The impact of more restrictive hydrocodone rescheduling on unintentional pediatric opioid exposures.

PURPOSE: To evaluate the impact of rescheduling hydrocodone combination products (HCPs) from schedule III of the Controlled Substances Act to the more restrictive schedule II on unintentional pediatric exposures (≤5 years old). METHODS: Using U.S. data on outpatient retail pharmacy dispensing, emergency department (ED) visits, and poison center (PC) exposure cases, we assessed trends in prescriptions dispensed and unintentional pediatric exposure cases involving hydrocodone (rescheduled from III to II) compared to oxycodone (schedule II) and codeine (schedule III for combination products) using descriptive and interrupted time-series (ITS) analyses during the 16 quarters before and after the October 2014 rescheduling of HCPs. RESULTS: Dispensing of hydrocodone products was declining before rescheduling but declined more steeply post-rescheduling. In ITS analyses, both hydrocodone and oxycodone had significant slope decreases in PC case rates in the post versus pre-period that was larger for hydrocodone, while codeine had a small but significant slope increase in PC case rates. An estimated 4202 ED visits for pediatric hydrocodone exposures occurred in the pre-period and 2090 visits occurred in the post-period, a significant decrease of 50.3%. Oxycodone exposures showed no significant decrease. CONCLUSIONS: Pediatric hydrocodone unintentional exposure ED visits and PC cases decreased after HCP rescheduling more than would be expected had the pre-rescheduling trend continued; the acceleration in the decrease in hydrocodone PC cases was partially offset by a slowing in the decrease in codeine-involved cases. The trend changes were likely due to multiple factors, including changes in dispensing that followed the rescheduling. Unintentional pediatric medication exposures and poisonings remain a public health concern requiring ongoing, multifaceted mitigation efforts.

Acute pain pathways: protocol for a prospective cohort study.

INTRODUCTION: Opioid analgesics are often used to treat moderate-to-severe acute non-cancer pain; however, there is little high-quality evidence to guide clinician prescribing. An essential element to developing evidence-based guidelines is a better understanding of pain management and pain control among individuals experiencing acute pain for various common diagnoses. METHODS AND ANALYSIS: This multicentre prospective observational study will recruit 1550 opioid-naïve participants with acute pain seen in diverse clinical settings including primary/urgent care, emergency departments and dental clinics. Participants will be followed for 6 months with the aid of a patient-centred health data aggregating platform that consolidates data from study questionnaires, electronic health record data on healthcare services received, prescription fill data from pharmacies, and activity and sleep data from a Fitbit activity tracker. Participants will be enrolled to represent diverse races and ethnicities and pain conditions, as well as geographical diversity. Data analysis will focus on assessing patients' patterns of pain and opioid analgesic use, along with other pain treatments; associations between patient and condition characteristics and patient-centred outcomes including resolution of pain, satisfaction with care and long-term use of opioid analgesics; and descriptive analyses of patient management of leftover opioids. ETHICS AND DISSEMINATION: This study has received approval from IRBs at each site. Results will be made available to participants, funders, the research community and the public. TRIAL REGISTRATION NUMBER: NCT04509115.

Patient-Reported Opioid Analgesic Use After Discharge from Surgical Procedures: A Systematic Review.

OBJECTIVE: This systematic review synthesizes evidence on patient-reported outpatient opioid analgesic use after surgery. METHODS: We searched PubMed (February 2019) and Web of Science and Embase (June 2019) for U.S. studies describing patient-reported outpatient opioid analgesic use. Two reviewers extracted data on opioid analgesic use, standardized the data on use , and performed independent quality appraisals based on the Cochrane Risk of Bias Tool and an adapted Newcastle-Ottawa scale. RESULTS: Ninety-six studies met the eligibility criteria; 56 had sufficient information to standardize use in oxycodone 5-mg tablets. Patient-reported opioid analgesic use varied widely by procedure type; knee and hip arthroplasty had the highest postoperative opioid use, and use after many procedures was reported as <5 tablets. In studies that examined excess tablets, 25-98% of the total tablets prescribed were reported to be excess, with most studies reporting that 50-70% of tablets went unused. Factors commonly associated with higher opioid analgesic use included preoperative opioid analgesic use, higher inpatient opioid analgesic use, higher postoperative pain scores, and chronic medical conditions, among others. Estimates also varied across studies because of heterogeneity in study design, including length of follow-up and inclusion/exclusion criteria. CONCLUSION: Self-reported postsurgery outpatient opioid analgesic use varies widely both across procedures and within a given procedure type. Contributors to within-procedure variation included patient characteristics, prior opioid use, intraoperative and perioperative factors, and differences in the timing of opioid use data collection. We provide recommendations to help minimize variation caused by study design factors and maximize interpretability of forthcoming studies for use in clinical guidelines and decision-making.

A comparison of opioid-involved fatalities captured in the National Poison Data System to data derived from US death certificate literal text.

PURPOSE: The purpose of the study is to describe and compare the number and characteristics of opioid-involved fatal cases captured in the National Poison Data System (NPDS) and in US death certificates. METHODS: NPDS, which collects data on all calls to US poison control centers, and Drug-Involved Mortality (DIM), which combines information from literal text of US death certificates and National Vital Statistics Systems, were queried for opioid-involved fatal cases from 2010 to 2015. Characteristics of the two case series were compared. RESULTS: DIM contained 154 016 opioid-involved overdose deaths, and NPDS contained 2524 fatal opioid exposures, a ratio of 61:1. The number of opioid deaths remained stable in NPDS but increased in DIM over the 6-year period. On average, deaths involving opioids with higher mean dosage strength (in morphine milligram equivalents) per unit among dispensed prescriptions were more likely to be captured in DIM relative to NPDS, as compared with those with a lower mean dosage strength per unit. The increase in fentanyl-related deaths seen in DIM since 2013 was not observed in NPDS. CONCLUSIONS: NPDS is a valuable drug safety surveillance resource due to its timeliness and drug specificity. However, it captures only a small fraction of opioid-involved fatal poisonings, and comparisons with data derived from death certificate literal text indicate that caution is warranted in making inferences about opioid-involved fatality trends over time or comparisons across opioids.

Using hospital use trends to improve transitional care.

BACKGROUND: This study evaluates the Northwestern Medicine Group Transitional Care clinic (NMG-TC), which transitions patients from an urban hospital to primary care at partner community clinics. We evaluate change over the 55 month study period in emergency department, observation or inpatient use within 90 days of an initial NMG-TC visit. METHODS: Electronic health records were used to determine patient demographic, insurance and clinical characteristics, including inflation-adjusted total hospital charges in the 90 days prior and the 90 days after an initial NMG-TC visit. Multiple logistic regression was used to estimate the likelihood of any 90-day post-NMG-TC visit hospital use, controlled for the simultaneous effects of patient characteristics and pre-visit hospital use level. RESULTS: There were 3318 patients with 90-day follow-up of whom 28.5% had 90 day post-visit hospital encounters. Patients with cancer, infectious disease or pain diagnoses at the time of a NMG-TC visit had the highest 90-day post-visit hospital use. The level of pre-NMG-TC visit hospital charges, the number of NMG-TC visit diagnostic categories and the number of NMG-TC visits all showed a sharply graded effect on subsequent hospital use. Patients with a first NMG-TC visit in the last nine months of the study (2015-2016) had a 38% lower likelihood of any 90-day hospital use (OR = 0.62, 95% CI = 0.45-0.84) as compared to patients seen in 2011-2012. CONCLUSION AND IMPLICATIONS: Reduced post-visit hospital use is likely related to increased clinic resources, Affordable Care Act insurance expansions, and improved clinical and community social service expertise. LEVEL OF EVIDENCE: Cohort study, Level 2.

The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages.

Previously, we reported that mutants of Legionella pneumophila lacking a type II secretion (T2S) system elicit higher levels of cytokines (e.g., interleukin-6 [IL-6]) following infection of U937 cells, a human macrophage-like cell line. We now show that this effect of T2S is also manifest upon infection of human THP-1 macrophages and peripheral blood monocytes but does not occur during infection of murine macrophages. Supporting the hypothesis that T2S acts to dampen the triggering of an innate immune response, we observed that the mitogen-activated protein kinase (MAPK) and nuclear transcription factor kappa B (NF-κB) pathways are more highly stimulated upon infection with the T2S mutant than upon infection with the wild type. By using short hairpin RNA to deplete proteins involved in specific pathogen-associated molecular pattern (PAMP) recognition pathways, we determined that the dampening effect of the T2S system was not dependent on nucleotide binding oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible protein I (RIG-I)-like receptors (RLRs), double-stranded RNA (dsRNA)-dependent protein kinase receptor (PKR), or TIR domain-containing adaptor inducing interferon beta (TRIF) signaling or an apoptosis-associated speck-like protein containing a CARD (ASC)- or caspase-4-dependent inflammasome. However, the dampening effect of T2S on IL-6 production was significantly reduced upon gene knockdown of myeloid differentiation primary response 88 (MyD88), TANK binding kinase 1 (TBK1), or Toll-like receptor 2 (TLR2). These data indicate that the L. pneumophila T2S system dampens the signaling of the TLR2 pathway in infected human macrophages. We also document the importance of PKR, TRIF, and TBK1 in cytokine secretion during L. pneumophila infection of macrophages.

IroT/mavN, a new iron-regulated gene involved in Legionella pneumophila virulence against amoebae and macrophages.

Legionella pneumophila is a pathogenic bacterium commonly found in water. Eventually, it could be transmitted to humans via inhalation of contaminated aerosols. Iron is known as a key requirement for the growth of L. pneumophila in the environment and within its hosts. Many studies were performed to understand iron utilization by L. pneumophila but no global approaches were conducted. In this study, transcriptomic analyses were performed, comparing gene expression in L. pneumophila in standard versus iron restricted conditions. Among the regulated genes, a newly described one, lpp_2867, was highly induced in iron-restricted conditions. Mutants lacking this gene in L. pneumophila were not affected in siderophore synthesis or utilization. On the contrary, they were defective for growth on iron-depleted solid media and for ferrous iron uptake. A sequence analysis predicts that Lpp_2867 is a membrane protein, suggesting that it is involved in ferrous iron transport. We thus named it IroT, for iron transporter. Infection assays showed that the mutants are highly impaired in intracellular growth within their environmental host Acanthamoeba castellanii and human macrophages. Taken together, our results show that IroT is involved, directly or indirectly, in ferrous iron transport and is a key virulence factor for L. pneumophila.

Nuclease activity of Legionella pneumophila Cas2 promotes intracellular infection of amoebal host cells.

Legionella pneumophila, the primary agent of Legionnaires' disease, flourishes in both natural and man-made environments by growing in a wide variety of aquatic amoebae. Recently, we determined that the Cas2 protein of L. pneumophila promotes intracellular infection of Acanthamoeba castellanii and Hartmannella vermiformis, the two amoebae most commonly linked to cases of disease. The Cas2 family of proteins is best known for its role in the bacterial and archeal clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated protein (Cas) system that constitutes a form of adaptive immunity against phage and plasmid. However, the infection event mediated by L. pneumophila Cas2 appeared to be distinct from this function, because cas2 mutants exhibited infectivity defects in the absence of added phage or plasmid and since mutants lacking the CRISPR array or any one of the other cas genes were not impaired in infection ability. We now report that the Cas2 protein of L. pneumophila has both RNase and DNase activities, with the RNase activity being more pronounced. By characterizing a catalytically deficient version of Cas2, we determined that nuclease activity is critical for promoting infection of amoebae. Also, introduction of Cas2, but not its catalytic mutant form, into a strain of L. pneumophila that naturally lacks a CRISPR-Cas locus caused that strain to be 40- to 80-fold more infective for amoebae, unequivocally demonstrating that Cas2 facilitates the infection process independently of any other component encoded within the CRISPR-Cas locus. Finally, a cas2 mutant was impaired for infection of Willaertia magna but not Naegleria lovaniensis, suggesting that Cas2 promotes infection of most but not all amoebal hosts.

Global discovery of colonization determinants in the squid symbiont Vibrio fischeri.

Animal epithelial tissue becomes reproducibly colonized by specific environmental bacteria. The bacteria (microbiota) perform critical functions for the host's tissue development, immune system development, and nutrition; yet the processes by which bacterial diversity in the environment is selected to assemble the correct communities in the host are unclear. To understand the molecular determinants of microbiota selection, we examined colonization of a simplified model in which the light organ of Euprymna scolopes squid is colonized exclusively by Vibrio fischeri bacteria. We applied high-throughput insertion sequencing to identify which bacterial genes are required during host colonization. A library of over 41,000 unique transposon insertions was analyzed before and after colonization of 1,500 squid hatchlings. Mutants that were reproducibly depleted following squid colonization represented 380 genes, including 37 that encode known colonization factors. Validation of select mutants in defined competitions against the wild-type strain identified nine mutants that exhibited a reproducible colonization defect. Some of the colonization factors identified included genes predicted to influence copper regulation and secretion. Other mutants exhibited defects in biofilm development, which is required for aggregation in host mucus and initiation of colonization. Biofilm formation in culture and in vivo was abolished in a strain lacking the cytoplasmic chaperone DnaJ, suggesting an important role for protein quality control during the elaboration of bacterial biofilm in the context of an intact host immune system. Overall these data suggest that cellular stress responses and biofilm regulation are critical processes underlying the reproducible colonization of animal hosts by specific microbial symbionts.