Methadone and buprenorphine-related deaths among people prescribed and not prescribed Opioid Agonist Therapy during the COVID-19 pandemic in England

BACKGROUND: The coronavirus pandemic resulted in many changes which had the potential to impact mortality related to opioid agonist therapy (OAT; methadone, buprenorphine), including changes in the prescribing and dispensing of OAT and patterns of drug availability and use. We aimed to assess the impact of the first lockdown (initiated March 23rd 2020) on methadone- and buprenorphine-related deaths in England in people both prescribed and not prescribed OAT using data from the National Programme on Substance Abuse Deaths. METHODS: This was a retrospective post-mortem toxicology study of OAT-related deaths which occurred in the 3-month period March 23rd to June 22nd in the years 2016-2020. Provisional data regarding numbers accessing treatment for opioid use disorder was provided by the National Drug Treatment Monitoring System. RESULTS: We found a 64% increase in methadone-related deaths in March to June 2020 compared to March to June 2019 (2019 n = 96; 2020 projected n = 157). There were increases in the mortality rate of both in-treatment decedents (22% increase; 2019 n = 45; an exponential smoothing model of the 2016-19 trend [α=0.5] predicted 44 deaths in 2020, 55 were reported) and decedents not prescribed methadone (74% increase; 2019 n = 46; 2016-19 trend predicted 43 deaths in 2020, 80 were reported). There was no increase in buprenorphine-related deaths (2019 n = 9/529; 2020 n = 11/566). There were no changes in the numbers of deaths where other opioids or multiple substances were detected, or in methadone levels detected. Numbers of people accessing treatment for opioid use disorder in 2020 did not decrease relative to previous years (p >0.05). CONCLUSIONS: Methadone-related deaths in non-prescribed individuals, but not prescribed individuals, increased considerably above the annual trend forecast for 2020 during the first COVID-19 lockdown in England. Further studies are thus needed to understand this difference

Drug survival of adalimumab, ustekinumab and secukinumab in patients with psoriasis: a prospective cohort study from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR).

BACKGROUND: Real-world biologic drug survival is an important proxy measure for effectiveness. Predictors of drug survival may help patients with psoriasis choose between biologic therapies. OBJECTIVES: (i) To assess the relative drug survival of adalimumab, ustekinumab and secukinumab in patients with psoriasis. (ii) To investigate predictors of biologic drug survival. METHODS: A prospective cohort study was performed in the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) between November 2007 and August 2019. We performed survival analysis and fitted a flexible parametric survival model for biologic discontinuation due to ineffectiveness. RESULTS: In total 9652 patients were included: 5543 starting on adalimumab (57·4%), 991 on secukinumab (10·3%) and 3118 on ustekinumab (32·3%). The overall drug survivals of adalimumab, secukinumab and ustekinumab in year 1 were 0·78 [95% confidence interval (CI) 0·77-0·79], 0·88 (95% CI 0·86-0·91) and 0·88 (95% CI 0·87-0·89), respectively. The adjusted hazard ratios (adjHRs) for discontinuation of adalimumab and secukinumab compared with ustekinumab were 2·11 (95% CI 1·76-2·54) and 0·67 (95% CI 0·40-1·11), respectively. The presence of psoriatic arthritis predicted for survival in the adalimumab and secukinumab cohorts (adjHR 0·67, 95% CI 0·51-0·88 and 0·70, 95% CI 0·40-1·24, respectively), but for discontinuation in the ustekinumab cohort (adjHR 1·42, 95% CI 1·12-1·81). Previous exposure to biologic therapies predicted for discontinuation in the ustekinumab and secukinumab cohorts (adjHR 1·54, 95% CI 1·26-1·89 and 1·49, 95% CI 0·91-2·45, respectively) and for survival in the adalimumab cohort (adjHR 0·71, 95% CI 0·55-0·92). CONCLUSIONS: Secukinumab and ustekinumab have similar sustained drug survival, while adalimumab has a lower drug survival in patients with psoriasis. Psoriatic arthritis and previous biologic experience were predictors with differential effects between the biologic therapies. What is already known about this topic? There is conflicting evidence over the real-world drug survival of secukinumab in patients with psoriasis. Data from registries to date suggest that secukinumab has a lower drug survival than that reported from clinical trials. What does this study add? This study found that secukinumab and ustekinumab had similar sustained drug survival in the real world, while the drug survival of adalimumab was lower, suggesting that the real-world drug survival of secukinumab is higher than previously reported. We found that psoriatic arthritis and previous biologic experience had differential effects on drug discontinuation in the three biologic cohorts. These predictors may help patients and clinicians choose the most appropriate biologic therapy

Arthroscopic Treatment of Acetabular Retroversion With Acetabuloplasty and Subspine Decompression: A Matched Comparison With Patients Undergoing Arthroscopic Treatment for Focal Pincer-Type Femoroacetabular Impingement.

BackgroundGlobal acetabular retroversion is classically treated with open reverse periacetabular osteotomy. Given the low morbidity and recent success associated with the arthroscopic treatment of femoroacetabular impingement (FAI), there may also be a role for arthroscopic treatment of acetabular retroversion. However, the safety and outcomes after hip arthroscopic surgery for retroversion need further study, and the effect of impingement from the anterior inferior iliac spine (subspine) in patients with retroversion is currently unknown.HypothesisArthroscopic treatment for global acetabular retroversion will be safe, and patients will have similar outcomes compared with a matched group undergoing arthroscopic treatment for focal pincer-type FAI.Study designCohort study; Level of evidence, 2.MethodsPatients undergoing hip arthroscopic surgery for symptomatic global acetabular retroversion were prospectively enrolled and compared with a matched group of patients undergoing arthroscopic surgery for focal pincer-type FAI. Both groups underwent the same arthroscopic treatment protocol. All patients were administered patient-reported outcome (PRO) measures, including the 12-item Short-Form Health Survey (SF-12) Physical Component Summary (PCS) and a Mental Component Summary (MCS), modified Harris Hip Score (mHHS), Hip disability and Osteoarthritis Outcome Score (HOOS), and visual analog scale (VAS) for pain preoperatively and at 1 year postoperatively.ResultsThere were no differences in age, sex, or body mass index between 39 hips treated for global acetabular retroversion and 39 hips treated for focal pincer-type FAI. There were no major or minor complications in either group. Patients who underwent arthroscopic treatment for global acetabular retroversion demonstrated similar significant improvements in postoperative PRO scores (scores increased by 17 to 43 points) as patients who underwent arthroscopic treatment for focal pincer-type FAI. Patients treated for retroversion who also underwent subspine decompression had greater improvement than patients who did not undergo subspine decompression for the HOOS-Pain (33.7 ± 15.3 vs 22.5 ± 17.6, respectively; P = .046) and HOOS-Quality of Life (49.7 ± 18.8 vs 34.6 ± 22.0, respectively; P = .030) scores.ConclusionArthroscopic treatment for acetabular retroversion is safe and provides significant clinical improvement similar to arthroscopic treatment for pincer-type FAI. Patients with acetabular retroversion who also underwent arthroscopic subspine decompression demonstrated greater improvements in pain and quality of life outcomes than those who underwent arthroscopic treatment without subspine decompression

Experimental and numerical study of strength mismatch in cross-weld tensile testing

The mechanical properties of welded boiler tubes used in power plants can be significantly altered as a result of the fabrication history, such as pre-straining and heat treatment. The primary aim of the study was to determine the effect of fabrication history on local tensile properties across the welds. This was achieved by testing cross-weld specimens machined from welded thin-walled tubes (with unstrained or pre-strained base metal) before and after heat treatment. Digital image correlation, which is a full-field strain measurement technique, was implemented in order to obtain the local stress–strain curves and to extract the corresponding local tensile properties such as offset proof stress. Evidence of strain hardening due to the constraint and thermo-mechanical cycles during the welding process was found in the heat-affected zone and evidence of softening was observed in the pre-strained base metal. It was found that the heat treatment process removed the effect of pre-straining and welding on the proof stress and the strength along the specimen was nearly homogenized. However, mapping the local stress–strain curves in the as-welded cross-weld specimens with pre-strained base metal has revealed abnormal strain relaxation with increase in load in the weld-affected region. For a better understanding of this behaviour, a tensile test of a cross-weld specimen with a large strength mismatch between the weld metal and the base metal was simulated using the finite element method. It was found that the strength mismatch in the specimen causes the development of biaxial stresses in the heat-affected zone once local yielding begins, and the use of global axial stress to construct the local stress–strain curve results in an apparent ‘reduced-strain’ anomaly. Nevertheless, for the strength mismatch ratios studied, this anomalous behaviour did not seem to significantly affect the determination of the local proof stress in the specimens

Bacterial membrane vesicles transport their DNA cargo into host cells

© 2017 The Author(s). Bacterial outer membrane vesicles (OMVs) are extracellular sacs containing biologically active products, such as proteins, cell wall components and toxins. OMVs are reported to contain DNA, however, little is known about the nature of this DNA, nor whether it can be transported into host cells. Our work demonstrates that chromosomal DNA is packaged into OMVs shed by bacteria during exponential phase. Most of this DNA was present on the external surfaces of OMVs, with smaller amounts located internally. The DNA within the internal compartments of Pseudomonas aeruginosa OMVs were consistently enriched in specific regions of the bacterial chromosome, encoding proteins involved in virulence, stress response, antibiotic resistance and metabolism. Furthermore, we demonstrated that OMVs carry DNA into eukaryotic cells, and this DNA was detectable by PCR in the nuclear fraction of cells. These findings suggest a role for OMV-associated DNA in bacterial-host cell interactions and have implications for OMV-based vaccines

Fluid dynamics - Turbulence without inertia

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62901/1/405027a0.pd

The ICAM-3/LFA-1 interaction is critical for epidermal Langerhans cell alloantigen presentation to CD4 + T cells

Intercellular adhesion molecule (ICAM)-3 is a recently described member of the immunoglobulin superfamily and, as such, is closely related to ICAM-1 and ICAM-2. All three ICAMS are cognate for the counter-receptor lymphocyte function associated antigen-1 (LFA-L CD11a/CD18). Unlike ICAM-1 and ICAM-2. ICAM-3 is constitutively expressed at high levels on resting leucocytes. We investigated the expression and function of ICAM-3 in normal skin ( n = 5), as well as its expression in psoriasis ( n = 4). atopic eczema ( n = 4), allergic (rhus) contact dermatitis ( n =3). and cutaneous T-cell lymphoma (CTCL. n =2). Five-micrometre cryostat sections of skin were stained using monoclonal antibodies to ICAM-3 and A well characterized immunoperoxidase technique. In normal skin. ICAM-3 was expressed by all cutaneous leucocytes hut most striking was the strong expression of ICAM-3 by Langerhans cells within both epidermis and dermis. This observation was confirmed by double-labelling with CD1a and negative staining with an IgG1 isotype control. In psoriasis, atopic eczema, allergic contact dermatitis, and CTCL. ICAM-3 was co-expressed on all CD1a + cells, although, in psoriasis, the intensity of ICAM-3 expression was reduced. Functional blocking experiments were performed to determine whether the observed ICAM-3 expression on Langerhans cells was functionally important in antigen presentation. CD4 + T cells were prepared from peripheral blood and 10 5 CD4 + T cells combined with 10 5 epidermal cells harvested from keratome biopsies of normal skin of an individual allogeneic to the T-cell donor. Addition of 50 Μg anti-ICAM-3 to the co-culture resulted in a consistent (50%) reduction in degree of alloantigen presentation by Langerhans cells to T cells. Inhibition was 77% of that produced by the addition of anti-LFA-1. These data indicate that ICAM-3 is constitutively expressed by Langerhans cells and is a major ligand for LFA-1 on CD4 + T cells during their response to Langerhans cells. Because fresh Langerhans ceils constitutively express little ICAM-1. whereas ICAM-3 is constitutively expressed at high levels, it would appear that 1CAM-3 is the dominant functional ICAM on in situ Langerhans cells in the normal epidermis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73969/1/j.1365-2133.1995.tb06911.x.pd

Theory of disk accretion onto supermassive black holes

Accretion onto supermassive black holes produces both the dramatic phenomena associated with active galactic nuclei and the underwhelming displays seen in the Galactic Center and most other nearby galaxies. I review selected aspects of the current theoretical understanding of black hole accretion, emphasizing the role of magnetohydrodynamic turbulence and gravitational instabilities in driving the actual accretion and the importance of the efficacy of cooling in determining the structure and observational appearance of the accretion flow. Ongoing investigations into the dynamics of the plunging region, the origin of variability in the accretion process, and the evolution of warped, twisted, or eccentric disks are summarized.Comment: Mostly introductory review, to appear in "Supermassive black holes in the distant Universe", ed. A.J. Barger, Kluwer Academic Publishers, in pres