DIALOR (DIgitAL cOaching for fRailty): protocol for a single-arm mixed-methods feasibility study of a digital health coaching intervention for older people with frailty in primary care.

BACKGROUND: Multidomain interventions in older adults offer the best opportunity to prevent, delay or reverse existing symptoms in the earlier stages of frailty and improve independence but can be costly, and difficult to deliver at scale. However, digital health interventions enable personalised care and empowerment through self-management of long-term conditions, used at any time and when combined with health coaching offer the potential to enhance well-being and facilitate the achievement of health-related goals. We aim to evaluate the feasibility and acceptability of a digital health platform for long-term disease management combined with health coaching for people living with mild-moderate frailty, targeting self-identified goals-activity, nutrition, mood, enhancing social engagement and well-being. METHODS AND ANALYSIS: This is a non-randomised feasibility, single-group, pretest/post-test study, using qualitative and quantitative methods. The digital health coaching intervention (DIALOR-DIgitAL cOaching for fRailty) has been developed for implementation to older adults, aged 65 years or older with mild to moderate frailty and diagnosis of one or more long-term health conditions in the community. Participants will receive 12 weeks of health coaching and have access to a mobile health platform for 6 months. The primary outcome measure is the acceptability and feasibility of DIALOR along with a range of secondary outcome measures (including frailty, functioning measures, quality of life, social engagement, diet quality and self-reported indicators) collected at baseline and at 6 months. The findings will inform whether a wider effectiveness trial is feasible and if so, how it should be designed. ETHICS AND DISSEMINATION: Ethical approval has been granted by the Southeast Scotland Research Ethics Committee 02 (reference: 22/SS/0064). Research findings will be disseminated in a range of different ways to engage different audiences, including publishing in open-access peer-reviewed journals, conference presentations, social media, dissemination workshop with patients, carers, and healthcare professionals and on institution websites.

Understanding the infection severity and epidemiological characteristics of mpox in the UK.

In May 2022, individuals infected with the monkeypox virus were detected in the UK without clear travel links to endemic areas. Understanding the clinical characteristics and infection severity of mpox is necessary for effective public health policy. The study period of this paper, from the 1st June 2022 to 30th September 2022, included 3,375 individuals that tested positive for the monkeypox virus. The posterior mean times from infection to hospital admission and length of hospital stay were 14.89 days (95% Credible Intervals (CrI): 13.60, 16.32) and 7.07 days (95% CrI: 6.07, 8.23), respectively. We estimated the modelled Infection Hospitalisation Risk to be 4.13% (95% CrI: 3.04, 5.02), compared to the overall sample Case Hospitalisation Risk (CHR) of 5.10% (95% CrI: 4.38, 5.86). The overall sample CHR was estimated to be 17.86% (95% CrI: 6.06, 33.11) for females and 4.99% (95% CrI: 4.27, 5.75) for males. A notable difference was observed between the CHRs that were estimated for each sex, which may be indicative of increased infection severity in females or a considerably lower infection ascertainment rate. It was estimated that 74.65% (95% CrI: 55.78, 86.85) of infections with the monkeypox virus in the UK were captured over the outbreak.

EMCDDA framework and practical guidance for naming cathinones.

Cathinones are often sold as "legal" alternatives to controlled stimulants such as amphetamine, MDMA and cocaine. Cathinones are the second largest group of new psychoactive substances (NPS), with close to 170 monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Although all cathinones are related to the parent compound cathinone, one of the psychoactive principles in khat, assigning consistent, informative and user-friendly common names to these substances is challenging. Over time different naming approaches have been applied, leading to cathinones being known by several names. This work provides a framework and practical examples for the consistent naming of cathinones which is easy to understand and can be applied by the forensic community, researchers, clinical practitioners, and policy makers. The scope of the issue and rationale for earlier naming approaches are also discussed. The new naming framework has been developed based on established naming approaches and centered around the common "cathinone," and "phenone" motifs/scaffolds. The proposed framework establishes clear rules to derive the EMCDDA framework names for cathinones. Each name is, in turn, composed by a principal name containing a parent letter, derived after the "cathinone" or the "phenone" scaffold. Additional substitutions are prepended to the principal name. The framework also provides for exceptions for several cathinones and structural analogs scheduled under UN and EU legislation.

Identifying employee, workplace and population characteristics associated with COVID-19 outbreaks in the workplace: a population-based study.

OBJECTIVES: To identify risk factors that contribute to outbreaks of COVID-19 in the workplace and quantify their effect on outbreak risk. METHODS: We identified outbreaks of COVID-19 cases in the workplace and investigated the characteristics of the individuals, the workplaces, the areas they work and the mode of commute to work, through data linkages based on Middle Layer Super Output Areas in England between 20 June 2021 and 20 February 2022. We estimated population-level associations between potential risk factors and workplace outbreaks, adjusting for plausible confounders identified using a directed acyclic graph. RESULTS: For most industries, increased physical proximity in the workplace was associated with increased risk of COVID-19 outbreaks, while increased vaccination was associated with reduced risk. Employee demographic risk factors varied across industry, but for the majority of industries, a higher proportion of black/African/Caribbean ethnicities and living in deprived areas, was associated with increased outbreak risk. A higher proportion of employees in the 60-64 age group was associated with reduced outbreak risk. There were significant associations between gender, work commute modes and staff contract type with outbreak risk, but these were highly variable across industries. CONCLUSIONS: This study has used novel national data linkages to identify potential risk factors of workplace COVID-19 outbreaks, including possible protective effects of vaccination and increased physical distance at work. The same methodological approach can be applied to wider occupational and environmental health research.

Forecasting influenza hospital admissions within English sub-regions using hierarchical generalised additive models.

BACKGROUND: Seasonal influenza places a substantial burden annually on healthcare services. Policies during the COVID-19 pandemic limited the transmission of seasonal influenza, making the timing and magnitude of a potential resurgence difficult to ascertain and its impact important to forecast. METHODS: We have developed a hierarchical generalised additive model (GAM) for the short-term forecasting of hospital admissions with a positive test for the influenza virus sub-regionally across England. The model incorporates a multi-level structure of spatio-temporal splines, weekly cycles in admissions, and spatial correlation. Using multiple performance metrics including interval score, coverage, bias, and median absolute error, the predictive performance is evaluated for the 2022-2023 seasonal wave. Performance is measured against autoregressive integrated moving average (ARIMA) and Prophet time series models. RESULTS: Across the epidemic phases the hierarchical GAM shows improved performance, at all geographic scales relative to the ARIMA and Prophet models. Temporally, the hierarchical GAM has overall an improved performance at 7 and 14 day time horizons. The performance of the GAM is most sensitive to the flexibility of the smoothing function that measures the national epidemic trend. CONCLUSIONS: This study introduces an approach to short-term forecasting of hospital admissions for the influenza virus using hierarchical, spatial, and temporal components. The methodology was designed for the real time forecasting of epidemics. This modelling framework was used across the 2022-2023 winter for healthcare operational planning by the UK Health Security Agency and the National Health Service in England.

Seasonal influenza causes a burden for hospitals and therefore it is useful to be able to accurately predict how many patients might be admitted with the disease. We attempted to predict influenza admissions up to 14 days in the future by creating a computational model that incorporates how the disease is reported and how it spreads. We evaluated our optimised model on data acquired during the winter of 2022-2023 data in England and compared it with previously developed models. Our model was better at modelling how influenza spreads and predicting future hospital admissions than the models we compared it to. Improving how influenza admissions are forecast can enable hospitals to prepare better for increased admissions, enabling improved treatment and reduced death for all patients in hospital over winter.

Nowcasting the 2022 mpox outbreak in England.

In May 2022, a cluster of mpox cases were detected in the UK that could not be traced to recent travel history from an endemic region. Over the coming months, the outbreak grew, with over 3000 total cases reported in the UK, and similar outbreaks occurring worldwide. These outbreaks appeared linked to sexual contact networks between gay, bisexual and other men who have sex with men. Following the COVID-19 pandemic, local health systems were strained, and therefore effective surveillance for mpox was essential for managing public health policy. However, the mpox outbreak in the UK was characterised by substantial delays in the reporting of the symptom onset date and specimen collection date for confirmed positive cases. These delays led to substantial backfilling in the epidemic curve, making it challenging to interpret the epidemic trajectory in real-time. Many nowcasting models exist to tackle this challenge in epidemiological data, but these lacked sufficient flexibility. We have developed a nowcasting model using generalised additive models that makes novel use of individual-level patient data to correct the mpox epidemic curve in England. The aim of this model is to correct for backfilling in the epidemic curve and provide real-time characteristics of the state of the epidemic, including the real-time growth rate. This model benefited from close collaboration with individuals involved in collecting and processing the data, enabling temporal changes in the reporting structure to be built into the model, which improved the robustness of the nowcasts generated. The resulting model accurately captured the true shape of the epidemic curve in real time.

From JWH-018 to OXIZIDS: Structural evolution of synthetic cannabinoids in the European Union from 2008 to present day.

With new synthetic cannabinoids (SCs) appearing on the European drug market every year, early warning systems are key to detect, monitor, and respond to threats posed by them. The European Union Early Warning System (EU EWS) implemented by the European Monitoring Centre for Drugs and Drug Addiction has monitored these substances since their first European detection in 2008. Since then, national and international responses have been implemented, aimed at tackling risks posed by SCs. Throughout this time, new SCs have emerged on the European market containing diverse structural moieties, appearing to be designed in a way that circumvents existing legal controls, contributing to a complex public health scenario. This study provides an inventory of the SCs detected in the EU from 2008 to 2022, describing their structural evolution by analysing separately four structural features: their core, tail, linker, and linked groups. The range of structural changes is analysed considering key milestones, including the year of first report by the European Union Early Warning System to the key legislative changes that have occurred since. The analysis shows that from June 2021 to July 2022, 20 out of 23 newly emerged SCs evade the generic SC legislation introduced in China in May 2021. This supports the hypothesis that the protection of public health benefits from timely information exchange and careful assessment of the risks associated with these substances. Additionally, the introduction of legal responses, albeit an important instrument to reduce the availability of dangerous substances on the market, may also be accompanied by unintended consequences.

EMCDDA framework and practical guidance for naming synthetic cannabinoids.

Synthetic cannabinoids (SCs), often sold as "legal" replacements for cannabis, are the largest group of new psychoactive substances monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Currently, close to 240 structurally heterogeneous SCs are monitored through the European Union (EU) Early Warning System, and attributing consistent, informative, and user-friendly names to SCs has been a challenge in the past. Over time, several naming conventions have been employed with the aim of making SCs more easily recognizable by non-chemists, including regulators. To achieve this, the names assigned need to contain detailed information on the structural features present in the substance. This work provides a theoretical framework and a practical hands-on guideline for consistent naming of SCs, which is easy to understand and can be applied by the forensic community, researchers, clinical practitioners, and policy-makers. The proposed framework builds on the established letter code system for molecular building blocks (core, linker, linked group, and tail) implemented by the EMCDDA in 2013 and has been expanded to incorporate additional structural features through substitution. The scope of the issue of attributing semi-systematic code names is illustrated, and earlier approaches used for naming SCs are discussed. The concepts and rules of the EMCDDA framework are described through a flowchart that provides a basis for naming new SCs, a graphical overview of the chemical diversity of SCs, and a detailed list of the SCs identified in the EU by the Early Warning System of the EMCDDA for reference.

Transmission dynamics of monkeypox in the United Kingdom: contact tracing study.

OBJECTIVE: To analyse the transmission dynamics of the monkeypox outbreak in the UK, declared a Public Health Emergency of International Concern in July 2022. DESIGN: Contact tracing study, linking data on case-contact pairs and on probable exposure dates. SETTING: Case questionnaires from the UK Health Security Agency (UKHSA), United Kingdom. PARTICIPANTS: 2746 people with polymerase chain reaction confirmed monkeypox virus in the UK between 6 May and 1 August 2022. MAIN OUTCOME MEASURES: The incubation period and serial interval of a monkeypox infection using two bayesian time delay models-one corrected for interval censoring (ICC-interval censoring corrected) and one corrected for interval censoring, right truncation, and epidemic phase bias (ICRTC-interval censoring right truncation corrected). Growth rates of cases by reporting date, when monkeypox virus was confirmed and reported to UKHSA, were estimated using generalised additive models. RESULTS: The mean age of participants was 37.8 years and 95% reported being gay, bisexual, and other men who have sex with men (1160 out of 1213 reporting). The mean incubation period was estimated to be 7.6 days (95% credible interval 6.5 to 9.9) using the ICC model and 7.8 days (6.6 to 9.2) using the ICRTC model. The estimated mean serial interval was 8.0 days (95% credible interval 6.5 to 9.8) using the ICC model and 9.5 days (7.4 to 12.3) using the ICRTC model. Although the mean serial interval was longer than the incubation period for both models, short serial intervals were more common than short incubation periods, with the 25th centile and the median of the serial interval shorter than the incubation period. For the ICC and ICRTC models, the corresponding estimates ranged from 1.8 days (95% credible interval 1.5 to 1.8) to 1.6 days (1.4 to 1.6) shorter at the 25th centile and 1.6 days (1.5 to 1.7) to 0.8 days (0.3 to 1.2) shorter at the median. 10 out of 13 linked patients had documented pre-symptomatic transmission. Doubling times of cases declined from 9.07 days (95% confidence interval 12.63 to 7.08) on the 6 May, when the first case of monkeypox was reported in the UK, to a halving time of 29 days (95% confidence interval 38.02 to 23.44) on 1 August. CONCLUSIONS: Analysis of the instantaneous growth rate of monkeypox incidence indicates that the epidemic peaked in the UK as of 9 July and then started to decline. Short serial intervals were more common than short incubation periods suggesting considerable pre-symptomatic transmission, which was validated through linked patient level records. For patients who could be linked through personally identifiable data, four days was the maximum time that transmission was detected before symptoms manifested. An isolation period of 16 to 23 days would be required to detect 95% of people with a potential infection. The 95th centile of the serial interval was between 23 and 41 days, suggesting long infectious periods.

DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles.

Etonitazene and related 2-benzylbenzimidazoles are potent analgetics invented in the research laboratories of the Swiss pharmaceutical giant CIBA in the late 1950s. Though the unprecedented structure distinguishes this class of compounds from poppy-derived and other synthetic analgetics, a range of studies indicate that these drugs are selective µ opioid receptor agonists possessing morphine-like pharmacotoxicological properties in animals as well as humans. Several unscheduled members of this synthetically readily accessible class of opioids that are not controlled under the international and national drug control systems have recently emerged on the illicit drug market. Among them, isotonitazene has been implicated in at least 200 fatalities in Europe and North America. None of the 2-benzylbenzimidazole derivatives have been developed into medicines, but etonitazene and some of its derivatives have been used as receptor probes and in addiction behavior studies in animals. The unique structure has inspired research on such benzimidazoles and related benzimidazolones of which "brorphine" made its debut as one of the newest psychoactive substance to emerge on the illicit opioid drug market in mid-2019. This in-depth review provides a historical introduction, an overview on the chemistry, pharmacological profiles, adverse effects, addiction liability, regulatory status, and the impact on chemical neuroscience of the 2-benzylbenzimidazoles. Structurally related benzimidazoles with opioid and/or analgesic properties are also discussed briefly.

Safety and pharmacokinetics of dolutegravir in HIV-positive pregnant women: a systematic review.

BACKGROUND: The integrase strand transfer inhibitor dolutegravir (DTG) is being introduced into low- and middle-income countries (LMICs) as an alternative to first-line treatment with non-nucleoside reverse transcriptase inhibitors. However, DTG is not yet widely recommended for use in pregnant women. The aim of this systematic review was to analyse all available data on birth outcomes and congenital anomalies in the infants of pregnant women treated with DTG. METHODS: A PubMed and Embase search was conducted using the terms "dolutegravir" or "DTG" and "pregnancy" or "pregnant" from the earliest available date on the database to 26 July 2017. Any reports involving women who were pregnant, HIV positive and taking DTG were included. The percentage of pregnant women with adverse birth outcomes or congenital anomalies in their infants after taking dolutegravir was compared with five historical control databases. RESULTS: There were six databases included in the main analysis of birth outcomes and congenital anomalies, with a total of 1200 pregnant women. The percentage of pregnant women taking DTG with adverse birth outcomes and congenital abnormalities was similar to results from historical control studies of HIV-positive women. However, there was significant heterogeneity among the six databases - the percentage of infants with congenital anomalies ranged from 0.0% in Botswana (0/116 infants) to 13.3% in IMPAACT P1026S (2/15 infants). CONCLUSIONS: Up to 15 million people could be on treatment with DTG in LMICs within the next 5 years, of whom a substantial percentage is likely to be women of child-bearing potential. In many countries with large HIV epidemics, unplanned pregnancies are common and access to antenatal clinic facilities may be limited. Continued pharmacovigilance is essential, but it is reassuring that no clear safety signals have been detected, to date, for pregnant women treated with DTG in terms of birth outcomes or congenital anomalies.

The synthesis and characterization N-methyl-3-phenyl-norbornan-2-amine (Camfetamine™).

N-Methyl-3-phenyl-norbornan-2-amine (N-methyl-3-phenylbicyclo[2.2.1]heptan-2-amine, Camfetamine(™) ) is available from a number of online legal highs/research chemicals' vendors. Although it was developed as an analeptic by Merck in the early 1960s, it was never commercialized. However, the Association of Independent Research Chemical Retailers (AIRCR), an umbrella organization for a number of online vendors, has redeveloped it for use as a recreational drug. N-Methyl-3-phenyl-norbornan-2-amine is closely related to fencamfamine which has been widely used as a central nervous system (CNS) stimulant and appetite suppressant. In this paper we describe the synthesis of N-methyl-3-phenyl-norbornan-2-amine, its characterization and interpretations of its electron impact, and electrospray ionization mass spectra.

The syntheses and characterization 3ß-(4-fluorobenzoyloxy)tropane (fluorotropacocaine) and its 3α isomer.

3ß-(4-Fluorobenzoyloxy)tropane (3ß-FBT, fluorotropacocaine) was first reported by Finnish authorities to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) via the Early Warning System (EWS) in 2008 and our own laboratory tentatively identified it in 2010 in several products purchased from head shops. Very little is known about this cocaine-like drug and, as no reference standards were available, we have synthesized and characterized both 3ß-FBT and its 3α isomer for use as reference standards. The two compounds are separable by gas chromatography (GC) but their electron-impact (EI) mass spectra were found to be almost identical. ¹9F NMR spectroscopy was also found to be a useful technique for distinguishing the two isomers.

The analysis of substituted cathinones. Part 3. Synthesis and characterisation of 2,3-methylenedioxy substituted cathinones.

The first synthesis of the 2,3-isomers of MDPV, butylone and methylone is reported. The isomers were characterised by (1)H and (13)C NMR spectroscopy and compared to the corresponding 3,4-isomers. A GC method is described which separates the 3,4- and the 2,3-isomers from each other. IR spectra of the 2,3-isomers are also compared with the corresponding 3,4-isomers. Two seized drug samples were analysed by GCMS and the samples were found to contain the 3,4-isomers.

Experimental infection of mice with hamster parvovirus: evidence for interspecies transmission of mouse parvovirus 3.

Hamster parvovirus (HaPV) was isolated 2 decades ago from hamsters with clinical signs similar to those induced in hamsters experimentally infected with other rodent parvoviruses. Genetically, HaPV is most closely related to mouse parvovirus (MPV), which induces subclinical infection in mice. A novel MPV strain, MPV3, was detected recently in naturally infected mice, and genomic sequence analysis indicates that MPV3 is almost identical to HaPV. The goal of the present studies was to examine the infectivity of HaPV in mice. Neonatal and weanling mice of several mouse strains were inoculated with HaPV. Tissues, excretions, and sera were harvested at 1, 2, 4, and 8 wk after inoculation and evaluated by quantitative PCR and serologic assays specific for HaPV. Quantitative PCR detected viral DNA quantities that greatly exceeded the quantity of virus in inocula in multiple tissues of infected mice. Seroconversion to both nonstructural and structural viral proteins was detected in most immunocompetent mice 2 or more weeks after inoculation with HaPV. In neonatal SCID mice, viral transcripts were detected in lymphoid tissues by RT-PCR and viral DNA was detected in feces by quantitative PCR at 8 wk after inoculation. No clinical signs, gross, or histologic lesions were observed. These findings are similar to those observed in mice infected with MPV. These data support the hypothesis that HaPV and MPV3 are likely variants of the same viral species, for which the mouse is the natural rodent host with rare interspecies transmission to the hamster.