Latent Class Analysis Reveals COVID-19-related Acute Respiratory Distress Syndrome Subgroups with Differential Responses to Corticosteroids.

Rationale: Two distinct subphenotypes have been identified in acute respiratory distress syndrome (ARDS), but the presence of subgroups in ARDS associated with coronavirus disease (COVID-19) is unknown. Objectives: To identify clinically relevant, novel subgroups in COVID-19-related ARDS and compare them with previously described ARDS subphenotypes. Methods: Eligible participants were adults with COVID-19 and ARDS at Columbia University Irving Medical Center. Latent class analysis was used to identify subgroups with baseline clinical, respiratory, and laboratory data serving as partitioning variables. A previously developed machine learning model was used to classify patients as the hypoinflammatory and hyperinflammatory subphenotypes. Baseline characteristics and clinical outcomes were compared between subgroups. Heterogeneity of treatment effect for corticosteroid use in subgroups was tested. Measurements and Main Results: From March 2, 2020, to April 30, 2020, 483 patients with COVID-19-related ARDS met study criteria. A two-class latent class analysis model best fit the population (P = 0.0075). Class 2 (23%) had higher proinflammatory markers, troponin, creatinine, and lactate, lower bicarbonate, and lower blood pressure than class 1 (77%). Ninety-day mortality was higher in class 2 versus class 1 (75% vs. 48%; P < 0.0001). Considerable overlap was observed between these subgroups and ARDS subphenotypes. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR cycle threshold was associated with mortality in the hypoinflammatory but not the hyperinflammatory phenotype. Heterogeneity of treatment effect to corticosteroids was observed (P = 0.0295), with improved mortality in the hyperinflammatory phenotype and worse mortality in the hypoinflammatory phenotype, with the caveat that corticosteroid treatment was not randomized. Conclusions: We identified two COVID-19-related ARDS subgroups with differential outcomes, similar to previously described ARDS subphenotypes. SARS-CoV-2 PCR cycle threshold had differential value for predicting mortality in the subphenotypes. The subphenotypes had differential treatment responses to corticosteroids.

Cryptococcus neoformans infective endocarditis after lung transplantation: a case report and review of the literature.

Cryptococcus neoformans infective endocarditis is rarely reported. In this report, we present a case of infective endocarditis secondary to Cryptococcus neoformans in a lung-transplant recipient and review the relevant literature. A 65-year-old man was hospitalized with hypoxemic respiratory failure and underwent left-sided single lung transplantation. In the setting of worsening hypoxemia, blood cultures were drawn, which grew C. neoformans. Lumbar puncture was performed, and CSF PCR was also positive for Cryptococcus. Further exposure history revealed that he had raised chickens while living in Peru. Transesophageal echocardiography showed an aortic valve vegetation, and he was diagnosed with cryptococcal infective endocarditis. He received liposomal amphotericin B and flucytosine for two weeks and was later transitioned to fluconazole. This case highlights the need for thorough social history prior to lung transplantation, as pulmonary colonization with C. neoformans may result in infective endocarditis after immunosuppression.

Fatal Toxicity Indices for Medicine-Related Deaths in New Zealand, 2008-2013.

INTRODUCTION: The fatal toxicity index (FTI) is a measure for assessing the relative risks of death due to the medicines prescribed in a population. This knowledge is useful for prescribers and informs medicine safety initiatives. This study aimed to calculate FTIs for the New Zealand population using three methodologies. METHODS: New Zealand coronial data describing medicine-related deaths from 1 January 2008 to 31 December 2013 were retrospectively extracted from the National Coronial Information System. Three fatal toxicity indices were derived using the number of deaths attributed to each pharmaceutical as the numerator and the total defined daily doses, number of patients and number of prescriptions as denominators. RESULTS: There were 703 medicine-related deaths, of which 627 were assessed as due to one primary contributor. Median decedent age was 48 years (interquartile range 37-58), and 319 (51%) were male. Deaths were intentional in 252 cases (40%), unintentional in 284 (45%) and unknown in 91 (15%). The majority of deaths (n = 486, 78%) occurred in the community. Opioids, antidepressants, antipsychotics and hypnotic-anxiolytics caused most fatalities. While the FTIs for individual medicines varied by denominator applied, methadone and clozapine fatalities were prominent in all three indices. The antidepressants clomipramine, dosulepin and doxepin consistently returned the highest FTIs in their group. CONCLUSION: New Zealand prescribers should be aware of the high relative risk of death associated with methadone and clozapine; that clomipramine, dosulepin and doxepin were identified as the most dangerous antidepressants; and that zopiclone carries a similar fatal risk to benzodiazepines. Varying results were found between the FTIs calculated, making comparisons, particularly between populations, difficult.

Deaths by poisoning in New Zealand, 2008-2013.

Introduction: While a number of developed countries have witnessed a decline in carbon monoxide (CO) deaths and increasing numbers of opioid-related fatalities, it is not known whether these or other trends have occurred in New Zealand. The aim of this study was, therefore, to review deaths due to poisoning in New Zealand, describe the causative substances, and identify any trends. Methods: Retrospective study reviewing New Zealand's poison-related death findings recorded in the National Coronial Information System (NCIS) database over the 6-year period 2008-2013. Results: We identified 1402 poisoning-related deaths recorded in the NCIS database representing a mortality rate of 5.4 deaths/100,000 population per year. The mortality rate due to poisoning was higher in males (6.96/100,000) than females (3.83/100,000). Fatalities peaked in the 40-50-year age group with the highest proportion of intentional deaths occurring in people aged 80-90 years. Pharmaceuticals accounted for 731 fatalities (52%) and chemicals 431 (31%), with multiple exposures occurring in 399 cases (28.5%). While CO was the leading cause of death throughout the period (n = 303, 21.6%), there was a significant reduction in the rate of CO fatalities from 1.69/100,000 population in 2008 to 0.94/100,000 in 2013 (IRR (95% CI) 2013/2008 0.56 (0.37-0.83)). There was, however, no statistically significant change in either the opioid-related death rate or the total number of deaths. Methadone was the leading pharmaceutical cause of fatality and the third most common cause overall, followed by morphine and codeine, with zopiclone and clozapine equally ranked as the sixth most common cause. Conclusion: While New Zealand has not suffered an "opioid epidemic" and has experienced a significant decline in CO deaths, the overall death rate due to poisoning has remained high. The development of accessible, timely, and relevant toxicovigilance systems would support the early implementation of interventions to reduce the leading causes of fatal poisoning.

Titanium dioxide nanoparticle exposure alters metabolic homeostasis in a cell culture model of the intestinal epithelium and Drosophila melanogaster.

Nanosized titanium dioxide (TiO2) is a common additive in food and cosmetic products. The goal of this study was to investigate if TiO2 nanoparticles affect intestinal epithelial tissues, normal intestinal function, or metabolic homeostasis using in vitro and in vivo methods. An in vitro model of intestinal epithelial tissue was created by seeding co-cultures of Caco-2 and HT29-MTX cells on a Transwell permeable support. These experiments were repeated with monolayers that had been cultured with the beneficial commensal bacteria Lactobacillus rhamnosus GG (L. rhamnosus). Glucose uptake and transport in the presence of TiO2 nanoparticles was assessed using fluorescent glucose analog 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG). When the cell monolayers were exposed to physiologically relevant doses of TiO2, a statistically significant reduction in glucose transport was observed. These differences in glucose absorption were eliminated in the presence of beneficial bacteria. The decrease in glucose absorption was caused by damage to intestinal microvilli, which decreased the surface area available for absorption. Damage to microvilli was ameliorated in the presence of L. rhamnosus. Complimentary studies in Drosophila melanogaster showed that TiO2 ingestion resulted in decreased body size and glucose content. The results suggest that TiO2 nanoparticles alter glucose transport across the intestinal epithelium, and that TiO2 nanoparticle ingestion may have physiological consequences.

A Pharmacoepidemiology Database System for Monitoring Risk Due to the Use of Medicines by New Zealand Primary Care Patients.

INTRODUCTION: The use of large record-linked healthcare databases for drug safety research and surveillance is now accepted practice. New Zealand's standardized national healthcare datasets provide the potential to automate the conduct of pharmacoepidemiological studies to provide rapid validation of medicine safety signals. OBJECTIVES: Our objectives were to describe the methodology undertaken by a semi-automated computer system developed to rapidly assess risk due to drug exposure in New Zealand's population of primary care patients and to compare results from three studies with previously published findings. METHODS: Data from three national databases were linked at the patient level in the automated studies. A retrospective nested case-control design was used to evaluate risk for upper gastrointestinal bleeding (UGIB), acute kidney failure (AKF), and serious arrhythmia associated with individual medicines, therapeutic classes of medicines, and concurrent use of medicines from multiple therapeutic classes. RESULTS: The patient cohort available for each study included 5,194,256 patients registered between 2007 and 2014, with a total of 34,630,673 patient-years at risk. An increased risk for UGIB was associated with non-steroidal anti-inflammatory drugs (NSAIDs) (adjusted odds ratio [AOR] 4.16, 95% confidence interval [CI] 3.90-4.43, p < 0.001) and selective serotonin reuptake inhibitors (AOR 1.39, 95% CI 1.20-1.62, p < 0.001); an increased risk for AKF was associated with NSAIDs (AOR 1.78, 95% CI 1.73-1.83, p < 0.001) and proton pump inhibitors (AOR 1.78, 95% CI 1.72-1.83, p < 0.001); and an increased risk for serious arrhythmia was associated with fluoroquinolones (AOR 1.38, 95% CI 1.26-151, p < 0.001) and penicillins (AOR 1.69, 95% CI 1.61-1.77, p < 0.001). CONCLUSIONS: Automated case-control studies using New Zealand's healthcare datasets can replicate associations of risk with drug exposure consistent with previous findings. Their speed of conduct enables systematic monitoring of risk for adverse events associated with a wide range of medicines.

Veratrum poisoning.

Several species of the Veratrum genus are associated with toxicity in humans and animals. The principal toxins are steroid alkaloids; some have a modified steroid template, whereas others differ in their esterified acid moieties. These alkaloids act by increasing the permeability of the sodium channels of nerve cells, causing them to fire continuously. Increased stimulation, associated with the vagal nerve results in a reflex that causes the triad of responses known as the Bezold-Jarisch reflex: hypotension, bradycardia and apnoea. Clinically, various Veratrum extracts were marketed for clinical use as antihypertensive drugs, but because of their narrow therapeutic index were withdrawn from the market. Following the ingestion of Veratrum alkaloids, expected signs and symptoms include vomiting and abdominal pain, followed by cardiovascular effects such as bradycardia, hypotension and cardiac conduction abnormalities and death. Similar symptoms arise in other mammalian species ingesting these alkaloids; teratogenic effects may occur to the fetuses of animals that have grazed on Veratrum californicum. Treatment consists of supportive care, with an emphasis on haemodynamic stability with fluid replacement, atropine and vasopressors. The onset of symptoms occurs between 30 minutes and 4 hours, and the duration of the illness can range from 1 to 10 days; however, with prompt supportive care, patients typically make a full recovery within 24 hours.

The effect of changes in surface wettability on two-phase saturated flow in horizontal replicas of single natural fractures.

By using translucent epoxy replicas of natural single fractures, it is possible to optically measure aperture distribution and directly observe NAPL flow. However, detailed characterization of epoxy reveals that it is not a sufficiently good analogue to natural rock for many two-phase flow studies. The surface properties of epoxy, which is hydrophobic, are quite unlike those of natural rock, which is generally assumed to be hydrophilic. Different surface wettabilities result in dramatically different two-phase flow behavior and residual distributions. In hydrophobic replicas, the NAPL flows in well-developed channels, displacing water and filling all of the pore space. In hydrophilic replicas, the invading NAPL is confined to the largest aperture pathways and flow frequently occurs in pulses, with no limited or no stable channel development, resulting in isolated blobs with limited accessible surface area. The pulsing and channel abandonment behaviors described are significantly different from the piston-flow frequently assumed in current modeling practice. In addition, NAPL never achieved total saturation in hydrophilic models, indicating that significantly more than a monolayer of water was bound to the model surface. Despite typically only 60-80% NAPL saturation, there was generally good agreement between theoretically calculated Young-Laplace aperture invasion boundaries and the observed minimum apertures invaded. The key to determining whether surface wettability is negligible, or not, lies in accurate characterization of the contaminant-geologic media system under study. As long as the triple-point contact angle of the system is low (<20 degrees), the assumption of perfect water wettability is not a bad one.

TOXINZ, the New Zealand Internet poisons information database: The first decade.

OBJECTIVE: The New Zealand National Poisons Centre has, over a number of years, developed an electronic poisons information database. In 2002, this was released as toxinz™ (University of Otago, Dunedin, New Zealand), an Internet accessible version. The objective of this study is to describe New Zealand subscriber utilisation of TOXINZ with an emphasis on pharmaceutical monographs viewed. METHODS: A retrospective review was conducted of records of New Zealand subscriber access to TOXINZ monographs during the period 1 January 2003 to 31 December 2012. Telephone enquiry data to the New Zealand National Poisons Centre was also obtained for the same time period. RESULTS: Over the decade, 201 255 TOXINZ monographs were accessed, with annual numbers of documents viewed doubling from 13 718 in 2003 to 28 782 in 2012. Pharmaceuticals were the largest group viewed with 132 316 documents accessed (65.7% of all documents), followed by monographs relating to chemicals 46 061 (22.9%), substances of abuse 6698 (3.3%), plants 6563 (3.3%), supportive care 4668 (2.3%), animals 2553 (1.3%), and other 2396 (1.2%). In regard to the pharmaceuticals, high or rapidly increasing levels of enquiries were identified for venlafaxine, quetiapine, paracetamol, zopiclone and tramadol. Investigation of telephone enquiries to the New Zealand National Poisons Centre showed total poisoning calls increased slightly over the 10 year period, whereas telephone enquiries from hospitals halved. CONCLUSION: The TOXINZ Internet accessible poisons information database has proved to be a well-utilised addition to the New Zealand National Poisons Centre's service.

Nitrate movement in shallow ground water from swine-lagoon-effluent spray fields managed under current application regulations.

Rapid increases in the swine (Sus scrofa domestica) population in the 1990s and associated potential for nitrate N pollution of surface waters led the state of North Carolina to adopt stringent waste management regulations in 1993. Our objectives were to characterize (i) nitrate N movement from waste application fields (WAFs) in shallow ground water, and (ii) soil, hydrologic, and biological factors influencing the amount of nitrate N in the adjacent stream. A ground water monitoring study was conducted for 36 mo on a swine farm managed under new regulations. Water table contours and lack of vertical gradients indicated horizontal flow over most of the site. Nitrate N concentrations in water from shallow wells in WAFs averaged 30 +/- 19 mg L(-1) and delta15N ratios for nitrate N were between +20 and +25 per mil. Nitrate N concentration decreased from field-edge to streamside wells by 22 to 99%. Measurement of delta18O and delta15N enrichment of nitrate in ground water throughout the WAF-riparian system indicated that denitrification has not caused significant 15N enrichment of nitrate. Over a 24-mo period, delta15N ratios for nitrate N in the stream approached delta15N ratios for nitrate N in ground water beneath WAFs indicating delivery of some waste-derived nitrate N to the stream in shallow ground water. Nitrate N concentrations in the stream were relatively low, averaging 1 mg L(-1). Dilution of high nitrate N water in shallow horizontal flow paths with low nitrate N water from deeper horizontal flow paths at or near the stream, some denitrification as ground water discharges through the stream bottom, and some denitrification in riparian zone contributed to this low nitrate N concentration.

Comparison of CD-Rom and Internet access to clinical information.

INTRODUCTION: The New Zealand National Poisons Centre has developed an extensive clinical poisons information database, TOXINZ. This resource was originally provided on a CD-Rom, and in 2002 made accessible solely via the Internet (www.toxinz.com). It was unknown whether users would prefer the CD-Rom or Internet version to access the same information. METHODS: In September 2003 a total of 100 questionnaires were mailed to the emergency departments of 15 hospitals to be answered by medical and nursing staff utilizing the Internet version of TOXINZ. The results were then compared with a nearly identical questionnaire conducted in the same way in the same hospitals when only the CD-Rom database version was available. RESULTS: There was a 79% response rate with both medical and nursing staff rating the poisons management recommendations highly when accessed both on CD-Rom and Internet. Statistically significant differences (p<0.05, Mann-Whitney U-test) identified the Internet accessed database as: supplying better visual aids, being more repetitive, harder to search, and more difficult to print. CONCLUSION: Those developing Internet accessible databases for a healthcare environment are encouraged to incorporate robust search functionality, mobility solutions, and an ability to integrate with other healthcare applications.

Availability of antidotes, antivenoms, and antitoxins in New Zealand hospital pharmacies.

AIM: To assess the adequacy of the types and quantities of antidotes, antivenoms and antitoxins held by New Zealand hospital pharmacies. METHODS: A list of 61 antidotes, antivenoms, antitoxins and their various forms was developed following literature review and consideration of national pharmaceutical listings. An Internet-accessible survey was then developed, validated and, during the period 28 February to 7 April 2014, sent to 24 hospital pharmacies nationally for completion. Results were assessed and compared with published guidelines for adequate stocking of antidotes in hospitals that provide emergency care. RESULTS: The response rate for the survey was 100%. Wide variation in stock levels were reported with only N- acetylcysteine and octreotide held in adequate quantities by all hospitals to manage a single patient for 24 hours. While archaic compounds were still stocked, newer and more effective pharmaceuticals were not. The national replacement cost for expiring drugs was estimated at $171,024, with smaller, more isolated facilities facing the greatest expense and difficulty in achieving timely resupply. CONCLUSION: Shortcomings in the types and quantities of antidotes, antivenoms and antitoxins held by New Zealand hospital pharmacies were recognised. This situation may be improved through national rationalisation of pharmaceutical storage and supply, and implementation of a national antidote database.

Clinical utility of an electronic poisons information and clinical decision support tool.

The objective of the study was to assess the use of a computer toxicology database/clinical decision aid by clinical practitioners. The study investigated the sources that Emergency Department (ED) personnel use to obtain toxicology information and performed a quality audit of the current database. A questionnaire survey of ED staff was used in departments with access to the New Zealand Poisons Centre Substance Database (NZSD), a toxicology CD ROM computer database. Outcome measures were reported use of alternative data sources when managing clinical toxicology presentations and the qualities of the NZSD. Computer databases are commonly used for the management of clinical toxicology cases and the toxicology computer database/clinical decision aid studied is well accepted and used in Emergency Medicine practice. The users of the NZSD assessed the usability and quality of the information of the database.

Awareness, acceptability and application of paracetamol overdose management guidelines in a New Zealand emergency department.

AIM: To measure emergency physicians' awareness, acceptance, access to and application of the Australasian Paracetamol Overdose Guidelines. METHODS: A retrospective record review of 100 consecutive presentations with the complaint of paracetamol overdose to the Dunedin Hospital Emergency Department, New Zealand, from 1 December 2011 to 31 December 2012, with: comparison of management to that recommended by the Guidelines, analysis of access to both an Internet poisons information resource and the New Zealand National Poisons Centre, survey of clinical staff opinion of the Guidelines and, comparison of actual and recommended management costs at commercial laboratory rates and with application of the WHO-CHOICE unit cost estimates for service delivery. RESULTS: Response rate to the survey was 92.9% with 96.2% of responders aware of or accessing the Guidelines when managing paracetamol overdose patients (0.28% of Emergency Department encounters). Record review identified adherence to the Guidelines in 19% of patients; the greatest deviation due to increased biochemical analysis (68% of patients) at a mean cost $59.32 per patient greater than recommended - junior doctors ordering twice the cost in investigations as their seniors. Mean cost of care was calculated at $686.89 per case. CONCLUSION: The application of poisons information guidelines by front-line medical staff is limited; innovative approaches to improve adherence to clinical management recommendations need to be considered.

Use of poisons information resources and satisfaction with electronic products by Victorian emergency department staff.

OBJECTIVE: ED staff use a range of poisons information resources of varying type and quality. The present study aims to identify those resources utilised in the state of Victoria, Australia, and assess opinion of the most used electronic products. METHODS: A previously validated self-administered survey was conducted in 15 EDs, with 10 questionnaires sent to each. The survey was then repeated following the provision of a 4-month period of access to Toxinz™, an Internet poisons information product novel to the region. The study was conducted from December 2010 to August 2011. RESULTS: There were 117 (78%) and 48 (32%) responses received from the first and second surveys, respectively, a 55% overall response rate. No statistically significant differences in professional group, numbers of poisoned patients seen or resource type accessed were identified between studies. The electronic resource most used in the first survey was Poisindex® (48.68%) and Toxinz™ (64.1%) in the second. There were statistically significant (P < 0.01) improvements in satisfaction in 26 of 42 questions between surveys, and no decrements. Although the majority of responders possessed mobile devices, less than half used them for poisons information but would do so if a reputable product was available. CONCLUSION: The order of poisons information sources most utilised was: consultation with a colleague, in-house protocols and electronic resources. There was a significant difference in satisfaction with electronic poisons information resources and a movement away from existing sources when choice was provided. Interest in increased use of mobile solutions was identified.

Improving clinician-patient communication of health risks when diagnostic test information is imprecise.

Both clinicians and patients experience difficulty with the statistical reasoning required to make inferences about health states on the basis of information derived from diagnostic tests. This problem will grow in importance as we move into the era of personalised medicine where an increasing supply of imprecise diagnostic tests meets an increasing demand to use such tests on the part of intelligent but statistically innumerate clinicians and patients. We describe a user-friendly, interactive, graphical interface for calculating, visualising, and communicating accurate inferences about uncertain health states when diagnostic information (test sensitivity and specificity, and health state prevalence) is imprecise and ambiguous in its application to a specific patient. The software is free, open-source, and runs on all popular PC operating systems (Windows, Mac, Linux).