Structure-Guided Mutagenesis Targeting Interactions between pp150 Tegument Protein and Small Capsid Protein Identify Five Lethal and Two Live Attenuated HCMV Mutants.

Human cytomegalovirus (HCMV) replication relies on a nucleocapsid coat of the 150kDa, subfamily-specific tegument phosphoprotein (pp150) to regulate cytoplasmic virion maturation. While recent structural studies revealed pp150-capsid interactions, the role of specific amino-acids involved in these interactions have not been established experimentally. In this study, pp150 and the small capsid protein (SCP), one of pp150's binding partners found atop the major capsid protein (MCP), were subjected to mutational and structural analyses. Mutations to clusters of polar or hydrophobic residues along the pp150-SCP interface abolished viral replication, with no replication detected in mutant virus-infected cells. Notably, a single point mutation at the pp150-MCP interface significantly attenuated viral replication, unlike the situation of pp150-deletion mutation where capsids degraded outside host nuclei. These functionally significant mutations targeting pp150-capsid interactions, particularly the pp150 K255E replication-attenuated mutant, can be explored to overcome the historical challenges of developing effective antivirals and vaccines against HCMV infection.

Evaluating police drug diversion in England: protocol for a realist evaluation.

There is increasing international interest in the use of police drug diversion schemes that offer people suspected of minor drug-related offences an educative or therapeutic intervention as an alternative to criminalisation. While there have been randomised trials of some such schemes for their effects on reducing offending, with generally positive results, less is known about the health outcomes, and what works, for whom, in what circumstances and why. This protocol reports on a realist evaluation of police drug diversion in England that has been coproduced by a team of academic, policing, health, and service user partners. The overall study design combines a qualitative assessment of the implementation, contexts, mechanisms, moderators and outcomes of schemes in Durham, Thames Valley and the West Midlands with a quantitative, quasi-experimental analysis of administrative data on the effects of being exposed to the presence of police drug diversion on reoffending and health outcomes. These will be supplemented with analysis of the cost-consequences of the evaluated schemes, an analysis of the equity of their implementation and effects, and a realist synthesis of the various findings from these different methods.

Has Sustained Time Away From Sports Due to the COVID-19 Pandemic Led to Increased Sport-Related Soft Tissue Injuries?

BACKGROUND: A decrease in sport-related injuries was observed in 2020, which has been attributed to COVID-19 and recommendations to suspend organized sports. In adult populations, increased injury rates have been noted in athletes returning to play after an extended period of reduced play, attributable to deconditioning. There is growing literature surrounding concern over increased injury risk after return to sport after the COVID-19 shutdowns. HYPOTHESIS: Like adults, pediatric patients experience an increase in sport-related injuries after periods of "deconditioning," such as during the COVID-19 shutdown. STUDY DESIGN: Descriptive epidemiology study. LEVEL OF EVIDENCE: Level 4. METHODS: The Consumer Product Safety Commission's National Electronic Injury Surveillance System database was queried to identify 13- to 18-year-old patients who sustained a sprain/strain type injury in 2019 or 2021 to an extremity, and involved sporting equipment for basketball, baseball/softball, soccer, and football. The control group was established as patients who sustained injury in 2019, and the post-COVID-19 group was established as those in 2021. Quantity of injuries sustained in these 2 groups were compared and analyzed by subgroup. RESULTS: There was a significant difference in the total number of sport-related sprains/strains in 2019 versus 2021 (P = 0.01), with more injuries in 2019 (n = 151,067) than in 2021 (n = 104,041). There were more injuries in boys than in girls. Proportion of injuries by sports were similar in both time periods. There was a significant decrease in basketball-related injuries by 21% (P ≤ 0.01, relative risk ratio [rrr] = 0.7979) and a significant increase in football-related injuries by 14% (P = 0.01, rrr = 1.1404) and in soccer injuries by 14.2% (P = 0.03, rrr = 1.1422). CONCLUSION: There is significant heterogeneity in injury rates by sports, with no conclusive increase in injuries, contrary to expectations. CLINICAL RELEVANCE: This study suggests that the relationship between deconditioning and injury may be less clear in the child-athlete, and gives recommendations for return to sport after extended breaks. STRENGTH-OF-RECOMMENDATION TAXONOMY (SORT): Level 2c.

A multicomponent psychosocial intervention to reduce substance use by adolescents involved in the criminal justice system: the RISKIT-CJS RCT.

Background: Substance use and offending are related in the context of other disinhibitory behaviours. Adolescents involved in the criminal justice system constitute a particularly vulnerable group, with a propensity to engage in risky behaviour that has long-term impact on their future health and well-being. Previous research of the RISKIT programme provided evidence of a potential effect in reducing substance use and risky behaviour in adolescents. Objectives: To evaluate the clinical effectiveness and cost-effectiveness of a multicomponent psychosocial intervention compared with treatment as usual in reducing substance use for substance-using adolescents involved in the criminal justice system. Design: A mixed-methods, prospective, pragmatic, two-arm, randomised controlled trial with follow-up at 6 and 12 months post randomisation. Setting: The study was conducted across youth offending teams, pupil referral units and substance misuse teams across four areas of England (i.e. South East, London, North West, North East). Participants: Adolescents aged between 13 and 17 years (inclusive), recruited between September 2017 and June 2020. Interventions: Participants were randomised to treatment as usual or to treatment as usual in addition to the RISKIT-Criminal Justice System (RISKIT-CJS) programme. The RISKIT-CJS programme was a multicomponent intervention and consisted of two individual motivational interviews with a trained youth worker (lasting 45 minutes each) and two group sessions delivered over half a day on consecutive weeks. Main outcome measures: At 12 months, we assessed per cent days abstinent from substance use over the previous 28 days. Secondary outcome measures included well-being, motivational state, situational confidence, quality of life, resource use and fidelity of interventions delivered. Results: A total of 693 adolescents were assessed for eligibility, of whom 505 (73%) consented. Of these, 246 (49%) were allocated to the RISKIT-CJS intervention and 259 (51%) were allocated to treatment as usual only. At month 12, the overall follow-up rate was 57%: 55% in the RISKIT-CJS arm and 59% in the treatment-as-usual arm. At month 12, we observed an increase in per cent days abstinent from substances in both arms of the study, from 61% to 85%, but there was no evidence that the RISKIT-CJS intervention was superior to treatment as usual. A similar pattern was observed for secondary outcomes. The RISKIT-CJS intervention was not found to be any more cost-effective than treatment as usual. The qualitative research indicated that young people were positive about learning new skills and acquiring new knowledge. Although stakeholders considered the intervention worthwhile, they expressed concern that it came too late for the target population. Limitations: Our original aim to collect data on offences was thwarted by the onset of the COVID-19 pandemic, and this affected both the statistical and economic analyses. Although 214 (87%) of the 246 participants allocated to the RISKIT-CJS intervention attended at least one individual face-to-face session, 98 (40%) attended a group session and only 47 (19%) attended all elements of the intervention. Conclusions: The RISKIT-CJS intervention was no more clinically effective or cost-effective than treatment as usual in reducing substance use among adolescents involved in the criminal justice system. Future research: The RISKIT-CJS intervention was considered more acceptable, and adherence was higher, in pupil referral units and substance misuse teams than in youth offending teams. Stakeholders in youth offending teams thought that the intervention was too late in the trajectory for their population. Trial registration: This trial is registered as ISRCTN77037777. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 11, No. 3. See the NIHR Journals Library website for further project information.

We explored how useful a psychological intervention was in reducing substance use among young people who had some involvement in the criminal justice system. We recruited young people aged between 13 and 17 years in four areas of England (i.e. South East, London, North West and North East). Young people were recruited from youth offending teams, pupil referral units and substance misuse teams. Those young people who were willing to participate were offered usual treatment and half, chosen at random, were offered an opportunity to take part in the RISKIT-Criminal Justice System (RISKIT-CJS) programme. The RISKIT-CJS programme had four distinct parts. The first was a 1-hour session that used an approach called motivational interviewing to explore the young person's substance use and discuss different strategies to change their behaviour. This was followed by two group sessions delivered over 2 consecutive weeks. These group sessions addressed risks associated with substance use, what triggers use and the health and social consequences. In addition, young people were taught new skills to help them manage in situations in which they might normally use substances. At the end of the group sessions, the young people had another motivational interview. Twelve months after participants started, we found that the frequency of substance use had decreased in both groups; however, the RISKIT-CJS intervention was no better than treatment as usual. When we spoke with young people who had taken part and staff involved with this population, we got a mixed picture. In some settings, particularly pupil referral units, the RISKIT-CJS intervention was well received by young people and staff, and staff felt that it was a useful additional resource to the work that they were currently undertaking. On the other hand, in the youth offending teams, the staff thought that the programme was too different from their normal work to be implemented easily and they considered the population they work with too established in their substance use and criminal activity to benefit from the programme.

Demographic Determinants of Residue Profiles of Fungicidal Compounds in Common Voles (Microtus arvalis) under Semi-Natural and Natural Conditions.

Environmental risks from plant protection products (PPPs) need to be assessed to ensure safe use. The risk assessments are generally carried out using the common vole as a focal species with conservative theoretical estimates of external exposure. These are then compared to dose-related toxicity endpoints established in toxicity studies, often with laboratory species. The aim of the present study was to determine the actual internal dosimetry of PPPs' active ingredients (AIs) in a population of common voles to provide the basis for informed higher tier risk assessment. As a proof of concept, two fungicidal AIs (fludioxonil and cyprodinil) were investigated using a range of application methodologies. Individuals were treated using oral gavage application (AI dose: 100/200 mg/kg) and fed treated grass (AI sprayed at 2 kg/ha) under laboratory, semi-natural, and natural conditions. Our results show that demographic factors play a significant role in the individual residue profile and that age structure is a key aspect that determines the overall exposure risk of a population. These results are consistent from laboratory to field conditions. Future approaches could establish dose-residue relationships that are reflective of natural food intake rates in wild common vole populations in the risk assessment of PPPs.

Analysis of the UK Government's 10-Year Drugs Strategy-a resource for practitioners and policymakers.

In 2021, during a drug-related death crisis in the UK, the Government published its ten-year drugs strategy. This article, written in collaboration with the Faculty of Public Health and the Association of Directors of Public Health, assesses whether this Strategy is evidence-based and consistent with international calls to promote public health approaches to drugs, which put 'people, health and human rights at the centre'. Elements of the Strategy are welcome, including the promise of significant funding for drug treatment services, the effects of which will depend on how it is utilized by services and local commissioners and whether it is sustained. However, unevidenced and harmful measures to deter drug use by means of punishment continue to be promoted, which will have deleterious impacts on people who use drugs. An effective public health approach to drugs should tackle population-level risk factors, which may predispose to harmful patterns of drug use, including adverse childhood experiences and socioeconomic deprivation, and institute evidence-based measures to mitigate drug-related harm. This would likely be more effective, and just, than the continuation of policies rooted in enforcement. A more dramatic re-orientation of UK drug policy than that offered by the Strategy is overdue.

The United Kingdom's first unsanctioned overdose prevention site; A proof-of-concept evaluation.

BACKGROUND: The United Kingdom (UK) is currently experiencing a public health crisis of drug-related deaths. The government has rejected recommendations to open overdose prevention services, under the Misuse of Drugs Act 1971. To report on the operation and use of an unsanctioned overdose prevention service which operated in Glasgow city centre from September 2020 to May 2021. METHODS: Description of the service, with analysis of data collected on its use. RESULTS: The service operated for nine months without permission or funding from official sources. We report on the 894 injections supervised and recorded, and nine successful interventions with overdose events (seven opioid/two cocaine). Powder cocaine injection predominated either alone (60.6%) or with heroin (22.1%). Injection was mostly in the groin (68.0%) or arm (16.8%). More injections were recorded by males (70.1%). Around 65% of injection events featured an individual who was on a buprenorphine/methadone prescription. CONCLUSION: It is feasible for an overdose prevention service to operate successfully in the UK without being shut down by the police or with negative consequences for the community. Future sites in the UK must tailor to the substances used by their potential clients, international trends (e.g. for fentanyl use) did not apply here. There is an urgent need and demand for these services in the UK to reduce harm, prevent and intervene during overdose, and provide vital psychosocial support for health and wellbeing in a highly marginalised population.

The details of decriminalization: Designing a non-criminal response to the possession of drugs for personal use.

Internationally, policymakers are considering alternative, non-criminal responses to the possession of drugs for personal use, or 'simple possession'. We show that 'decriminalization' is not a simple, unified model; rather, there are meaningful differences in policies and options available as part of a non-criminal response. Responses include various decriminalization, diversion, and depenalization approaches. However, what details need to be considered in developing these approaches? In this paper, we eschew these labels and present an overview of key design features of non-criminal responses to simple possession and consider some of the equity considerations of the choices available, including reform architecture (the objectives and legal framework); eligibility criteria (population-, place-, and drug-based criteria); and actions taken (deterrence, therapeutic, and enforcement strategies). This paper does not evaluate individual features or models, but instead offers a practical framework that can be used to deliberate on potential reform decisions.

The Double Effect of COVID-19 Confinement Measures and Economic Recession on High-Risk Drug Users and Drug Services.

The ongoing COVID-19 pandemic is likely to have a profound impact on the lives of high-risk drug users and on the services responding to their needs in at least two important ways: first, through the restrictive measures introduced to mitigate the spread of the virus and, second, as a result of extensive economic downturn. Currently there is great uncertainty as to the future intensity and duration of the pandemic. In addition, the lessons we have been able to learn from previous economic downturns may be of limited applicability to the current situation, which differs in a number of significant respects. Experience nevertheless suggests that the potential consequences for drug users' health and well-being may be severe. The ongoing uncertainty serves to underline the importance of close monitoring of the drug situation and preparing flexible and innovative solutions to be able to meet new challenges which may arise.

Critical realism and the 'ontological politics of drug policy'.

This article explores the question of what we can consider to be real in drug policy. It examines two increasingly common aspects of drug policy analysis; radical constructionist critique and successionist data science. It shows how researchers using these assumptions have produced interesting findings, but also demonstrates their theoretical incoherence, based on their shared 'flat ontology'. The radical constructionist claim that reality is produced within research methods - as seen in some qualitative studies - is shown to be unsustainably self-defeating. It is analytically 'paralyzing'. This leads to two inconsistencies in radical constructionist studies; empirical ambivalence and ersatz epistemic egalitarianism. The Humean successionist approach of econometric data science is also shown to be unsustainable, and unable to provide explanations of identified patterns in data. Four consequent, limiting characteristics of this type of drug policy research are discussed: causal inference at a distance, monofinality, limited causal imagination, and overly confident causal claims. The article goes on to describe the critical realist approach towards 'depth ontology' and 'generative causation'. It provides examples of how this approach is deployed in critical realist reviews and discourse analysis of drug policy. It concludes by arguing that critical realism enables more deeply explanatory, methodologically eclectic and democratically inclusive analysis of drug policy development and effects.

Is policy 'liberalization' associated with higher odds of adolescent cannabis use? A re-analysis of data from 38 countries.

BACKGROUND: Policy makers worldwide face the choice of whether to reform cannabis policy from the 'full prohibition' model. A paper by Shi et al. (2015) suggested that such 'liberalization' is significantly associated with higher odds of adolescent cannabis use. AIM: To test the validity and reliability of Shi et al's conclusion that the HBSC data show an association between policy 'liberalization' and increased likelihood of adolescent cannabis use. METHODS: Replication and re-analysis of the same pooled data from three waves of the Health Behaviour in School-aged Children (HBSC) survey (2001/2, 2005/6 and 2009/10). This replicates - as far as possible - the coding and analytical strategy of the Shi et al article. The re-analysis makes some improvements by: excluding a variable ('number of siblings') for which many cases have missing data; including available data from the theoretically relevant case of Sweden for the latter two waves of the HBSC survey, which Shi et al omit; and including random slopes for gender between countries as well as random intercepts for countries in the mixed effects model, as the predictive effect of gender on cannabis use varies across countries. RESULTS: Shi et al's verbal summary of their findings is not supported by detailed interpretation of their own numerical results. Without making the suggested amendments, it is possible to find a statistically significant association between policy 'liberalization' and higher odds of some measures of adolescent cannabis use. But when these improvements are made, this association becomes statistically non-significant. CONCLUSION: Using a larger and more theoretically relevant sample of the HBSC respondents and an improved statistical model shows that the HBSC data do not reveal a statistically significant association between policy 'liberalization' and higher odds of adolescent cannabis use.

'Being human' and the 'moral sidestep' in drug policy: Explaining government inaction on opioid-related deaths in the UK.

BACKGROUND: With drug-related deaths at record levels in the UK, the government faces two potential sources of pressure to implement more effective policies. One source is the individuals and families who are most likely to suffer from such deaths; i.e. working class people living in de-industrialised areas. The other source is experts who argue for different policy on the basis of research evidences. AIM: This article aims to explain why, in the face of these two potential sources of pressure, the UK government has not implemented effective measures to reduce deaths. METHOD: The article uses critical realist discourse analysis of official documents and ministerial speeches on recent British drug policy (2016-2018). It explore this discourse through the theoretical lens of Archer's (2000) ideas on 'being human' and by drawing on Sayer's (2005) work on the 'moral significance of class'. RESULTS: Members of economically 'residual' groups (including working class people who use heroin) are excluded from articulating their interests in 'late welfare capitalism' in a project of depersonalising 'class contempt' through which politicians cast the people most likely to die as passive, 'vulnerable' 'abjects'. Conservative politicians dismiss 'evidence-based' ideas on the reduction of drug-related death through a 'moral sidestep'. They defend policy on the basis of its relevance to conservative moral principles, not effectiveness. This is consistent with the broader moral and political pursuit of partial state shrinkage which Conservative politicians and the social groups they represent have pursued since the 1970s.