total hospital costs, length of stay (LOS), readmission risk, and mortality. RESULTS: Of 549,433 admissions, 434 CAUTIs and 3,177 non-CAUTI HOUTIs were observed. The overall rate of HOB likely secondary to HOUTI was 3.7%. Total numbers of secondary HOB were higher in non-CAUTI HOUTIs compared to CAUTI (101 vs 34). HOB secondary to non-CAUTI HOUTI was more likely to originate outside the ICU compared to CAUTI (69.3% vs 44.1%). CAUTI was associated with adjusted incremental total hospital cost and LOS of $9,807 (P < .0001) and 3.01 days (P < .0001) while non-CAUTI HOUTI was associated with adjusted incremental total hospital cost and LOS of $6,874 (P < .0001) and 2.97 days (P < .0001). CONCLUSION: CAUTI and non-CAUTI HOUTI were associated with deleterious outcomes. Non-CAUTI HOUTI occurred more often and was associated with a higher facility aggregate volume of HOB than CAUTI. Patients at risk for UTIs in the hospital represent a vulnerable population who may benefit from surveillance and prevention efforts, particularly in the non-ICU setting.

Targeted Drug Delivery for the Treatment of Abdominal Pain in Chronic Pancreatitis: A Retrospective Case Series.

Abdominal pain secondary to chronic pancreatitis (CP) is difficult to manage and often requires chronic oral opioid therapy (OOT). Targeted drug delivery (TDD) allows for a diminished dose of opioid intake and improved pain levels. TDD has been used in different pain syndromes with only limited reports in CP. OBJECTIVE: The objective of this article is to perform a retrospective review of CP patients treated with TDD versus OOT to compare chronic pain control and consumed morphine-equivalent doses. METHODS: Patients receiving TDD between September 2011 and August 2018 were included. All patients were weaned off oral opioids one week before intrathecal trial and pump implantation. Patients with intrathecal trials providing at least 50% pain relief underwent pump implantation. Data were collected while on OOT and at two weeks, three months, and nine months post-implant. Data were analyzed with Microsoft Excel 365 MSO using means and standard deviations. P-values were calculated using a two-tailed student's t-test with paired two-sample means. RESULTS: Twenty-three patients were analyzed. Pre-trial average pain score was 6.5/10 with a mean improvement with trials greater than 71%. The mean chronic baseline oral morphine milligram equivalents (MME) was 188. The mean MME on TDD at two weeks (0.36), three months (1.39), and nine months (2.47) were significantly lower than OOT. Mean pain scores were 6, 4.9, and 5.6 at two weeks, three months, and nine months, respectively, compared to 6.5 on OOT. DISCUSSION: The results of this study indicate that TDD provides improved pain control with significantly lower opioid doses.

Opportunities to Enhance Diagnostic Testing and Antimicrobial Stewardship: A Qualitative Multinational Survey of Healthcare Professionals.

INTRODUCTION: Antimicrobial resistance (AMR) is a global public health challenge. Global efforts to decrease AMR through antimicrobial stewardship (AMS) initiatives include education and optimising the use of diagnostic technologies and antibiotics. Despite this, economic and societal challenges hinder AMS efforts. The objective of this study was to obtain insights from healthcare professionals (HCPs) on current challenges and identify opportunities for optimising diagnostic test utilisation and AMS efforts. METHODS: Three hundred HCPs from six countries (representing varied gross national incomes per capita, healthcare system structure, and AMR rates) were surveyed between November 2022 through January 2023. A targeted literature review and expert interviews were conducted to inform survey development. Descriptive statistics were used to summarise survey responses. RESULTS: These findings suggest that the greatest challenges to diagnostic test utilisation were economic in nature; many HCPs reported that AMS initiatives were lacking investment (32.3%) and resourcing (40.3%). High resistance rates were considered the greatest barriers to appropriate antimicrobial use (52.0%). Most HCPs found local and national guidelines to be very useful (≥ 51.0%), but areas for improvement were noted. The importance of AMS initiatives was confirmed; diagnostic practices were acknowledged to have a positive impact on decreasing AMR (70.3%) and improving patient outcomes (81.0%). CONCLUSION: AMS initiatives, including diagnostic technology utilisation, are pivotal to decreasing AMR rates. Interpretation of these survey results suggests that while HCPs consider diagnostic practices to be important in AMS efforts, several barriers to successful implementation still exist including patient/institutional costs, turnaround time of test results, resourcing, AMR burden, and education. While some barriers differ by country, these survey results highlight areas of opportunities in all countries for improved use of diagnostic technologies and broader AMS efforts, as perceived by HCPs. Greater investment, resourcing, education, and updated guidelines offer opportunities to further strengthen global AMS efforts.

Antimicrobials are medications used to treat infections caused by bacteria (e.g. antibiotics), viruses, parasites, and fungi. Over time, these microbes may become resistant to antimicrobials, limiting how well they work. This often happens as a result of overuse, using antimicrobials when there is not an infection, or using an inappropriate antimicrobial. Antimicrobial resistance is a growing global problem. Antimicrobial stewardship programs aim to improve appropriate use of antimicrobials. Diagnostic testing plays an important role in these programs by identifying the microbes responsible for infections so patients can be given the right treatment as quickly as possible. We aimed to obtain the perspective of healthcare professionals from six countries on the challenges of and ways to improve diagnostic testing and antimicrobial stewardship programs. We found that some of the greatest challenges were related to costs. Approximately one-third of participants said that antimicrobial stewardship initiatives were lacking investment (32.3%) and resourcing (40.3%). High rates of antimicrobial resistance were identified as the greatest barriers to appropriate antimicrobial use (52.0%). Participants said that diagnostic practices have a positive impact on decreasing antimicrobial resistance (70.3%) and improving patient outcomes (81.0%). Overall, we found that healthcare professionals consider diagnostic tests to be an important part of antimicrobial stewardship, but there are several barriers to their success, including patient/hospital costs, turnaround time of test results, resourcing, antimicrobial resistance, and education. To overcome these barriers, increased funding, education, and resourcing, regular guideline updates, and development of optimised testing algorithms may help to improve antimicrobial stewardship and ultimately decrease antimicrobial resistance.

Phase transfer of triangular silver nanoprisms from aqueous to organic solvent by an amide coupling reaction.

In this paper, we describe a procedure for the phase transfer of silver nanoprisms (AgNPrs) from aqueous solution to chloroform via an amide coupling reaction. AgNPrs are first modified with 16-mercaptohexadecanoic acid (MHA), and then primary or secondary amines are attached to the carboxylic acid end of the MHA ligand through a carbodiimide-mediated amide coupling step. Secondary amines, such as dicyclohexylamine and diphenylamine, are found to solubilize the nanoparticles in chloroform, whereas primary amines (e.g., butylamine and hexadecylamine) do not result in phase transfer. It is found that the AgNPrs functionalized with dicyclohexylamine show the highest stability and the least aggregation after undergoing phase transfer; in contrast, with a less nucleophilic amine, such as diphenylamine, the amide coupling reaction does not go to completion and the resultant AgNPrs are less stable and more prone to aggregation.

Unplanned 120-Day ED Visits and Readmission Rates Following Common Stone Procedures.

OBJECTIVE: To quantify emergency department (ED) visits and hospital admissions (HA) after common urologic stone procedures including ureteroscopy (URS), shockwave lithotripsy (SWL), and percutaneous nephrolithotomy (PCL) which are a concern of payors, providers, and patients. MATERIALS AND METHODS: This is a retrospective cohort study using claims data from the IBM MarketScan Commercial and Medicare Supplement databases. Adults with a urologic stone diagnosis and no history of stone procedure in prior 12 months who underwent stone procedures between 2012 and 2017 were included. All-cause ED visits and HA were evaluated during 30, 60, 90, and 120-day periods following the index urologic stone procedure. RESULTS: A total of 166,287 patients were included in the analytic cohort. For inpatient-indexed procedures, cumulative ED visits rates following stone procedure at 120 days was 18.8% for URS, 19.2% for SWL, and 23.6% for PCL. A similar trend was observed with ED visit rates, following outpatient indexed procedures at 120 days with a cumulative rate of 14.2% of SWL patients, 14.9% of URS patients, and 17.3% of PCL. A similar trend was found when examining HA. ED and HA rates increased steadily through the 120-day time period. CONCLUSION: Rates of ED visits and HA following common stone procedures continue to rise at least up to 120 days following the index procedure whether in the outpatient or inpatient settings. While rates of unplanned care are similar for URS and SWL, patients undergoing PCL return to the hospital at higher rates.

Peripheral Nerve Stimulation in Chronic Knee Pain: A Case Series.

Introduction Chronic knee pain is increasing in prevalence and is associated with substantial limitations in functional mobility. Peripheral nerve stimulation (PNS) has been increasingly used to treat various chronic pain conditions. However, there is a paucity of research exploring the potential therapeutic benefit of PNS for chronic knee pain. Methods This research is a retrospective case series of all patients who received PNS for the treatment of chronic knee pain performed at a single-center academic medical institution between March 2021 and June 2022. The primary outcome was percent pain reduction six months after implantation. Outcome data was obtained via chart review and phone calls to patients. Secondary outcomes included percent pain reduction two weeks and two months after implantation and adverse medical events related to the procedure and nerve stimulation. Results Fourteen individual patients received PNS for chronic knee pain during the study period. Three of these patients received bilateral PNS for a total of 17 cases. The mean percent pain reduction six months after implantation was 52% (SD=28.2) (N=12). A total of 75.0% of participants (9/12) reported ≥50% reductions in pain six months after implantation. No adverse events were reported relating to the implantation procedure and/or nerve stimulation. Conclusion PNS is a safe and efficacious treatment modality for chronic knee pain with demonstrated long-term benefit. Further research should clarify patient factors associated with improved treatment response.