Securing Safe Supply During COVID-19 and Beyond: Scoping Review and Knowledge Mobilization

Background Safe supply is defined as the legal and regulated provision of drugs with mind and/or body altering properties that have been typically accessible only through the illegal drug market. In response to the coronavirus disease 2019 (COVID-19) pandemic and related social/physical distancing measures, efforts have been made to scale up and increase access to safe supply programs in an effort to reduce overdose and other drug- and drug policy-related risks. However, it remains unclear whether these efforts taken thus far have meaningfully mitigated the barriers to safe supply experienced by People Who Use Drugs (PWUD), both during and beyond the context of COVID-19. We thus undertook a scoping review to identify key concepts, strategies and gaps in evidence with respect to the provision of safe supply during pandemics and other emergencies. Methods We conducted three searches across Scopus, Medline, Embase, CINAHL, and The Cochrane Central Register of Controlled Trials (CENTRAL) for peer-reviewed and grey literature articles to understand barriers/facilitators to both accessing and prescribing legal, pharmaceutical-grade drugs, including opioids, benzodiazepines, and/or stimulants during public health emergencies from January 1 2002 to June 30 2020. We also included opioid agonist therapies (OAT) during emergency conditions. All potential sources underwent title/abstract screening and duplicate full- text review to determine eligibility for inclusion. Three reviewers extracted characteristics and barriers/facilitators to accessing or prescribing drugs for each study, and these were then inductively analyzed to identify common themes. Key stakeholders (PWUD, prescribers, and policymakers/regulators) informed the search strategy and validated findings and interpretations. Input from PWUD and prescribers was gathered through Advisory Committee meetings and one-on-one consultations, respectively. Results We screened 9,839 references and included 169 studies (135 peer-reviewed articles and 36 grey literature reports). From 119 articles, we identified 35 themes related to barriers/facilitators to prescribing safe supply or OAT. Few studies (n=24) focused on emergency or pandemic contexts. Among the most frequently reported barriers were restrictive laws or policies (n= 33; 28%). The most frequently cited facilitator was temporary legal or regulatory exemptions (n= 16; 13%). Further stakeholder consultation identified barriers/facilitators to safe supply absent in the reviewed literature: PWUD reported barriers including lack of access to desired substances, concerns about child apprehension, and a lack of cultural competency within safe supply/OAT programs; prescribers reported barriers including regional differences in service delivery, colleague support, and a lack of, or disagreement between, clinical guidance documents. Conclusion We identified multiple barriers and facilitators to accessing and/or prescribing safe supply or OAT. With few peer-reviewed studies on safe supply models, particularly in the context of emergencies, input from PWUD and other stakeholders offered crucial insights not reflected in the existing literature. To address the overdose epidemic stemming from the criminalization of an unregulated drug supply, prescribers, regulators, and public health authorities should focus on scaling up, and then evaluating, diverse safe supply frameworks that address the facilitators and barriers we have identified

Leukotriene B-4-Neutrophil Elastase Axis Drives Neutrophil Reverse Transendothelial Cell Migration In Vivo

This work was supported by generous funds from the Wellcome Trust (098291/Z/12/Z to S.N.). T.C. was supported by the ERC (ENDHORET). The work was also supported in part by funds from the William Harvey Research Foundation

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

It is time for us all to embrace person-centred language for people in prison and people who were formerly in prison

The use of person-centred language is well accepted regarding substance use and infectious disease healthcare and research, and appropriate acronyms have become commonplace, e.g., “people who inject drugs (PWID) ”has mostly replaced phrases like “injecting drugs users ”. However, the use of the term’s ‘prisoner’ or ‘prisoners’ remains common. Although less common, terms such as ‘offenders’ and ‘inmates’ are also still used on occasion. This persists despite calls from people with lived experience of incarceration, and fellow academics, to stop using these terms. Given the considerable overlap between substance use, infectious diseases, and incarceration, in this commentary we discuss how they interact, including the stigma that is common to each. We propose that using person-centred language (i.e., people in prison or people formerly in prison) needs to become the default language used when presenting research related to people in prison or people formerly in prison. This is a much- needed step in efforts to overcome the continued stigma that people in prison face while incarcerated from prison officers and other employees, including healthcare providers. Likewise, overcoming stigma, including legalised discrimination, that follows people who were formerly in prison upon gaining their freedom is critical, as this impacts their health and related social determinants, including employment and housing

BRAND: A platform for closed-loop experiments with deep network models.

Objective.Artificial neural networks (ANNs) are state-of-the-art tools for modeling and decoding neural activity, but deploying them in closed-loop experiments with tight timing constraints is challenging due to their limited support in existing real-time frameworks. Researchers need a platform that fully supports high-level languages for running ANNs (e.g. Python and Julia) while maintaining support for languages that are critical for low-latency data acquisition and processing (e.g. C and C++).Approach.To address these needs, we introduce the Backend for Realtime Asynchronous Neural Decoding (BRAND). BRAND comprises Linux processes, termednodes, which communicate with each other in agraphvia streams of data. Its asynchronous design allows for acquisition, control, and analysis to be executed in parallel on streams of data that may operate at different timescales. BRAND uses Redis, an in-memory database, to send data between nodes, which enables fast inter-process communication and supports 54 different programming languages. Thus, developers can easily deploy existing ANN models in BRAND with minimal implementation changes.Main results.In our tests, BRAND achieved <600 microsecond latency between processes when sending large quantities of data (1024 channels of 30 kHz neural data in 1 ms chunks). BRAND runs a brain-computer interface with a recurrent neural network (RNN) decoder with less than 8 ms of latency from neural data input to decoder prediction. In a real-world demonstration of the system, participant T11 in the BrainGate2 clinical trial (ClinicalTrials.gov Identifier: NCT00912041) performed a standard cursor control task, in which 30 kHz signal processing, RNN decoding, task control, and graphics were all executed in BRAND. This system also supports real-time inference with complex latent variable models like Latent Factor Analysis via Dynamical Systems.Significance.By providing a framework that is fast, modular, and language-agnostic, BRAND lowers the barriers to integrating the latest tools in neuroscience and machine learning into closed-loop experiments

Association of baseline hematoma and edema volumes with one-year outcome and long-term survival after spontaneous intracerebral hemorrhage: A community-based inception cohort study

Background Hospital-based studies have reported variable associations between outcome after spontaneous intracerebral hemorrhage and peri-hematomal edema volume. Aims In a community-based study, we aimed to investigate the existence, strength, direction, and independence of associations between intracerebral hemorrhage and peri-hematomal edema volumes on diagnostic brain CT and one-year functional outcome and long-term survival. Methods We identified all adults, resident in Lothian, diagnosed with first-ever, symptomatic spontaneous intracerebral hemorrhage between June 2010 and May 2013 in a community-based, prospective inception cohort study. We defined regions of interest manually and used a semi-automated approach to measure intracerebral hemorrhage volume, peri-hematomal edema volume, and the sum of these measurements (total lesion volume) on first diagnostic brain CT performed at ≤3 days after symptom onset. The primary outcome was death or dependence (scores 3–6 on the modified Rankin Scale) at one-year after intracerebral hemorrhage. Results Two hundred ninety-two (85%) of 342 patients (median age 77.5 y, IQR 68–83, 186 (54%) female, median time from onset to CT 6.5 h (IQR 2.9–21.7)) were dead or dependent one year after intracerebral hemorrhage. Peri-hematomal edema and intracerebral hemorrhage volumes were colinear ( R2 = 0.77). In models using both intracerebral hemorrhage and peri-hematomal edema, 10 mL increments in intracerebral hemorrhage (adjusted odds ratio (aOR) 1.72 (95% CI 1.08–2.87); p = 0.029) but not peri-hematomal edema volume (aOR 0.92 (0.63–1.45); p = 0.69) were independently associated with one-year death or dependence. 10 mL increments in total lesion volume were independently associated with one-year death or dependence (aOR 1.24 (1.11–1.42); p = 0.0004). Conclusion Total volume of intracerebral hemorrhage and peri-hematomal edema, and intracerebral hemorrhage volume alone on diagnostic brain CT, undertaken at three days or sooner, are independently associated with death or dependence one-year after intracerebral hemorrhage, but peri-hematomal edema volume is not. Data access statement Anonymized summary data may be requested from the corresponding author. </jats:sec

Biological Flora of the British Isles: Eryngium maritimum

Summary 1. This account presents information on all aspects of the biology of Eryngium maritimum L. (Sea Holly) that are relevant to understanding its ecological characteristics and behaviour. The main topics are presented within the standard framework of the Biological Flora of the British Isles: distribution, habitat, communities, responses to biotic factors, responses to environment, structure and physiology, phenology, floral and seed characters, herbivores and disease, history and conservation. 2. Eryngium maritimum is a native perennial hemicryptophyte, with a large taproot, spiny and leathery leaves and a pale bluish inflorescence. It has a more or less continuous distribution in suitable habitats along the coasts of Great Britain and Ireland up to about 55° N, but it is more scattered further north. On the west coast, it is found south of the Hebrides, and on the east coast, with some exceptions, south of Yorkshire. In Europe, it has a wide, but mainly southern temperate, European distribution along the coasts of the Atlantic Ocean, the Baltic, the Mediterranean, and the Black and Azov Seas. Its northern distribution limit is at c. 60° N. 3. Eryngium maritimum grows typically on sand and shingle beaches, foredunes and yellow dunes, as well as in semi-fixed grey dunes. Its habitats have full sunlight and are more or less dry. It occurs in many coastal plant communities from the beach inland, and because of its wide European distribution, it occurs with members of several different biogeographical species groups. 4. Protected from grazing by its spininess and sclerophylly, E. maritimum is nevertheless vulnerable to direct damage by trampling. It supports few insect herbivores, probably because of chemical defences. Historically, it has had a great number of medicinal uses. 5. Eryngium maritimum is unable to withstand competition from faster and more densely growing plant species. In many coastal regions, in both temperate and mediterranean parts of Europe, it is one of the rarest and most threatened plant species, mainly because of habitat loss and land-use changes

Long-term efficacy and safety of eculizumab in Japanese patients with generalized myasthenia gravis: A subgroup analysis of the REGAIN open-label extension study

The terminal complement inhibitor eculizumab was shown to improve myasthenia gravis-related symptoms in the 26-week, phase 3, randomized, double-blind, placebo-controlled REGAIN study (NCT01997229). In this 52-week sub-analysis of the open-label extension of REGAIN (NCT02301624), eculizumab's efficacy and safety were assessed in 11 Japanese and 88 Caucasian patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. For patients who had received placebo during REGAIN, treatment with open-label eculizumab resulted in generally similar outcomes in the Japanese and Caucasian populations. Rapid improvements were maintained for 52 weeks, assessed by change in score from open-label extension baseline to week 52 (mean [standard error]) using the following scales (in Japanese and Caucasian patients, respectively): Myasthenia Gravis Activities of Daily Living (−2.4 [1.34] and − 3.3 [0.65]); Quantitative Myasthenia Gravis (−2.9 [1.98] and − 4.3 [0.79]); Myasthenia Gravis Composite (−4.5 [2.63] and − 4.9 [1.19]); and Myasthenia Gravis Quality of Life 15-item questionnaire (−8.6 [5.68] and − 6.5 [1.93]). Overall, the safety of eculizumab was consistent with its known safety profile. In this interim sub-analysis, the efficacy and safety of eculizumab in Japanese and Caucasian patients were generally similar, and consistent with the overall REGAIN population