Nutrient-dependent control of RNA polymerase II elongation rate regulates specific gene expression programs by alternative polyadenylation.

Transcription by RNA polymerase II (RNAPII) is a dynamic process with frequent variations in the elongation rate. However, the physiological relevance of variations in RNAPII elongation kinetics has remained unclear. Here we show in yeast that a RNAPII mutant that reduces the transcription elongation rate causes widespread changes in alternative polyadenylation (APA). We unveil two mechanisms by which APA affects gene expression in the slow mutant: 3' UTR shortening and gene derepression by premature transcription termination of upstream interfering noncoding RNAs. Strikingly, the genes affected by these mechanisms are enriched for functions involved in phosphate uptake and purine synthesis, processes essential for maintenance of the intracellular nucleotide pool. As nucleotide concentration regulates transcription elongation, our findings argue that RNAPII is a sensor of nucleotide availability and that genes important for nucleotide pool maintenance have adopted regulatory mechanisms responsive to reduced rates of transcription elongation.

Repression of pervasive antisense transcription is the primary role of fission yeast RNA polymerase II CTD serine 2 phosphorylation.

The RNA polymerase II carboxy-terminal domain (CTD) consists of conserved heptapeptide repeats that can be phosphorylated to influence distinct stages of the transcription cycle, including RNA processing. Although CTD-associated proteins have been identified, phospho-dependent CTD interactions have remained elusive. Proximity-dependent biotinylation (PDB) has recently emerged as an alternative approach to identify protein-protein associations in the native cellular environment. In this study, we present a PDB-based map of the fission yeast RNAPII CTD interactome in living cells and identify phospho-dependent CTD interactions by using a mutant in which Ser2 was replaced by alanine in every repeat of the fission yeast CTD. This approach revealed that CTD Ser2 phosphorylation is critical for the association between RNAPII and the histone methyltransferase Set2 during transcription elongation, but is not required for 3' end processing and transcription termination. Accordingly, loss of CTD Ser2 phosphorylation causes a global increase in antisense transcription, correlating with elevated histone acetylation in gene bodies. Our findings reveal that the fundamental role of CTD Ser2 phosphorylation is to establish a chromatin-based repressive state that prevents cryptic intragenic transcription initiation.

The Nrd1-like protein Seb1 coordinates cotranscriptional 3' end processing and polyadenylation site selection.

Termination of RNA polymerase II (RNAPII) transcription is associated with RNA 3' end formation. For coding genes, termination is initiated by the cleavage/polyadenylation machinery. In contrast, a majority of noncoding transcription events in Saccharomyces cerevisiae does not rely on RNA cleavage for termination but instead terminates via a pathway that requires the Nrd1-Nab3-Sen1 (NNS) complex. Here we show that the Schizosaccharomyces pombe ortholog of Nrd1, Seb1, does not function in NNS-like termination but promotes polyadenylation site selection of coding and noncoding genes. We found that Seb1 associates with 3' end processing factors, is enriched at the 3' end of genes, and binds RNA motifs downstream from cleavage sites. Importantly, a deficiency in Seb1 resulted in widespread changes in 3' untranslated region (UTR) length as a consequence of increased alternative polyadenylation. Given that Seb1 levels affected the recruitment of conserved 3' end processing factors, our findings indicate that the conserved RNA-binding protein Seb1 cotranscriptionally controls alternative polyadenylation.

Senataxin homologue Sen1 is required for efficient termination of RNA polymerase III transcription.

R-loop disassembly by the human helicase Senataxin contributes to genome integrity and to proper transcription termination at a subset of RNA polymerase II genes. Whether Senataxin also contributes to transcription termination at other classes of genes has remained unclear. Here, we show that Sen1, one of two fission yeast homologues of Senataxin, promotes efficient termination of RNA polymerase III (RNAP3) transcription in vivo. In the absence of Sen1, RNAP3 accumulates downstream of RNAP3-transcribed genes and produces long exosome-sensitive 3'-extended transcripts. Importantly, neither of these defects was affected by the removal of R-loops. The finding that Sen1 acts as an ancillary factor for RNAP3 transcription termination in vivo challenges the pre-existing view that RNAP3 terminates transcription autonomously. We propose that Sen1 is a cofactor for transcription termination that has been co-opted by different RNA polymerases in the course of evolution.

Prior Incarceration Is Associated with Poor Mental Health at Midlife: Findings from a National Longitudinal Cohort Study.

BACKGROUND: People with mental illnesses and people living in poverty have higher rates of incarceration than others, but relatively little is known about the long-term impact that incarceration has on an individual's mental health later in life. OBJECTIVE: To evaluate prior incarceration's association with mental health at midlife. DESIGN: Retrospective cohort study PARTICIPANTS: Participants from the National Longitudinal Survey of Youth 1979 (NLSY79)-a nationally representative age cohort of individuals 15 to 22 years of age in 1979-who remained in follow-up through age 50. MAIN MEASURES: Midlife mental health outcomes were measured as part of a health module administered once participants reached 50 years of age (2008-2019): any mental health history, any depression history, past-year depression, severity of depression symptoms in the past 7 days (Center for Epidemiologic Studies Depression [CES-D] scale), and mental health-related quality of life in the past 4 weeks (SF-12 Mental Component Score [MCS]). The main exposure was any incarceration prior to age 50. KEY RESULTS: Among 7889 participants included in our sample, 577 (5.4%) experienced at least one incarceration prior to age 50. Prior incarceration was associated with a greater likelihood of having any mental health history (predicted probability 27.0% vs. 16.6%; adjusted odds ratio [aOR] 1.9 [95%CI: 1.4, 2.5]), any history of depression (22.0% vs. 13.3%; aOR 1.8 [95%CI: 1.3, 2.5]), past-year depression (16.9% vs. 8.6%; aOR 2.2 [95%CI: 1.5, 3.0]), and high CES-D score (21.1% vs. 15.4%; aOR 1.5 [95%CI: 1.1, 2.0]) and with a lower (worse) SF-12 MCS (-2.1 points [95%CI: -3.3, -0.9]; standardized mean difference -0.24 [95%CI: -0.37, -0.10]) at age 50, when adjusting for early-life demographic, socioeconomic, and behavioral factors. CONCLUSIONS: Prior incarceration was associated with worse mental health at age 50 across five measured outcomes. Incarceration is a key social-structural driver of poor mental health.

Association of Early Opioid Withdrawal Treatment Strategy and Patient-Directed Discharge Among Hospitalized Patients with Opioid Use Disorder.

BACKGROUND: Medical hospitalizations for people with opioid use disorder (OUD) frequently result in patient-directed discharges (PDD), often due to untreated pain and withdrawal. OBJECTIVE: To investigate the association between early opioid withdrawal management strategies and PDD. DESIGN: Retrospective cohort study using three datasets representing 362 US hospitals. PARTICIPANTS: Adult patients hospitalized between 2009 and 2015 with OUD (as identified using ICD-9-CM codes or inpatient buprenorphine administration) and no PDD on the day of admission. INTERVENTIONS: Opioid withdrawal management strategies were classified based on day-of-admission receipt of any of the following treatments: (1) medications for OUD (MOUD) including methadone or buprenorphine, (2) other opioid analgesics, (3) adjunctive symptomatic medications without opioids (e.g., clonidine), and (4) no withdrawal treatment. MAIN MEASURES: PDD was assessed as the main outcome and hospital length of stay as a secondary outcome. KEY RESULTS: Of 6,715,286 hospitalizations, 127,158 (1.9%) patients had OUD and no PDD on the day of admission, of whom 7166 (5.6%) had a later PDD and 91,051 (71.6%) patients received some early opioid withdrawal treatment (22.3% MOUD; 43.4% opioid analgesics; 5.9% adjunctive medications). Compared to no withdrawal treatment, MOUD was associated with a lower risk of PDD (adjusted odds ratio [aOR] = 0.73, 95%CI 0.68-0.8, p < .001), adjunctive treatment alone was associated with higher risk (aOR = 1.13, 95%CI: 1.01-1.26, p = .031), and treatment with opioid analgesics alone was associated with similar risk (aOR 0.95, 95%CI: 0.89-1.02, p = .148). Among those with PDD, both MOUD (adjusted incidence rate ratio [aIRR] = 1.24, 95%CI: 1.17-1.3, p < .001) and opioid analgesic treatments (aIRR = 1.39, 95%CI: 1.34-1.45, p < .001) were associated with longer hospital stays. CONCLUSIONS: MOUD was associated with decreased risk of PDD but was utilized in < 1 in 4 patients. Efforts are needed to ensure all patients with OUD have access to effective opioid withdrawal management to improve the likelihood they receive recommended hospital care.

Co-transcriptional RNA cleavage by Drosha homolog Pac1 triggers transcription termination in fission yeast.

Transcription termination of protein-coding genes in eukaryotic cells usually relies on a tight coordination between the cleavage and polyadenylation of the pre-mRNA, and 5'-3' degradation of the downstream nascent transcript. Here we investigated the contribution of the essential fission yeast endonuclease Pac1, a homolog of human Drosha that cleaves hairpin RNA structures, in triggering polyadenylation-independent transcription termination. Using ChIP-sequencing in Pac1-deficient cells, we found that Pac1 triggers transcription termination at snRNA and snoRNA genes as well as at specific protein-coding genes. Notably, we found that Pac1-dependent premature termination occurred at two genes encoding conserved transmembrane transporters whose expression were strongly repressed by Pac1. Analysis by genome editing indicated that a stem-loop structure in the nascent transcript directs Pac1-mediated cleavage and that the regions upstream and downstream of the Pac1 cleavage site in the targeted mRNAs were stabilized by mutation of nuclear 3'-5' and 5'-3' exonucleases, respectively. Our findings unveil a premature transcription termination pathway that uncouples co-transcriptional RNA cleavage from polyadenylation, triggering rapid nuclear RNA degradation.

Variation in Initiation, Engagement, and Retention on Medications for Opioid Use Disorder Based on Health Insurance Plan Design.

BACKGROUND: The association between cost-sharing and receipt of medication for opioid use disorder (MOUD) is unknown. METHODS: We constructed a cohort of 10,513 commercially insured individuals with a new diagnosis of opioid use disorder and information on insurance cost-sharing in a large national deidentified claims database. We examined 4 cost-sharing measures: (1) pharmacy deductible; (2) medical service deductible; (3) pharmacy medication copay; and (4) medical office copay. We measured MOUD (naltrexone, buprenorphine, or methadone) initiation (within 14 d of diagnosis), engagement (second receipt within 34 d of first), and 6-month retention (continuous receipt without 14-d gap). We used multivariable logistic regression to assess the association between cost-sharing and MOUD initiation, engagement, and retention. We calculated total out-of-pocket costs in the 30 days following MOUD initiation for each type of MOUD. RESULTS: Of 10,513 individuals with incident opioid use disorder, 1202 (11%) initiated MOUD, 742 (7%) engaged, and 253 (2%) were retained in MOUD at 6 months. A high ($1000+) medical deductible was associated with a lower odds of initiation compared with no deductible (odds ratio: 0.85, 95% confidence interval: 0.74-0.98). We found no significant associations between other cost-sharing measures for initiation, engagement, or retention. Median initial 30-day out-of-pocket costs ranged from $100 for methadone to $710 for extended-release naltrexone. CONCLUSIONS: Among insurance plan cost-sharing measures, only medical services deductible showed an association with decreased MOUD initiation. Policy and benefit design should consider ways to reduce cost barriers to initiation and retention in MOUD.

Patient Perspectives on Improving Patient-Provider Relationships and Provider Communication During Opioid Tapering.

BACKGROUND: Efforts to reduce opioid overdose fatalities have resulted in tapering (i.e., reducing or discontinuing) opioid prescriptions despite a limited understanding of patients' experiences. OBJECTIVE: To explore patients' perspectives on opioid taper experiences to ultimately improve taper processes and outcomes. DESIGN: Qualitative study. PARTICIPANTS: Patients on long-term opioid therapy for chronic pain who had undergone a reduction of opioid daily prescribed dosage of ≥50% in the past 2 years in two distinct medical systems and regions. APPROACH: From 2019 to 2020, we conducted semi-structured interviews that were audio-recorded, transcribed, systematically coded, and analyzed to summarize the content and identify key themes regarding taper experiences overall and with particular attention to patient-provider relationships and provider communication during tapers. KEY RESULTS: Participants (n=41) had lived with chronic pain for an average of 17.4 years (range, 3-36 years) and described generally adverse experiences with opioid tapers, the initiation of which was not always adequately justified or explained to them. Consequences of tapers ranged from minor to substantial and included withdrawal, mobility issues, emotional distress, exacerbated mental health symptoms, and feelings of social stigmatization for which adequate supports were typically unavailable. Narratives highlighted the consequential role of patient-provider relationships throughout taper experiences, with most participants describing significant interpersonal challenges including poor provider communication and limited patient engagement in decision making. A few participants identified qualities of providers, relationships, and communication that fostered more positive taper experiences and outcomes. CONCLUSIONS: From patients' perspectives, opioid tapers can produce significant physical, emotional, and social consequences, sometimes reducing trust and engagement in healthcare. Patient-provider relationships and communication influence patients' perceptions of the quality and outcomes of opioid tapers. To improve patients' experiences of opioid tapers, tapering plans should be based on individualized risk-benefit assessments and involve patient-centered approaches and improved provider communication.

Do Urine Drug Tests Reveal Substance Misuse Among Patients Prescribed Opioids for Chronic Pain?

BACKGROUND: Urine drug testing (UDT) is a recommended risk mitigation strategy for patients prescribed opioids for chronic pain, but evidence that UDT supports identification of substance misuse is limited. OBJECTIVE: Identify the prevalence of UDT results that may identify substance misuse, including diversion, among patients prescribed opioids for chronic pain. DESIGN: Retrospective cohort study. SUBJECTS: Patients (n=638) receiving opioids for chronic pain who had one or more UDTs, examining up to eight substances per sample, during a one 1-year period. MAIN MEASURES: Experts adjudicated the clinical concern that UDT results suggest substance misuse or diversion as not concerning, uncertain, or concerning. KEY RESULTS: Of 638 patients, 48% were female and 49% were over age 55 years. Patients had a median of three UDTs during the intervention year. We identified 37% of patients (235/638) with ≥1 concerning UDT and a further 35% (222/638) having ≥1 uncertain UDT. We found concerning UDTs due to non-detection of a prescribed substance in 24% (156/638) of patients and detection of a non-prescribed substance in 23% (147/638). Compared to patients over 65 years, those aged 18-34 years were more likely to have concerning UDT results with an adjusted odds ratio (AOR) of 4.8 (95% confidence interval [CI] 1.9-12.5). Patients with mental health diagnoses (AOR 1.6 [95% CI 1.1-2.3]) and substance use diagnoses (AOR 2.3 [95% CI 1.5-3.7]) were more likely to have a concerning UDT result. CONCLUSIONS: Expert adjudication of UDT results identified clinical concern for substance misuse in 37% of patients receiving opioids for chronic pain. Further research is needed to determine if UDTs impact clinical practice or patient-related outcomes.

Effect of police action on low-barrier substance use disorder service utilization.

BACKGROUND: Police action can increase risky substance use patterns by people who use drugs (PWUD), but it is not known how increased police presence affects utilization of low-barrier substance use disorder bridge clinics. Increased police presence may increase or decrease treatment-seeking behavior. We examined the association between Operation Clean Sweep (OCS), a 2-week police action in Boston, MA, and visit volume in BMC's low-barrier buprenorphine bridge clinic. METHODS: In this retrospective cohort, we used segmented regression to investigate whether the increased police presence during OCS was associated with changes in bridge clinic visits. We used General Internal Medicine (GIM) clinic visit volume as a negative control. We examined visits during the 6 weeks prior, 2 weeks during, and 4 weeks after OCS (June 18-September 11, 2019). RESULTS: Bridge clinic visits were 2.8 per provider session before, 2.0 during, and 3.0 after OCS. The mean number of GIM clinic visits per provider session before OCS was 7.0, 6.8 during, and 7.0 after OCS. In adjusted segmented regression models for bridge clinic visits per provider session, there was a nonsignificant level increase (0.643 P = 0.171) and significant decrease in slope (0.100, P = 0.045) during OCS. After OCS completed, there was a significant level increase (1.442, P = 0.003) and slope increase in visits per provider session (0.141, P = 0.007). There was no significant change in GIM clinic volume during the study period. CONCLUSIONS: The increased policing during OCS was associated with a significant decrease in bridge clinic visits. Following the completion of OCS, there was a significant increase in clinic visits, suggesting pent-up demand for medications for opioid use disorder, a life-saving treatment.

Against Medical Advice Discharges in Injection and Non-injection Drug Use-associated Infective Endocarditis: A Nationwide Cohort Study.

BACKGROUND: Among those with injection drug use-associated infective endocarditis (IDU-IE), against medical advice (AMA) discharge is common and linked to adverse outcomes. Understanding trends, risk factors, and timing is needed to reduce IDU-IE AMA discharges. METHODS: We identified individuals ages 18-64 with International Classification of Diseases, 9thRevision, diagnosis codes for infective endocarditis (IE) in the National Inpatient Sample, a representative sample of United States hospitalizations from January 2010 to September 2015. We plotted unadjusted quarter-year trends for AMA discharges and used multivariable logistic regression to identify factors associated with AMA discharge among IE hospitalizations, comparing IDU-IE with non-IDU-IE. RESULTS: We identified 7259 IDU-IE and 23 633 non-IDU-IE hospitalizations. Of these hospitalizations, 14.2% of IDU-IE and 1.9% of non-IDU-IE resulted in AMA discharges. More than 30% of AMA discharges for both groups occurred before hospital day 3. In adjusted models, IDU status (adjusted odds ratio [AOR], 3.92; 95% confidence interval [CI], 3.43-4.48)] was associated with increased odds of AMA discharge. Among IDU-IE, women (AOR, 1.21; 95% CI, 1.04-1.41) and Hispanics (AOR, 1.32; 95% CI, 1.03-1.69) had increased odds of AMA discharge, which differed from non-IDU-IE. Over nearly 6 years, odds of AMA discharge increased 12% per year for IDU-IE (AOR, 1.12; 95% CI, 1.07-1.18) and 6% per year for non-IDU-IE (AOR, 1.06; 95% CI. 1.00-1.13). CONCLUSIONS: AMA discharges have risen among individuals with IDU-IE and non-IDE-IE. Among those who inject drugs, AMA discharges were more common and increases sharper. Efforts that address the rising fraction, disparities, and timing of IDU-IE AMA discharges are needed.

Proximity-dependent biotinylation mediated by TurboID to identify protein-protein interaction networks in yeast.

The use of proximity-dependent biotinylation assays coupled to mass spectrometry (PDB-MS) has changed the field of protein-protein interaction studies. However, despite the recurrent and successful use of BioID-based protein-protein interactions screening in mammalian cells, the implementation of PDB-MS in yeast has not been effective. Here, we report a simple and rapid approach in yeast to effectively screen for proximal and interacting proteins in their natural cellular environment by using TurboID, a recently described version of the BirA biotin ligase. Using the protein arginine methyltransferase Rmt3 and the RNA exosome subunits, Rrp6 and Dis3, the application of PDB-MS in yeast by using TurboID was able to recover protein-protein interactions previously identified using other biochemical approaches and provided new complementary information for a given protein bait. The development of a rapid and effective PDB assay that can systematically analyze protein-protein interactions in living yeast cells opens the way for large-scale proteomics studies in this powerful model organism.

Epidemiology, Outcomes, and Trends of Patients With Sepsis and Opioid-Related Hospitalizations in U.S. Hospitals.

OBJECTIVES: Widespread use and misuse of prescription and illicit opioids have exposed millions to health risks including serious infectious complications. Little is known, however, about the association between opioid use and sepsis. DESIGN: Retrospective cohort study. SETTING: About 373 U.S. hospitals. PATIENTS: Adults hospitalized between January 2009 and September 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sepsis was identified by clinical indicators of concurrent infection and organ dysfunction. Opioid-related hospitalizations were identified by the International Classification of Diseases, 9th Revision, Clinical Modification codes and/or inpatient orders for buprenorphine. Clinical characteristics and outcomes were compared by sepsis and opioid-related hospitalization status. The association between opioid-related hospitalization and all-cause, in-hospital mortality in patients with sepsis was assessed using mixed-effects logistic models to adjust for baseline characteristics and severity of illness.The cohort included 6,715,286 hospitalizations; 375,479 (5.6%) had sepsis, 130,399 (1.9%) had opioid-related hospitalizations, and 8,764 (0.1%) had both. Compared with sepsis patients without opioid-related hospitalizations (n = 366,715), sepsis patients with opioid-related hospitalizations (n = 8,764) were younger (mean 52.3 vs 66.9 yr) and healthier (mean Elixhauser score 5.4 vs 10.5), had more bloodstream infections from Gram-positive and fungal pathogens (68.9% vs 47.0% and 10.6% vs 6.4%, respectively), and had lower in-hospital mortality rates (10.6% vs 16.2%; adjusted odds ratio, 0.73; 95% CI, 0.60-0.79; p < 0.001 for all comparisons). Of 1,803 patients with opioid-related hospitalizations who died in-hospital, 928 (51.5%) had sepsis. Opioid-related hospitalizations accounted for 1.5% of all sepsis-associated deaths, including 5.7% of sepsis deaths among patients less than 50 years old. From 2009 to 2015, the proportion of sepsis hospitalizations that were opioid-related increased by 77% (95% CI, 40.7-123.5%). CONCLUSIONS: Sepsis is an important cause of morbidity and mortality in patients with opioid-related hospitalizations, and opioid-related hospitalizations contribute disproportionately to sepsis-associated deaths among younger patients. In addition to ongoing efforts to combat the opioid crisis, public health agencies should focus on raising awareness about sepsis among patients who use opioids and their providers.

Disparities in Opioid Overdose Death Trends by Race/Ethnicity, 2018-2019, From the HEALing Communities Study.

Objectives. To examine trends in opioid overdose deaths by race/ethnicity from 2018 to 2019 across 67 HEALing Communities Study (HCS) communities in Kentucky, New York, Massachusetts, and Ohio. Methods. We used state death certificate records to calculate opioid overdose death rates per 100 000 adult residents of the 67 HCS communities for 2018 and 2019. We used Poisson regression to calculate the ratio of 2019 to 2018 rates. We compared changes by race/ethnicity by calculating a ratio of rate ratios (RRR) for each racial/ethnic group compared with non-Hispanic White individuals. Results. Opioid overdose death rates were 38.3 and 39.5 per 100 000 for 2018 and 2019, respectively, without a significant change from 2018 to 2019 (rate ratio = 1.03; 95% confidence interval [CI] = 0.98, 1.08). We estimated a 40% increase in opioid overdose death rate for non-Hispanic Black individuals (RRR = 1.40; 95% CI = 1.22, 1.62) relative to non-Hispanic White individuals but no change among other race/ethnicities. Conclusions. Overall opioid overdose death rates have leveled off but have increased among non-Hispanic Black individuals. Public Health Implications. An antiracist public health approach is needed to address the crisis of opioid-related harms. (Am J Public Health. 2021;111(10):1851-1854. https://doi.org/10.2105/AJPH.2021.306431).

HIV testing among people with and without substance use disorder in emergency departments: A nationwide cohort study.

OBJECTIVE: To determine HIV testing trends during emergency department (ED) visits among those with and without substance use disorder (SUD) and examine factors associated with test receipt. METHODS: We identified individuals age ≥ 15 with an ED visit between 2014 and 2018 in the National Hospital Ambulatory Medical Care Survey (NHAMCS), a representative sample of United States ED visits. We examined HIV testing trends by SUD status and used multivariable logistic regression accounting for NHAMCS's complex survey design to identify factors associated with HIV testing. RESULTS: We identified 6399 SUD and 75,498 non-SUD ED visits. Of SUD visits, 1.4% [95% Confidence Interval (95%CI 0.9-1.9)] resulted in HIV testing compared to 0.6% (95%CI 0.4-0.7) of non-SUD visits. During the second half of the study (Q3, 2016 - Q4, 2018), HIV testing increased from 1.1% (95%CI 0.6-1.6) to 1.7% (95%CI 1.0-2.5) among those with SUD and from 0.5% (95%CI 0.3-0.6) to 0.6% (95%CI 0.5-0.8) among those without SUD. In adjusted models, SUD status was associated with increased odds of HIV testing [Adjusted Odds Ratio (AOR) 1.6 (95%CI 1.1-2.2)]. Those receiving toxicology testing (AOR 2.2, 95%CI 1.6-3.2), Black (AOR 3.6, 95%CI 2.6-4.9) and Hispanic people (AOR 2.7, 95%CI 1.9-3.7), insured by Medicaid (AOR 1.6, 95%CI 1.2-2.2) or self-pay (AOR 1.7, 95%CI 1.1-2.8), and with venipuncture (AOR 3.0, 95%CI 2.2-4.1) also had greater odds of HIV testing. CONCLUSION: HIV testing in the ED was rare, but slightly more common in individuals with SUD. Efforts to increase ED HIV testing among people with SUD are needed.

Effect of Publicly Reported Aortic Valve Surgery Outcomes on Valve Surgery in Injection Drug- and Non-Injection Drug-Associated Endocarditis.

BACKGROUND: Injection drug use-associated infective endocarditis (IDU-IE) is rising and valve surgery is frequently indicated. The effect of initiating public outcomes reporting for aortic valve surgery on rates of valve surgery and in-hospital mortality for endocarditis is not known. METHODS: For an interrupted time series analysis, we used data from the National Inpatient Sample, a representative sample of United States inpatient hospitalizations, from January 2010 to September 2015. We included individuals aged 18-65 with an International Classification of Diseases, Ninth Revision (ICD-9) diagnosis of endocarditis. We defined IDU-IE using a validated combination of ICD-9 codes. We used segmented logistic regression to assess for changes in valve replacement and in-hospital mortality rates after the public reporting initiation in January 2013. RESULTS: We identified 7322 hospitalizations for IDU-IE and 23 997 for non-IDU-IE in the sample, representing 36 452 national IDU-IE admissions and 119 316 non-IDU admissions, respectively. Following the implementation of public reporting in 2013, relative to baseline trends, the odds of valve replacement decreased by 4.0% per quarter (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.93-0.99), with no difference by IDU status. The odds of an in-patient death decreased by 2.0% per quarter for both IDU-IE and non-IDU-IE cases following reporting (OR 0.98, 95% CI 0.97-0.99). CONCLUSIONS: Initiating public reporting was associated with a significant decrease in valve surgery for all IE cases, regardless of IDU status, and a reduction in-hospital mortality for patients with IE. Patients with IE may have less access to surgery as a consequence of public reporting. To understand how reduced valve surgery impacts overall mortality, future studies should examine the postdischarge mortality rate.

Comparative analysis of alternative polyadenylation in S. cerevisiae and S. pombe.

Alternative polyadenylation (APA) is a widespread mechanism that generates mRNA isoforms with distinct properties. Here we have systematically mapped and compared cleavage and polyadenylation sites (PASs) in two yeast species, S. cerevisiae and S. pombe Although >80% of the mRNA genes in each species were found to display APA, S. pombe showed greater 3' UTR size differences among APA isoforms than did S. cerevisiae PASs in different locations of gene are surrounded with distinct sequences in both species and are often associated with motifs involved in the Nrd1-Nab3-Sen1 termination pathway. In S. pombe, strong motifs surrounding distal PASs lead to higher abundances of long 3' UTR isoforms than short ones, a feature that is opposite in S. cerevisiae Differences in PAS placement between convergent genes lead to starkly different antisense transcript landscapes between budding and fission yeasts. In both species, short 3' UTR isoforms are more likely to be expressed when cells are growing in nutrient-rich media, although different gene groups are affected in each species. Significantly, 3' UTR shortening in S. pombe coordinates with up-regulation of expression for genes involved in translation during cell proliferation. Using S. pombe strains deficient for Pcf11 or Pab2, we show that reduced expression of 3'-end processing factors lengthens 3' UTR, with Pcf11 having a more potent effect than Pab2. Taken together, our data indicate that APA mechanisms in S. pombe and S. cerevisiae are largely different: S. pombe has many of the APA features of higher species, and Pab2 in S. pombe has a different role in APA regulation than its mammalian homolog, PABPN1.

Response to Propoxyphene Market Withdrawal: Analgesic Substitutes, Doses, and Adverse Events.

OBJECTIVE: Experts cautioned that patients affected by the November 2010 withdrawal of the opioid analgesic propoxyphene might receive riskier prescriptions. To explore this, we compared drug receipts and outcomes among propoxyphene users before and aftermarket withdrawal. STUDY DESIGN: Using OptumLabs data, we studied 3 populations: commercial, Medicare Advantage (MA) aged (age 65+ y) and MA disabled (age below 65 y) enrollees. The exposed enrollees received propoxyphene in the 3 months before market withdrawal (n=13,622); historical controls (unexposed) received propoxyphene 1 year earlier (n=9971). Regression models estimated daily milligrams morphine equivalent (MME), daily prescription acetaminophen dose, potentially toxic acetaminophen doses, nonopioid prescription analgesics receipt, emergency room visits, and diagnosed falls, motor vehicle accidents, and hip fractures. PRINCIPAL FINDINGS: Aged MA enrollees illustrate the experience of all 3 populations examined. Following the market withdrawal, propoxyphene users in the exposed cohort experienced an abrupt decline of 69% in average daily MME, compared with a 14% decline in the unexposed. Opioids were discontinued by 34% of the exposed cohort and 18% of the unexposed. Tramadol and hydrocodone were the most common opioids substituted for propoxyphene. The proportion of each group receiving ≥4 g of prescription acetaminophen per day decreased from 12% to 2% in the exposed group but increased from 6% to 8% among the unexposed. Adverse events were rare and not significantly different in exposed versus unexposed groups. CONCLUSIONS: After propoxyphene market withdrawal, many individuals experienced abrupt discontinuation of opioids. Policymakers might consider supporting appropriate treatment transitions and monitoring responses following drug withdrawals.

Relative Cost Differences of Initial Treatment Strategies for Newly Diagnosed Opioid Use Disorder: A Cohort Study.

BACKGROUND: Relative costs of care among treatment options for opioid use disorder (OUD) are unknown. METHODS: We identified a cohort of 40,885 individuals with a new diagnosis of OUD in a large national de-identified claims database covering commercially insured and Medicare Advantage enrollees. We assigned individuals to 1 of 6 mutually exclusive initial treatment pathways: (1) Inpatient Detox/Rehabilitation Treatment Center; (2) Behavioral Health Intensive, intensive outpatient or Partial Hospitalization Services; (3) Methadone or Buprenorphine; (4) Naltrexone; (5) Behavioral Health Outpatient Services, or; (6) No Treatment. We assessed total costs of care in the initial 90 day treatment period for each strategy using a differences in differences approach controlling for baseline costs. RESULTS: Within 90 days of diagnosis, 94.8% of individuals received treatment, with the initial treatments being: 15.8% for Inpatient Detox/Rehabilitation Treatment Center, 4.8% for Behavioral Health Intensive, Intensive Outpatient or Partial Hospitalization Services, 12.5% for buprenorphine/methadone, 2.4% for naltrexone, and 59.3% for Behavioral Health Outpatient Services. Average unadjusted costs increased from $3250 per member per month (SD $7846) at baseline to $5047 per member per month (SD $11,856) in the 90 day follow-up period. Compared with no treatment, initial 90 day costs were lower for buprenorphine/methadone [Adjusted Difference in Differences Cost Ratio (ADIDCR) 0.65; 95% confidence interval (CI), 0.52-0.80], naltrexone (ADIDCR 0.53; 95% CI, 0.42-0.67), and behavioral health outpatient (ADIDCR 0.54; 95% CI, 0.44-0.66). Costs were higher for inpatient detox (ADIDCR 2.30; 95% CI, 1.88-2.83). CONCLUSION: Improving health system capacity and insurance coverage and incentives for outpatient management of OUD may reduce health care costs.