Buprenorphine versus dihydrocodeine for opiate detoxification in primary care: a randomised controlled trial

Background Many drug users present to primary care requesting detoxification from illicit opiates. There are a number of detoxification agents but no recommended drug of choice. The purpose of this study is to compare buprenorphine with dihydrocodeine for detoxification from illicit opiates in primary care. Methods Open label randomised controlled trial in NHS Primary Care (General Practices), Leeds, UK. Sixty consenting adults using illicit opiates received either daily sublingual buprenorphine or daily oral dihydrocodeine. Reducing regimens for both interventions were at the discretion of prescribing doctor within a standard regimen of not more than 15 days. Primary outcome was abstinence from illicit opiates at final prescription as indicated by a urine sample. Secondary outcomes during detoxification period and at three and six months post detoxification were recorded. Results Only 23% completed the prescribed course of detoxification medication and gave a urine sample on collection of their final prescription. Risk of non-completion of detoxification was reduced if allocated buprenorphine (68% vs 88%, RR 0.58 CI 0.35–0.96, p = 0.065). A higher proportion of people allocated to buprenorphine provided a clean urine sample compared with those who received dihydrocodeine (21% vs 3%, RR 2.06 CI 1.33–3.21, p = 0.028). People allocated to buprenorphine had fewer visits to professional carers during detoxification and more were abstinent at three months (10 vs 4, RR 1.55 CI 0.96–2.52) and six months post detoxification (7 vs 3, RR 1.45 CI 0.84–2.49). Conclusion Informative randomised trials evaluating routine care within the primary care setting are possible amongst drug using populations. This small study generates unique data on commonly used treatment regimens

Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision

Glutaric aciduria type 1 is a rare inherited neurometabolic disorder of lysine metabolism caused by pathogenic gene variations in GCDH (cytogenic location: 19p13.13), resulting in deficiency of mitochondrial glutaryl-CoA dehydrogenase (GCDH) and, consequently, accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid and glutarylcarnitine detectable by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Depending on residual GCDH activity, biochemical high and low excreting phenotypes have been defined. Most untreated individuals present with acute onset of striatal damage before age 3 (to 6) years, precipitated by infectious diseases, fever or surgery, resulting in irreversible, mostly dystonic movement disorder with limited life expectancy. In some patients, striatal damage develops insidiously. In recent years, the clinical phenotype has been extended by the finding of extrastriatal abnormalities and cognitive dysfunction, preferably in the high excreter group, as well as chronic kidney failure. Newborn screening is the prerequisite for pre-symptomatic start of metabolic treatment with low lysine diet, carnitine supplementation and intensified emergency treatment during catabolic episodes, which, in combination, have substantially improved neurologic outcome. In contrast, start of treatment after onset of symptoms cannot reverse existing motor dysfunction caused by striatal damage. Dietary treatment can be relaxed after the vulnerable period for striatal damage, that is, age 6 years. However, impact of dietary relaxation on long-term outcomes is still unclear. This third revision of evidence-based recommendations aims to re-evaluate previous recommendations (Boy et al., J Inherit Metab Dis, 2017;40(1):75-101; Kolker et al., J Inherit Metab Dis 2011;34(3):677-694; Kolker et al., J Inherit Metab Dis, 2007;30(1):5-22) and to implement new research findings on the evolving phenotypic diversity as well as the impact of non-interventional variables and treatment quality on clinical outcomes

The future of zoonotic risk prediction

In the light of the urgency raised by the COVID-19 pandemic, global investment in wildlife virology is likely to increase, and new surveillance programmes will identify hundreds of novel viruses that might someday pose a threat to humans. To support the extensive task of laboratory characterization, scientists may increasingly rely on data-driven rubrics or machine learning models that learn from known zoonoses to identify which animal pathogens could someday pose a threat to global health. We synthesize the findings of an interdisciplinary workshop on zoonotic risk technologies to answer the following questions. What are the prerequisites, in terms of open data, equity and interdisciplinary collaboration, to the development and application of those tools? What effect could the technology have on global health? Who would control that technology, who would have access to it and who would benefit from it? Would it improve pandemic prevention? Could it create new challenges? This article is part of the theme issue 'Infectious disease macroecology: parasite diversity and dynamics across the globe'.Peer reviewe

Harnessing the biodiversity value of Central and Eastern European farmland

A large proportion of European biodiversity today depends on habitat provided by low-intensity farming practices, yet this resource is declining as European agriculture intensifies. Within the European Union, particularly the central and eastern new member states have retained relatively large areas of species-rich farmland, but despite increased investment in nature conservation here in recent years, farmland biodiversity trends appear to be worsening. Although the high biodiversity value of Central and Eastern European farmland has long been reported, the amount of research in the international literature focused on farmland biodiversity in this region remains comparatively tiny, and measures within the EU Common Agricultural Policy are relatively poorly adapted to support it. In this opinion study, we argue that, 10years after the accession of the first eastern EU new member states, the continued under-representation of the low-intensity farmland in Central and Eastern Europe in the international literature and EU policy is impeding the development of sound, evidence-based conservation interventions. The biodiversity benefits for Europe of existing low-intensity farmland, particularly in the central and eastern states, should be harnessed before they are lost. Instead of waiting for species-rich farmland to further decline, targeted research and monitoring to create locally appropriate conservation strategies for these habitats is needed now.Peer reviewe

The Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) prisons project: a randomised controlled trial comparing dihydrocodeine and buprenorphine for opiate detoxification

<p>Abstract</p> <p>Background</p> <p>Many opiate users entering British prisons require prescribed medication to help them achieve abstinence. This commonly takes the form of a detoxification regime. Previously, a range of detoxification agents have been prescribed without a clear evidence base to recommend a drug of choice. There are few trials and very few in the prison setting. This study compares dihydrocodeine with buprenorphine.</p> <p>Methods</p> <p>Open label, pragmatic, randomised controlled trial in a large remand prison in the North of England. Ninety adult male prisoners requesting an opiate detoxification were randomised to receive either daily sublingual buprenorphine or daily oral dihydrocodeine, given in the context of routine care. All participants gave written, informed consent. Reducing regimens were within a standard regimen of not more than 20 days and were at the discretion of the prescribing doctor. Primary outcome was abstinence from illicit opiates as indicated by a urine test at five days post detoxification. Secondary outcomes were collected during the detoxification period and then at one, three and six months post detoxification. Analysis was undertaken using relative risk tests for categorical data and unpaired t-tests for continuous data.</p> <p>Results</p> <p>64% of those approached took part in the study. 63 men (70%) gave a urine sample at five days post detoxification. At the completion of detoxification, by intention to treat analysis, a higher proportion of people allocated to buprenorphine provided a urine sample negative for opiates (abstinent) compared with those who received dihydrocodeine (57% vs 35%, RR 1.61 CI 1.02–2.56). At the 1, 3 and 6 month follow-up points, there were no significant differences for urine samples negative for opiates between the two groups. Follow up rates were low for those participants who had subsequently been released into the community.</p> <p>Conclusion</p> <p>These findings would suggest that dihydrocodeine should not be routinely used for detoxification from opiates in the prison setting. The high relapse rate amongst those achieving abstinence would suggest the need for an increased emphasis upon opiate maintenance programmes in the prison setting.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN07752728</p

Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration: A united approach

Item does not contain fulltextCerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE)

The future of zoonotic risk prediction

In the light of the urgency raised by the COVID-19 pandemic, global investment in wildlife virology is likely to increase, and new surveillance programmes will identify hundreds of novel viruses that might someday pose a threat to humans. To support the extensive task of laboratory characterization, scientists may increasingly rely on data-driven rubrics or machine learning models that learn from known zoonoses to identify which animal pathogens could someday pose a threat to global health. We synthesize the findings of an interdisciplinary workshop on zoonotic risk technologies to answer the following questions. What are the prerequisites, in terms of open data, equity and interdisciplinary collaboration, to the development and application of those tools? What effect could the technology have on global health? Who would control that technology, who would have access to it and who would benefit from it? Would it improve pandemic prevention? Could it create new challenges? This article is part of the theme issue ‘Infectious disease macroecology: parasite diversity and dynamics across the globe’.NSF BII 2021909; the University of Toronto EEB Fellowship; the Wellcome Trust; the National Institute of Allergy and Infectious Diseases of the National Institutes of Health and the Defense Threat Reduction Agency.http://rstb.royalsocietypublishing.orgam2022Medical Virolog

Effects of different energy cropping systems on plant diversity in Central German agricultural landscapes

Der große Artenreichtum der mitteleuropäischen Kulturlandschaften ist zu weiten Teilen unmittelbar von bestimmten extensiven Formen der Landbewirtschaftung abhängig. Vielfältige, artenreiche Biozönosen waren und sind ein wichtiger Bestandteil landwirtschaftlicher Nutzflächen. Sie haben sich seit dem Neolithikum im Wechselspiel mit den landwirtschaftlichen Wirtschaftsweisen kontinuierlich weiterentwickelt. Erst als synthetische Pflanzenschutzmittel, Mineraldünger und leistungsstarke Landmaschinen in der zweiten Hälfte des 20. Jahrhunderts weite Verbreitung erfuhren, setzte ein bis dato beispielloser, stetiger und schneller Rückgang der Artenvielfalt von Äckern, Wiesen und Weiden ein. Trotz politischer Absichtserklärungen den raschen Artenschwund zu stoppen, hat sich der Druck auf die verbleibenden Populationen auch in den letzten Jahren weiter erhöht. Der Klimawandel und der Wunsch die Abhängigkeit von endlichen fossilen Energieträgern zu reduzieren, haben dazu geführt, dass die Nachfrage nach Ackerland zum Anbau von Energiepflanzen, bedingt durch einschlägige Subventionen, stark gestiegen ist. Nur wenige wissenschaftliche Publikationen haben sich bisher mit den Folgen der schnellen Ausweitung des Energiepflanzenanbaus Ackerflora beschäftigt. Diese Dissertation soll dazu beitragen, diese Lücke durch Untersuchungen der Habitatbedingungen (Bewirtschaftungsmethoden, Lichtklima im Bestand, Bodenchemie) und der Phytodiversität in verschiedenen Energiepflanzenbeständen (Silomais zur Biogaserzeugung, Winterraps zur Biodieselherstellung, Kurzumtriebsplantagen (KUP) aus Pappeln oder Weiden zur Hackschnitzelverbrennung) zu schließen. Die Energiepflanzenbestände wurden zudem mit konventionellem Wintergetreide zur Nahrungs- und Futtermittelproduktion (Winterweizen und -gerste) und mit extensiven Weizenbeständen aus Agrarumweltmaßnahmen (AUM) verglichen. Die Untersuchungsergebnisse weisen eindeutig darauf hin, dass die eigentlichen Ursachen des starken Phytodiversitätsverlustes auf Äckern weiter reichen und grundlegender sind als der Anbau von Energiepflanzen. Es wurde gezeigt, dass die Phytozönosen im Inneren von Bioenergiemais- und Rapsäckern sowie auch in Wintergetreidebeständen extrem verarmt sind (im Mittel 3–6 Arten 100 m 2). Die durchschnittliche Stickstoffdüngung (195 kg N ha-1 a-1) und der Herbizidbehandlungsindex (HI = 1.8) waren sowohl in Mais- als auch in Winterweizenbeständen ähnlich hoch. Eine Bedrohung für die Pflanzenartenvielfalt durch übermäßige Phosphatdüngung (im Mittel 96 kg P2O5 ha-1 a-1) wurde jedoch vor allem beim Maisanbau festgestellt. Zudem war die Beschattung in Maisbeständen erhöht (11 % PAR Transmissivität im Vergleich zu 19 % in Wintergetreide), was mit einem Rückgang der mittleren Artenzahlen am Feldrand einherging (11 Arten 100 m-2 im Mais, 15 Arten 100 m-2 in Wintergetreide). Die Pflanzengesellschaften konventioneller Äcker wurden regionsübergreifend von nur 5–10 häufigen Problemunkrautarten dominiert. Maisbestände wiesen als Sommerkulturen eine von Winterkulturen leicht abweichende Artenzusammensetzung auf. Eine ausgeglichene Mischung von konventionellem Mais, Winterraps und Wintergetreide in der Agrarlandschaft bietet mehr Arten einen geeigneten Lebensraum als jede dieser Kulturen für sich genommen. Insgesamt waren die Habitatbedingungen auf den im Rahmen von AUM extensiv bewirtschafteten Äckern jedoch wesentlich heterogener und boten einer weitaus größeren Zahl von Pflanzenarten (darunter auch seltene und bedrohte Taxa) geeignete Lebensbedingungen. Im Mittel wurden 21 Arten 100 m-2 im Inneren und 33 Arten am Feldrand gezählt. Auch die Regressionsmodelle weisen darauf hin, dass moderate Beschränkungen der Herbizidbehandlungsintensität oder der Düngung, die sich im Rahmen der zur Zeit üblichen konventionellen Bewirtschaftungspraktiken bewegen, kaum dazu beitragen den Rückgang der Ackerflora zu stoppen. Neue, an die jeweiligen regionalen Gegebenheiten angepasste Konzepte und extensive Ackerhabitate sind hierzu unerlässlich.  Die Vegetationsaufnahmen zeigen zudem, dass die Phytodiversität von KUP mit dem Alter der Plantagen stark zurückgeht. Junge KUP, ohne Düngung und mit nur geringem Herbizideinsatz, wiesen eine mit frühen Sukzessionsstadien von Ackerbrachen vergleichbare Artenzusammensetzung auf. Im Gegensatz hierzu wurden die 5–8 jährigen, dichtgepflanzten Plantagen von wenigen stickstoffliebenden Habitatgeneralisten dominiert. Obwohl sie seit mehreren Jahren weder gedüngt noch mit Herbiziden behandelt wurden, waren diese Bestände zudem dunkler (1–4 % PAR Transmissivität) und nur wenig artenreicher (8–19 Arten 75 m-2) als einjährige Energiepflanzenkulturen. Die Pflanzung von 5–20 m breiten Energieholzstreifen zur Zerteilung großer Schläge in strukturarmen, landwirtschaftlichen Intensivregionen kann jedoch aus naturschutzfachlicher Sicht empfohlen werden, insbesondere wenn Maßnahmen nur Erhöhung der Habitatvielfalt in den Plantagen ergriffen werden. Um die grundlegenden Ursachen des Pflanzenartenschwundes in Agrarlandschaften zu beheben, erscheint es jedoch darüber hinaus dringend notwendig, ein langfristig angelegtes Netzwerk extensiver Feldflorareservate zu begründen, um dauerhaft überlebensfähige Ackerwildkrautpopulationen zu erhalten und eine Ausbreitung dieser Arten in die weitere Agrarlandschaft in Zukunft wieder zu ermöglichen. Um politische Entscheidungsfindungen zu unterstützen, erscheint es notwendig im Rahmen von zukünftigen Forschungsprojekten den Blickwinkel vom Feld auf die Landschaftsebene zu erweitern und verbleibende offene Fragen über die Wirkungen der Ackerflora auf andere taxonomischen Gruppen zu klären

Fostering the Development of ESL/ASL Bilinguals

This article provides a bilingual perspective about literacy development in deaf students and uses the bilingual perspective to recommend effective teaching strategies for this group of students with special needs. In the case of deaf students, however, the bilingualism is not between two oral languages, but between American Sign Language (ASU and written English. The analogy of Deaf education to bilingual education is imperfect, as the article shows, but nonetheless helpful in suggesting educational strategies. One difference from classic bilingual education is the difference in mode of the two languages, with ASL using a haptic mode (signing) and written English using a visual mode. Another difference is the nontraditional nature of Deaf communities. Although ASL communities certainly have histories and traditions, Deaf individuals rarely learn these from family ties or immersion in a kinship-based culture that "speaks" ASL. Despite these differences in language mode and cultural transmission, teaching deaf students benefits from many strategies usually associated with the teaching of second languages, including fostering motivation, developing self concepts, understanding language development, knowing elements of a student's first language, allowing judicious translation,focusing on comprehension rather than syntax, and incorporating cultural values and native speakers-signers as role models

VISTA Ligation Reduces Antitumor T-Cell Activity in Pancreatic Cancer

Immunotherapy has shown promising results in multiple solid tumors and hematological malignancies. However, pancreatic ductal adenocarcinoma (PDAC) has been largely refractory to current clinical immunotherapies. The V-domain Ig suppressor of T-cell activation (VISTA) inhibits T-cell effector function and maintains peripheral tolerance. Here, we determine VISTA expression in nontumorous pancreatic (n = 5) and PDAC tissue using immunohistochemistry (n = 76) and multiplex immunofluorescence staining (n = 67). Additionally, VISTA expression on tumor-infiltrating immune cells and matched blood samples (n = 13) was measured with multicolor flow cytometry. Further, the effect of recombinant VISTA on T-cell activation was investigated in vitro, and VISTA blockade was tested in an orthotopic PDAC mouse model in vivo. PDAC showed significantly higher VISTA expression compared to that of a nontumorous pancreas. Patients with a high density of VISTA-expressing tumor cells had reduced overall survival. The VISTA expression of CD4+ and CD8+ T cells was increased after stimulation and particularly after a coculture with tumor cells. We detected a higher level of proinflammatory cytokine (TNFα and IFNγ) expression by CD4+ and CD8+ T cells, which was reversed with the addition of recombinant VISTA. A VISTA blockade reduced tumor weights in vivo. The VISTA expression of tumor cells has clinical relevance, and its blockade may be a promising immunotherapeutic strategy for PDAC