Significant toxicity following an increase in poisonings with designer benzodiazepines in the Netherlands between 2010 and 2020

BACKGROUND: Designer benzodiazepines (DBs) are an emerging class of new psychoactive substances. While structurally derived from pharmaceutical benzodiazepines, their toxicological profile is less clear. We investigated time trends in the rate of DB poisonings and their clinical toxicity. METHODS: A retrospective observational study was performed on the incidence rate of DB poisonings, relative to all recreational drug poisonings reported to the Dutch Poisons Information Center (DPIC) from 2010 to 2020. Time-trend analysis was performed using Poisson regression. A prospective cohort study was performed on toxicity of DBs, including the Poisoning Severity Score, from January 2016-June 2019. Data was collected through telephone interviews. RESULTS: Between 2010 and 2020, the DPIC was consulted on 142 DB exposures. The incidence rate of DB exposures increased from 0.1% to 4.3%, with a year effect estimate of 1.35 (95% CI [1.14;1.54]). Twenty different DBs were reported, mostly etizolam (33%), clonazolam (17%), and flunitrazolam (8%). During consultation (often shortly after exposure), poisoning was graded moderate-severe in 29% of cases (n = 146). In the prospective cohort sample with follow-up (n = 22), 86% of cases (n = 19) showed a moderate-severe poisoning. The severity of poisoning did not differ between mono- and mixed intoxications. Frequently reported symptoms in the prospective cohort sample included drowsiness (86%), confusion (59%), and agitation (55%). Coma was observed in seven cases (32%) and respiratory depression requiring mechanical ventilation in five cases (23%). CONCLUSION: The rate of DB poisonings reported to the DPIC strongly increased from 2010 to 2020, indicating increased (ab)use of DBs. Most DB exposures resulted in moderate-severe toxicity with neurological effects

High Incidence of Signs of Neuropathy and Self-Reported Substance Use Disorder for Nitrous Oxide in Patients Intoxicated with Nitrous Oxide

Introduction: The number of patients with excessive nitrous oxide (N2O) use and neurological disorders has been rising, indicating an addictive potential of N2O. We studied the incidence of self-reported substance use disorder (SUD)-related symptoms, signs of neuropathy, and the patterns of use in N2O-intoxicated patients. Methods: The Dutch Poisons Information Center (DPIC) provides information by telephone on the management of intoxications to healthcare professionals. Retrospective data on signs of neuropathy and patterns of use were collected for all N2O intoxications reported to the DPIC in 2021 and 2022. Frequent and heavy use were self-reported as "often/frequent/weekly use"and as "use of tanks or >50 balloons/session,"respectively. From this cohort, we included patients with excessive N2O use or signs of neuropathy in a prospective observational cohort study. Online surveys were sent 1 week, 1 month, and 3 months after DPIC consultation. The survey included the drug use disorder questionnaire (validated to measure self-reported substance abuse [SA] and substance dependence [SD] based on Diagnostic and Statistical Manual of Mental Disorders [DSM]-IV-TR criteria) and questions on patterns of use and signs of neuropathy. DSM-IV-TR criteria were translated to DSM-V criteria to score for mild, moderate, or severe SUD, with 2-3, 4-5, or ≥6 symptoms, respectively. Results: We included 101 N2O-intoxicated patients in the retrospective study. Of these, 41% showed signs of neuropathy (N = 41), 53% used N2O tanks to fill balloons (N = 53), 71% used them frequently (N = 72), and 76% used them heavily (N = 77). We included 75 patients in the prospective study and 10 (13%) completed the first survey. All 10 patients fulfilled the criteria for SA and SD (DSM-IV-TR, median number of questions answered "yes"= 10/12), all used N2O tanks to fill balloons, and 90% (N = 9) experienced signs of neuropathy. After 1 and 3 months, 6/7 and 1/1 patients, respectively, continued to fulfill SA and SD criteria. Translating to DSM-V criteria, 1/10 patients fulfilled the criteria for (self-reported) mild SUD, 1/10 patients for moderate SUD, and 8/10 patients for severe SUD, 1 week after consultation. Conclusion: The high proportion of N2O-intoxicated patients reporting frequent and heavy use of N2O indicates an addictive potential of N2O. Although follow-up rate was low, all patients fulfilled self-reported SA, SD (DSM-IV-TR), and SUD (DSM-V) criteria for N2O. Somatic healthcare professionals treating patients with N2O intoxications should be aware of possible addictive behavior in patients. The screening, brief intervention, and referral to treatment approach should be considered to treat patients with self-reported SUD symptoms

Characterizations of how species mediate ecosystem properties require more comprehensive functional effect descriptors

The importance of individual species in mediating ecosystem process and functioning is generally accepted, but categorical descriptors that summarize species-specific contributions to ecosystems tend to reference a limited number of biological traits and underestimate the importance of how organisms interact with their environment. Here, we show how three functionally contrasting sediment-dwelling marine invertebrates affect fluid and particle transport - important processes in mediating nutrient cycling - and use high-resolution reconstructions of burrow geometry to determine the extent and nature of biogenic modification. We find that individual functional effect descriptors fall short of being able to adequately characterize how species mediate the stocks and flows of important ecosystem properties and that, in contrary to common practice and understanding, they are not substitutable with one another because they emphasize different aspects of species activity and behavior. When information derived from these metrics is combined with knowledge of how species behave and modify their environment, however, detailed mechanistic information emerges that increases the likelihood that a species functional standing will be appropriately summarized. Our study provides evidence that more comprehensive functional effect descriptors are required if they are to be of value to those tasked with projecting how altered biodiversity will influence future ecosystems

Facial-muscle weakness, speech disorders and dysphagia are common in patients with classic infantile Pompe disease treated with enzyme therapy

Classic infantile Pompe disease is an inherited generalized glycogen storage disorder caused by deficiency of lysosomal acid α-glucosidase. If left untreated, patients die before one year of age. Although enzyme-replacement therapy (ERT) has significantly prolonged lifespan, it has also revealed new aspects of the disease. For up to 11 years, we investigated the frequency and consequences of facial-muscle weakness, speech disorders and dysphagia in long-term survivors. Sequential photographs were used to determine the timing and severity of facial-muscle weakness. Using standardized articulation tests and fibreoptic endoscopic evaluation of swallowing, we investigated speech and swallowing function in a subset of patients. This study included 11 patients with classic infantile Pompe disease. Median age at the start of ERT was 2.4 months (range 0.1-8.3 months), and median age at the end of the study was 4.3 years (range 7.7 months −12.2 years). All patients developed facial-muscle weakness before the age of 15 months. Speech was studied in four patients. Articulation was disordered, with hypernasal resonance and reduced speech intelligibility in all four. Swallowing function was studied in six patients, the most important findings being ineffective swallowing with residues of food (5/6), penetration or aspiration (3/6), and reduced pharyngeal and/or laryngeal sensibility (2/6). We conclude that facial-muscle weakness, speech disorders and dysphagia are common in long-term survivors receiving ERT for classic infantile Pompe disease. To improve speech and reduce the risk for aspiration, early treatment by a speech therapist and regular swallowing assessments are recommended

High-temperature superconducting screens for magnetic field-error cancellation in accelerator magnets

Accelerators magnets must have minimal magnetic field imperfections to reduce particle-beam instabilities. In the case of coils made of high-temperature superconducting (HTS) tapes, the magnetization due to persistent currents adds an undesired field contribution, potentially degrading the magnetic field quality. In this paper we study the use of superconducting screens based on HTS tapes for reducing the magnetic field imperfections in accelerator magnets. The screens exploit the magnetization by persistent currents to cancel out the magnetic field error. The screens are aligned with the main field component, such that only the undesired field components are compensated. The screens are self-regulating, and do not require any externally applied source of energy. Measurements in liquid nitrogen at 77 K show for dipole-field configurations a significant reduction of the magnetic field error up to a factor of four. The residual error is explained via numerical simulations accounting for the geometric defects in the HTS screens, achieving satisfactory agreement with experimental results. Simulations show that if screens are increased in width and thickness, and operated at 4.5 K, field errors may be eliminated almost entirely for the typical excitation cycles of accelerator magnets

Resource Quantity Affects Benthic Microbial Community Structure and Growth Efficiency in a Temperate Intertidal Mudflat

Estuaries cover <1% of marine habitats, but the carbon dioxide (CO2) effluxes from these net heterotrophic systems contribute significantly to the global carbon cycle. Anthropogenic eutrophication of estuarine waterways increases the supply of labile substrates to the underlying sediments. How such changes affect the form and functioning of the resident microbial communities remains unclear. We employed a carbon-13 pulse-chase experiment to investigate how a temperate estuarine benthic microbial community at 6.5°C responded to additions of marine diatom-derived organic carbon equivalent to 4.16, 41.60 and 416.00 mmol C m−2. The quantities of carbon mineralized and incorporated into bacterial biomass both increased significantly, albeit differentially, with resource supply. This resulted in bacterial growth efficiency increasing from 0.40±0.02 to 0.55±0.04 as substrates became more available. The proportions of diatom-derived carbon incorporated into individual microbial membrane fatty acids also varied with resource supply. Future increases in labile organic substrate supply have the potential to increase both the proportion of organic carbon being retained within the benthic compartment of estuaries and also the absolute quantity of CO2 outgassing from these environments

The Dutch chronic lower limb-threatening ischemia registry (THRILLER): A study protocol for popliteal and infrapopliteal endovascular interventions

INTRODUCTION: Chronic limb-threatening ischemia (CLTI) is the end stage of peripheral arterial disease (PAD) and is associated with high amputation rates, mortality and disease-related health care costs. In infrapopliteal arterial disease (IPAD), endovascular revascularization should be considered for the majority of anatomical and clinical subgroups of CLTI. However, a gap of high-quality evidence exists in this field. The aim of the Dutch Chronic Lower Limb-Threatening Ischemia Registry (THRILLER) is to collect real world data on popliteal and infrapopliteal endovascular interventions. METHODS: THRILLER is a clinician-driven, prospective, multicenter, observational registry including all consecutive patients that undergo a popliteal or infrapopliteal endovascular intervention in seven Dutch hospitals. We estimate that THRILLER will include 400-500 interventions annually. Standardized follow-up visits with wound monitoring, toe pressure measurement and duplex ultrasonography will be scheduled at 6-8 weeks and 12 months after the intervention. The independent primary endpoints are primary patency, limb salvage and amputation free survival. Patients must give informed consent before participation and will be included according to predefined reporting standards. A data log of patients who meet the inclusion criteria but are not included in the registry will be maintained. We intend to conduct the first interim analysis two years after the start of inclusion. The results will be published in a scientific journal. DISCUSSION: Despite innovations in medical therapy and revascularization techniques, patients with CLTI undergoing endovascular revascularization still have a moderate prognosis. Previous prospective cohort studies were hampered by small sample sizes or heterogeneous reporting. Randomized controlled trials (RCTs) have high costs, potential conflicts of interest and give a limited reflection of daily practice. THRILLER aims to provide the largest prospective well phenotyped up-to-date dataset on treatment outcomes in CLTI patients to answer multiple underexplored research questions regarding diagnostics, medication, patient selection, treatment strategies and post intervention follow-up

First Cold Powering Test of REBCO Roebel Wound Coil for the EuCARD2 Future Magnet Development Project

EuCARD-2 is a project partly supported by FP7-European Commission aiming at exploring accelerator magnet technology for 20 T dipole operating field. The EuCARD-2 collaboration is liaising with similar programs for high field magnets in the USA and Japan. EuCARD-2 focuses, through the work-package 10 'Future magnets,' on the development of a 10 kA-class superconducting, high current density cable suitable for accelerator magnets, for a 5 T stand-alone dipole of 40 mm bore and about 1 m length. After standalone testing, the magnet will possibly be inserted in a large bore background dipole, to be tested at a peak field up to 18 T. This paper starts by reporting on a few of the highlight simulations that demonstrate the progress made in predicting: dynamic current distribution and influence on field quality, complex quench propagation between tapes, and minimum quench energy in the multitape cable. The multiphysics output importantly helps predicting quench signals and guides the development of the novel early detection systems. Knowing current position within individual tapes of each cable we present stress distribution throughout the coils. We report on the development of the mechanical component and assembly processes selected for Feather-M2 the 5 T EuCARD2 magnet. We describe the CERN variable temperature flowing helium cold gas test system. We describe the parallel integration of the FPGA early quench detection system, using pickup coils and temperature sensors, alongside the standard CERN magnet quench detection system using voltage taps. Finally we report on the first cold tests of the REBCO 10 kA class Roebel subscale coil named Feather-M0

German evidence-based guidelines for the treatment of Psoriasis vulgaris (short version)

Psoriasis vulgaris is a common and chronic inflammatory skin disease which has the potential to significantly reduce the quality of life in severely affected patients. The incidence of psoriasis in Western industrialized countries ranges from 1.5 to 2%. Despite the large variety of treatment options available, patient surveys have revealed insufficient satisfaction with the efficacy of available treatments and a high rate of medication non-compliance. To optimize the treatment of psoriasis in Germany, the Deutsche Dermatologische Gesellschaft and the Berufsverband Deutscher Dermatologen (BVDD) have initiated a project to develop evidence-based guidelines for the management of psoriasis. The guidelines focus on induction therapy in cases of mild, moderate, and severe plaque-type psoriasis in adults. The short version of the guidelines reported here consist of a series of therapeutic recommendations that are based on a systematic literature search and subsequent discussion with experts in the field; they have been approved by a team of dermatology experts. In addition to the therapeutic recommendations provided in this short version, the full version of the guidelines includes information on contraindications, adverse events, drug interactions, practicality, and costs as well as detailed information on how best to apply the treatments described (for full version, please see Nast et al., JDDG, Suppl 2:S1–S126, 2006; or http://www.psoriasis-leitlinie.de)

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.