Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose Mortality

OBJECTIVE: Previous studies examining opioid dose and overdose risk provide limited granularity by milligram strength and instead rely on thresholds. We quantify dose-dependent overdose mortality over a large spectrum of clinically common doses. We also examine the contributions of benzodiazepines and extended release opioid formulations to mortality. DESIGN: Prospective observational cohort with one year follow-up. SETTING: One year in one state (NC) using a controlled substances prescription monitoring program, with name-linked mortality data. SUBJECTS: Residential population of North Carolina (n = 9,560,234), with 2,182,374 opioid analgesic patients. METHODS: Exposure was dispensed prescriptions of solid oral and transdermal opioid analgesics; person-years calculated using intent-to-treat principles. Outcome was overdose deaths involving opioid analgesics in a primary or additive role. Poisson models were created, implemented using generalized estimating equations. RESULTS: Opioid analgesics were dispensed to 22.8% of residents. Among licensed clinicians, 89.6% prescribed opioid analgesics, and 40.0% prescribed ER formulations. There were 629 overdose deaths, half of which had an opioid analgesic prescription active on the day of death. Of 2,182,374 patients prescribed opioids, 478 overdose deaths were reported (0.022% per year). Mortality rates increased gradually across the range of average daily milligrams of morphine equivalents. 80.0% of opioid analgesic patients also received benzodiazepines. Rates of overdose death among those co-dispensed benzodiazepines and opioid analgesics were ten times higher (7.0 per 10,000 person-years, 95 percent CI: 6.3, 7.8) than opioid analgesics alone (0.7 per 10,000 person years, 95 percent CI: 0.6, 0.9). CONCLUSIONS: Dose-dependent opioid overdose risk among patients increased gradually and did not show evidence of a distinct risk threshold. There is urgent need for guidance about combined classes of medicines to facilitate a better balance between pain relief and overdose risk

Physarum Can Compute Shortest Paths

Physarum Polycephalum is a slime mold that is apparently able to solve shortest path problems. A mathematical model has been proposed by biologists to describe the feedback mechanism used by the slime mold to adapt its tubular channels while foraging two food sources s0 and s1. We prove that, under this model, the mass of the mold will eventually converge to the shortest s0 - s1 path of the network that the mold lies on, independently of the structure of the network or of the initial mass distribution. This matches the experimental observations by the biologists and can be seen as an example of a "natural algorithm", that is, an algorithm developed by evolution over millions of years.Comment: Accepted in SODA 201

Cetuximab Plus Carboplatin and Paclitaxel With or Without Bevacizumab Versus Carboplatin and Paclitaxel With or Without Bevacizumab in Advanced NSCLC (SWOG S0819): A Randomised, Phase 3 Study

Background EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. We hypothesised that EGFR copy number by fluorescence in-situ hybridisation (FISH) can identify patients most likely to benefit from these drugs combined with chemotherapy and we aimed to explore the activity of cetuximab with chemotherapy in patients with advanced NSCLC who are EGFR FISH-positive. Methods We did this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico. We randomly assigned (1:1) eligible patients with treatment-naive stage IV NSCLC to receive paclitaxel (200 mg/m 2; every 21 days) plus carboplatin (area under the curve of 6 by modified Calvert formula; every 21 days) or carboplatin plus paclitaxel and bevacizumab (15 mg/kg; every 21 days), either with cetuximab (250 mg/m 2 weekly after loading dose; cetuximab group) or without (control group), stratified by bevacizumab treatment, smoking status, and M-substage using a dynamic-balancing algorithm. Co-primary endpoints were progression-free survival in patients with EGFR FISH-positive cancer and overall survival in the entire study population. We analysed clinical outcomes with the intention-to-treat principle and analysis of safety outcomes included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (number NCT00946712). Findings Between Aug 13, 2009, and May 30, 2014, we randomly assigned 1313 patients to the control group (n=657; 277 with bevacizumab and 380 without bevacizumab in the intention-to-treat population) or the cetuximab group (n=656; 283 with bevacizumab and 373 without bevacizumab in the intention-to-treat population). EGFR FISH was assessable in 976 patients and 400 patients (41%) were EGFR FISH-positive. The median follow-up for patients last known to be alive was 35·2 months (IQR 22·9–39·9). After 194 progression-free survival events in the cetuximab group and 198 in the control group in the EGFR FISH-positive subpopulation, progression-free survival did not differ between treatment groups (hazard ratio [HR] 0·92, 95% CI 0·75–1·12; p=0·40; median 5·4 months [95% CI 4·5–5·7] vs 4·8 months [3·9–5·5]). After 570 deaths in the cetuximab group and 593 in the control group, overall survival did not differ between the treatment groups in the entire study population (HR 0·93, 95% CI 0·83–1·04; p=0·22; median 10·9 months [95% CI 9·5–12·0] vs 9·2 months [8·7–10·3]). In the prespecified analysis of EGFR FISH-positive subpopulation with squamous cell histology, overall survival was significantly longer in the cetuximab group than in the control group (HR 0·58, 95% CI 0·36–0·86; p=0·0071), although progression-free survival did not differ between treatment groups in this subgroup (0·68, 0·46–1·01; p=0·055). Overall survival and progression-free survival did not differ among patients who were EGFR FISH non-positive with squamous cell histology (HR 1·04, 95% CI 0·78–1·40; p=0·77; and 1·02, 0·77–1·36; p=0·88 respectively) or patients with non-squamous histology regardless of EGFR FISH status (for EGFR FISH-positive 0·88, 0·68–1·14; p=0·34; and 0·99, 0·78–1·27; p=0·96; respectively; and for EGFR FISH non-positive 1·00, 0·85–1·17; p=0·97; and 1·03, 0·88–1·20; p=0·69; respectively). The most common grade 3–4 adverse events were decreased neutrophil count (210 [37%] in the cetuximab group vs 158 [25%] in the control group), decreased leucocyte count (103 [16%] vs 74 [20%]), fatigue (81 [13%] vs 74 [20%]), and acne or rash (52 [8%] vs one [\u3c 1%]). 59 (9%) patients in the cetuximab group and 31 (5%) patients in the control group had severe adverse events. Deaths related to treatment occurred in 32 (6%) patients in the cetuximab group and 13 (2%) patients in the control group. Interpretation Although this study did not meet its primary endpoints, prespecified subgroup analyses of patients with EGFR FISH-positive squamous-cell carcinoma cancers are encouraging and support continued evaluation of anti-EGFR antibodies in this subpopulation

Study protocol: developing, disseminating, and implementing a core outcome set for selective fetal growth restriction in monochorionic twin pregnancies.

BACKGROUND: Selective fetal growth restriction in monochorionic twin pregnancies is associated with an increased risk of perinatal mortality and morbidity and represents a clinical dilemma. Interventions include expectant management with early preterm delivery if there are signs of fetal compromise, selective termination of the compromised twin, fetoscopic laser coagulation of the communicating placental vessels or termination of the whole pregnancy. Previous studies evaluating interventions have reported many different outcomes and outcome measures. Such variation makes comparing, contrasting, and combining results challenging, limiting ongoing research on this uncommon condition to inform clinical practice. We aim to produce, disseminate, and implement a core outcome set for selective fetal growth restriction research in monochorionic twin pregnancies. METHODS: An international steering group, including professionals, researchers, and lay experts, has been established to oversee the development of this core outcome set. The methods have been guided by the Core Outcome Measures in Effectiveness Trials Initiative Handbook. Potential core outcomes will be developed by undertaking a systematic review of studies evaluating interventions for selective fetal growth restriction in monochorionic twin pregnancies. Potential core outcomes will be entered into a three-round Delphi survey and key stakeholders including clinical professionals, researchers, and lay experts will be invited to participate. Repeated reflection and rescoring of individual outcomes should encourage group and individual stakeholder convergence towards consensus outcomes which will be entered into a modified Nominal Group Technique to finalize the core outcome set. Once core outcomes have been agreed, we will establish standardized definitions and recommend high-quality measurement instruments for each outcome. DISCUSSION: The development, dissemination, and implementation of a core outcome set for selective fetal growth restriction should ensure that future research protocols select, collect, and report outcomes and outcome measures in a standardized manner. Data synthesis will be possible on a broad level and rigorous implementation should advance the quality of research studies and their effective use in order to guide clinical practice, improve patient care, maternal, short-term perinatal outcomes, and long-term neurodevelopmental outcomes. TRIAL REGISTRATION: Core Outcome Measures in Effectiveness Trials (COMET) registration number: 998. International Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD42018092697 . 18th April 2018

Genotypic resistance testing in HIV by arrayed primer extension

The analysis of mutations that are associated with the occurrence of drug resistance is important for monitoring the antiretroviral therapy of patients infected with human immunodeficiency virus (HIV). Here, we describe the establishment and successful application of Arrayed Primer Extension (APEX) for genotypic resistance testing in HIV as a rapid and economical alternative to standard sequencing. The assay is based on an array of oligonucleotide primers that are immobilised via their 5′-ends. Upon hybridisation of template DNA, a primer extension reaction is performed in the presence of the four dideoxynucleotides, each labelled with a distinct fluorophore. The inserted label immediately indicates the sequence at the respective position. Any mutation changes the colour pattern. We designed a microarray for the analysis of 26 and 33 codons in the HIV protease and reverse transcriptase, respectively, which are of special interest with respect to drug resistance. The enormous genome variability of HIV represents a big challenge for genotypic resistance tests, which include a hybridisation step, both in terms of specificity and probe numbers. The use of degenerated oligonucleotides resulted in a significant reduction in the number of primers needed. For validation, DNA of 94 and 48 patients that exhibited resistance to inhibitors of HIV protease and reverse transcriptase, respectively, were analysed. The validation included HIV subtype B, prevalent in industrialised countries, as well as non-subtype B samples that are more common elsewhere

Neutrophil cell surface receptors and their intracellular signal transduction pathways

AbstractNeutrophils play a critical role in the host defense against bacterial and fungal infections, but their inappropriate activation also contributes to tissue damage during autoimmune and inflammatory diseases. Neutrophils express a large number of cell surface receptors for the recognition of pathogen invasion and the inflammatory environment. Those include G-protein-coupled chemokine and chemoattractant receptors, Fc-receptors, adhesion receptors such as selectins/selectin ligands and integrins, various cytokine receptors, as well as innate immune receptors such as Toll-like receptors and C-type lectins. The various cell surface receptors trigger very diverse signal transduction pathways including activation of heterotrimeric and monomeric G-proteins, receptor-induced and store-operated Ca2+ signals, protein and lipid kinases, adapter proteins and cytoskeletal rearrangement. Here we provide an overview of the receptors involved in neutrophil activation and the intracellular signal transduction processes they trigger. This knowledge is crucial for understanding how neutrophils participate in antimicrobial host defense and inflammatory tissue damage and may also point to possible future targets of the pharmacological therapy of neutrophil-mediated autoimmune or inflammatory diseases

Developing a core outcome set for future infertility research : An international consensus development study

STUDY QUESTION: Can a core outcome set to standardize outcome selection, collection and reporting across future infertility research be developed? SUMMARY ANSWER: A minimum data set, known as a core outcome set, has been developed for randomized controlled trials (RCTs) and systematic reviews evaluating potential treatments for infertility. WHAT IS KNOWN ALREADY: Complex issues, including a failure to consider the perspectives of people with fertility problems when selecting outcomes, variations in outcome definitions and the selective reporting of outcomes on the basis of statistical analysis, make the results of infertility research difficult to interpret. STUDY DESIGN, SIZE, DURATION: A three-round Delphi survey (372 participants from 41 countries) and consensus development workshop (30 participants from 27 countries). PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus science methods. MAIN RESULTS AND THE ROLE OF CHANCE: The core outcome set consists of: viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin and higher multiple pregnancy); pregnancy loss (accounting for ectopic pregnancy, miscarriage, stillbirth and termination of pregnancy); live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital anomaly. Time to pregnancy leading to live birth should be reported when applicable. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods which have inherent limitations, including the representativeness of the participant sample, Delphi survey attrition and an arbitrary consensus threshold. WIDER IMPLICATIONS OF THE FINDINGS: Embedding the core outcome set within RCTs and systematic reviews should ensure the comprehensive selection, collection and reporting of core outcomes. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement, and over 80 specialty journals, including the Cochrane Gynaecology and Fertility Group, Fertility and Sterility and Human Reproduction, have committed to implementing this core outcome set. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund and Maurice and Phyllis Paykel Trust. The funder had no role in the design and conduct of the study, the collection, management, analysis or interpretation of data, or manuscript preparation. B.W.J.M. is supported by a National Health and Medical Research Council Practitioner Fellowship (GNT1082548). S.B. was supported by University of Auckland Foundation Seelye Travelling Fellowship. S.B. reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. J.M.L.K. reports research sponsorship from Ferring and Theramex. R.S.L. reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.J.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. C.N. reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. A.S. reports consultancy fees from Guerbet. E.H.Y.N. reports research sponsorship from Merck. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form

Epithelial-mesenchymal transition and cancer stem cells: a dangerously dynamic duo in breast cancer progression

Aberrant activation of a latent embryonic program - known as the epithelial-mesenchymal transition (EMT) - can endow cancer cells with the migratory and invasive capabilities associated with metastatic competence. The induction of EMT entails the loss of epithelial characteristics and the de novo acquisition of a mesenchymal phenotype. In breast cancer, the EMT state has been associated with cancer stem cell properties including expression of the stem cell-associated CD44+/CD24-/low antigenic profile, self-renewal capabilities and resistance to conventional therapies. Intriguingly, EMT features are also associated with stem cells isolated from the normal mouse mammary gland and human breast reduction tissues as well as the highly aggressive metaplastic and claudin-low breast tumor subtypes. This has implications for the origin of these breast tumors as it remains unclear whether they derive from cells that have undergone EMT or whether they represent an expansion of a pre-existing stem cell population that expresses EMT-associated markers to begin with. In the present review, we consider the current evidence connecting EMT and stem cell attributes and discuss the ramifications of these newly recognized links for our understanding of the emergence of distinct breast cancer subtypes and breast cancer progression