Evaluation of a large-scale health department naloxone distribution program: Per capita naloxone distribution and overdose morality

OBJECTIVES: To report per-capita distribution of take-home naloxone to lay bystanders and evaluate changes in opioid overdose mortality in the county over time. METHODS: Hamilton County Public Health in southwestern Ohio led the program from Oct 2017-Dec 2019. Analyses included all cartons distributed within Hamilton County or in surrounding counties to people who reported a home address within Hamilton County. Per capita distribution was estimated using publicly available census data. Opioid overdose mortality was compared between the period before (Oct 2015-Sep 2017) and during (Oct 2017-Sep 2019) the program. RESULTS: A total of 10,416 cartons were included for analyses, with a total per capita distribution of 1,275 cartons per 100,000 county residents (average annual rate of 588/100,000). Median monthly opioid overdose mortality in the two years before (28 persons, 95% CI 25-31) and during (26, 95% CI 23-28) the program did not differ significantly. CONCLUSIONS: Massive and rapid naloxone distribution to lay bystanders is feasible. Even large-scale take-home naloxone distribution may not substantially reduce opioid overdose mortality rates

A Retrospective Real-World Study of the Effectiveness and Tolerability of Tildrakizumab in UK Adults with Moderate-to-Severe Chronic Plaque Psoriasis

INTRODUCTION: As with most medicines historically, clinicians prescribing tildrakizumab have relied on information derived from registration studies undertaken in a prospective controlled clinical trial setting. More recently, clinicians, policymakers, and commissioners increasingly rely on real-world data to inform both policy and practice. METHODS: A retrospective real-world data study was undertaken at four specialist dermatology departments in the United Kingdom. All adult patients treated with tildrakizumab for moderate-to-severe plaque psoriasis were included, with data being collected for 122 patients. RESULTS: Psoriatic patients on tildrakizumab tended to be overweight (median body mass index of 32 (range 19–59) (n = 61); 26/68 (38%)  120 kg). The study population had high levels of comorbidities (83/116, 72%), multiple special sites (39/117, 33%), and histories of biological treatments (81/100, 81%). Most patients (61/80, 76%) initiated on tildrakizumab were switched from another biological treatment. Tildrakizumab was effective, with 91/122 (75%) patients remaining on treatment for the duration of the study—a median of 12 months per patient (range 1–29 months)—and achieving a change in median Psoriasis Area and Severity Index (PASI) from 12 to 0.35 and in Dermatology Life Quality Index (DLQI) from 20 to 0. The response rate was 57/66 (86%) when tildrakizumab was used as the first- or second-line biologic compared to 19/31 (61%) when used as the third- to seventh-line. Thirty-three (78.6%) patients over 90 kg of weight received the 200-mg dose of tildrakizumab. All but one (n = 8) patient with body weight over 120 kg maintained response over time. There was one treatment discontinuation; a patient who had a local sensitivity reaction. CONCLUSIONS: In UK clinical practice, tildrakizumab was well tolerated and effective at doses of 100 mg or 200 mg in a range of patient phenotypes

Orally active antischistosomal early leads identified from the open access malaria box.

BACKGROUND: Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs. METHODOLOGY: We studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo. PRINCIPAL FINDINGS: Promising antischistosomal activity (IC50: 1.4-9.5 µM) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 µM against adult S. mansoni. Two promising early leads were identified, namely a N,N'-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively. CONCLUSIONS/SIGNIFICANCE: The two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development

The jellification of north temperate lakes.

Calcium (Ca) concentrations are decreasing in softwater lakes across eastern North America and western Europe. Using long-term contemporary and palaeo-environmental field data, we show that this is precipitating a dramatic change in Canadian lakes: the replacement of previously dominant pelagic herbivores (Ca-rich Daphnia species) by Holopedium glacialis, a jelly-clad, Ca-poor competitor. In some lakes, this transformation is being facilitated by increases in macro-invertebrate predation, both from native (Chaoborus spp.) and introduced (Bythotrephes longimanus) zooplanktivores, to which Holopedium, with its jelly coat, is relatively invulnerable. Greater representation by Holopedium within cladoceran zooplankton communities will reduce nutrient transfer through food webs, given their lower phosphorus content relative to daphniids, and greater absolute abundances may pose long-term problems to water users. The dominance of jelly-clad zooplankton will likely persist while lakewater Ca levels remain low.This work was primarily supported by grants from the Natural Sciences and Engineering Research Council of Canada and funding from the Ontario Ministry of the Environment.This is the accepted manuscript. The final version is available at http://rspb.royalsocietypublishing.org/content/282/1798/20142449

The global oscillation network group site survey. II. Results

The Global Oscillation Network Group (GONG) Project will place a network of instruments around the world to observe solar oscillations as continuously as possible for three years. The Project has now chosen the six network sites based on analysis of survey data from fifteen sites around the world. The chosen sites are: Big Bear Solar Observatory, California; Mauna Loa Solar Observatory, Hawaii; Learmonth Solar Observatory, Australia; Udaipur Solar Observatory, India; Observatorio del Teide, Tenerife; and Cerro Tololo Interamerican Observatory, Chile. Total solar intensity at each site yields information on local cloud cover, extinction coefficient, and transparency fluctuations. In addition, the performance of 192 reasonable components analysis. An accompanying paper describes the analysis methods in detail; here we present the results of both the network and individual site analyses. The selected network has a duty cycle of 93.3%, in good agreement with numerical simulations. The power spectrum of the network observing window shows a first diurnal sidelobe height of 3 × 10⁻⁴ with respect to the central component, an improvement of a factor of 1300 over a single site. The background level of the network spectrum is lower by a factor of 50 compared to a single-site spectrum

Arsenic as an Endocrine Disruptor: Arsenic Disrupts Retinoic Acid Receptor–and Thyroid Hormone Receptor–Mediated Gene Regulation and Thyroid Hormone–Mediated Amphibian Tail Metamorphosis

Background: Chronic exposure to excess arsenic in drinking water has been strongly associated with increased risks of multiple cancers, diabetes, heart disease, and reproductive and developmental problems in humans. We previously demonstrated that As, a potent endocrine disruptor at low, environmentally relevant levels, alters steroid signaling at the level of receptor-mediated gene regulation for all five steroid receptors. Objectives: The goal of this study was to determine whether As can also disrupt gene regulation via the retinoic acid (RA) receptor (RAR) and/or the thyroid hormone (TH) receptor (TR) and whether these effects are similar to previously observed effects on steroid regulation. Methods and results: Human embryonic NT2 or rat pituitary GH3 cells were treated with 0.01–5 μM sodium arsenite for 24 hr, with or without RA or TH, respectively, to examine effects of As on receptor-mediated gene transcription. At low, noncytotoxic doses, As significantly altered RAR-dependent gene transcription of a transfected RAR response element–luciferase construct and the native RA-inducible cytochrome P450 CYP26A gene in NT2 cells. Likewise, low-dose As significantly altered expression of a transfected TR response element–luciferase construct and the endogenous TR-regulated type I deiodinase (DIO1) gene in a similar manner in GH3 cells. An amphibian ex vivo tail metamorphosis assay was used to examine whether endocrine disruption by low-dose As could have specific pathophysiologic consequences, because tail metamorphosis is tightly controlled by TH through TR. TH-dependent tail shrinkage was inhibited in a dose-dependent manner by 0.1– 4.0 μM As. Conclusions: As had similar effects on RAR- and TR-mediated gene regulation as those previously observed for the steroid receptors, suggesting a common mechanism or action. Arsenic also profoundly affected a TR-dependent developmental process in a model animal system at very low concentrations. Because RAR and TH are critical for both normal human development and adult function and their dysregulation is associated with many disease processes, disruption of these hormone receptor–dependent processes by As is also potentially relevant to human developmental problems and disease risk

Statins Enhance Clonal Growth of Late Outgrowth Endothelial Progenitors and Increase Myocardial Capillary Density in the Chronically Ischemic Heart

Coronary artery disease and ischemic heart disease are leading causes of heart failure and death. Reduced blood flow to heart tissue leads to decreased heart function and symptoms of heart failure. Therapies to improve heart function in chronic coronary artery disease are important to identify. HMG-CoA reductase inhibitors (statins) are an important therapy for prevention of coronary artery disease, but also have non-cholesterol lowering effects. Our prior work showed that pravastatin improves contractile function in the chronically ischemic heart in pigs. Endothelial progenitor cells are a potential source of new blood vessels in ischemic tissues. While statins are known to increase the number of early outgrowth endothelial progenitor cells, their effects on late outgrowth endothelial progenitor cells (LOEPCs) and capillary density in ischemic heart tissue are not known. We hypothesized that statins exert positive effects on the mobilization and growth of late outgrowth EPCs, and capillary density in ischemic heart tissue.We determined the effects of statins on the mobilization and growth of late outgrowth endothelial progenitor cells from pigs. We also determined the density of capillaries in myocardial tissue in pigs with chronic myocardial ischemia with or without treatment with pravastatin. Pravastatin therapy resulted in greater than two-fold increase in CD31+ LOEPCs versus untreated animals. Addition of pravastatin or simvastatin to blood mononuclear cells increased the number of LOEPCs greater than three fold in culture. Finally, in animals with chronic myocardial ischemia, pravastatin increased capillary density 46%.Statins promote the derivation, mobilization, and clonal growth of LOEPCs. Pravastatin therapy in vivo increases myocardial capillary density in chronically ischemic myocardium, providing an in vivo correlate for the effects of statins on LOEPC growth in vitro. Our findings provide evidence that statin therapy can increase the density of capillaries in the chronically ischemic heart

Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer’s disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562

The Wolbachia Genome of Brugia malayi: Endosymbiont Evolution within a Human Pathogenic Nematode

Complete genome DNA sequence and analysis is presented for Wolbachia, the obligate alpha-proteobacterial endosymbiont required for fertility and survival of the human filarial parasitic nematode Brugia malayi. Although, quantitatively, the genome is even more degraded than those of closely related Rickettsia species, Wolbachia has retained more intact metabolic pathways. The ability to provide riboflavin, flavin adenine dinucleotide, heme, and nucleotides is likely to be Wolbachia's principal contribution to the mutualistic relationship, whereas the host nematode likely supplies amino acids required for Wolbachia growth. Genome comparison of the Wolbachia endosymbiont of B. malayi (wBm) with the Wolbachia endosymbiont of Drosophila melanogaster (wMel) shows that they share similar metabolic trends, although their genomes show a high degree of genome shuffling. In contrast to wMel, wBm contains no prophage and has a reduced level of repeated DNA. Both Wolbachia have lost a considerable number of membrane biogenesis genes that apparently make them unable to synthesize lipid A, the usual component of proteobacterial membranes. However, differences in their peptidoglycan structures may reflect the mutualistic lifestyle of wBm in contrast to the parasitic lifestyle of wMel. The smaller genome size of wBm, relative to wMel, may reflect the loss of genes required for infecting host cells and avoiding host defense systems. Analysis of this first sequenced endosymbiont genome from a filarial nematode provides insight into endosymbiont evolution and additionally provides new potential targets for elimination of cutaneous and lymphatic human filarial disease