Understanding and optimising an identification/brief advice (IBA) service about alcohol in the community pharmacy setting

This is the final report of an evaluation into the identification/brief advice (IBA) service about alcohol in community pharmacy settings in the North West of England. Since 2007, almost 100 pharmacies in the North West have - at some point - been commissioned to provide an identification and brief advice (IBA) service for alcohol. This evaluation sought to understand how the service had been adapted for and implemented in the community pharmacy setting, and how its potential might be maximised. Its aims were: 1. To characterise, consolidate and optimise both the constant and variable elements of the pharmacy alcohol identification/brief advice (IBA) service in NHS Northwest, and 2. To inform planning for current and future pharmacy based services promoting safe consumption of alcohol. The evaluation was split into three main workstreams, supported by a preliminary scoping phase, and combined quantitative and qualitative methods: • Descriptive and comparative statistical analysis of pharmacy alcohol IBA data; • In-pharmacy work, including observation of staff engagement with customers, recording consultations between staff and customers, follow-up telephone interviews with customers, and group feedback interviews with pharmacy staff; • Stakeholder engagement through self-completion surveys, semi-structured interviews and a workshop. This report gives the background to the project, and details the methods, results and implications

A pilot telephone intervention to increase uptake of breast cancer screening in socially deprived areas in Scotland (TELBRECS):study protocol for a randomised controlled trial

BACKGROUND Breast cancer accounts for almost 30% of all cancers and is the second leading cause of cancer deaths in women in Scotland. Screening is key to early detection. The Scottish Breast Screening Programme is a nationwide, free at point of delivery screening service, to which all women aged between 50 and 70 years are invited to attend every 3 years. Currently over three-quarters of invited women regularly attend screening. However, women from more deprived areas are much less likely to attend: for example in the 3 years from 2010-2012 only 63% of women in the most deprived area attended the East of Scotland Breast Screening programme versus 81% in the least deprived. Research has suggested that reminders (telephone or letter) and brief, personalised interventions addressing barriers to attendance may be helpful in increasing uptake in low-income women. METHODS/DESIGN We will employ a brief telephone reminder and support intervention, whose purpose is to elicit and address any mistaken beliefs women have about breast screening, with the aim that the perceived benefits of screening come to outweigh any perceived barriers for individuals. We will test whether this intervention, plus a simple anticipated regret manipulation, will lead to an increase in the uptake of breast cancer screening amongst low-income women who have failed to attend a first appointment, in a randomised controlled trial with 600 women. Participants will be randomly allocated to one of four treatment arms i.e. 1) Letter reminder (i.e. Treatment as usual: CONTROL); 2) Telephone reminder (TEL), 3) Telephone reminder plus telephone support (TEL-SUPP) and 4) Telephone reminder plus support plus AR (TEL-SUPP-AR). The primary outcome will be attendance at breast screening within 3 months of the reminder letter. DISCUSSION If this simple telephone support intervention (with or without AR intervention) leads to a significant increase in breast screening attendance, this would represent a rare example of a theoretically-driven, relatively simple psychological intervention that could result in earlier detection of breast cancer amongst an under-served group of lower socio-economic women. TRIAL REGISTRATION Current Controlled trials: ISRCTN06039270. Registered 16th January 2014

Direct spectrum of the benchmark t dwarf HD 19467 B

This is the final version of the article. Available from the American Astronomical Society / IOP Publishing via the DOI in this record.HD 19467 B is presently the only directly imaged T dwarf companion known to induce a measurable Doppler acceleration around a solar-type star. We present spectroscopy measurements of this important benchmark object taken with the Project 1640 integral field unit at Palomar Observatory. Our high-contrast R ≈ 30 observations obtained simultaneously across the JH bands confirm the cold nature of the companion as reported from the discovery article and determine its spectral type for the first time. Fitting the measured spectral energy distribution to SpeX/IRTF T dwarf standards and synthetic spectra from BT-Settl atmospheric models, we find that HD 19467 B is a T5.5 ± 1 dwarf with effective temperature Teff = 978+20 -43 K. Our observations reveal significant methane absorption affirming its substellar nature. HD 19467 B shows promise to become the first T dwarf that simultaneously reveals its mass, age, and metallicity independent from the spectrum of light that it emits.The TrenDS high-contrast imaging program is supported by NASA Origins of Solar Systems grant NNX13AB03G and the NASA Early Career Fellowship program. A portion of this work was supported by the National Science Foundation under Grant Numbers AST-0215793, 0334916, 0520822, 0804417 and 1245018. This work was partially supported by NASA ADAP grant 11-ADAP11-0169 and NSF award AST 1211568. A portion of the research in this Letter was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration. J.A. is supported by the National Physical Science Consortium. This research has benefitted from the SpeX Prism Spectral Libraries, maintained by Adam Burgasser.1

Mitotic Arrest in Teratoma Susceptible Fetal Male Germ Cells

Formation of germ cell derived teratomas occurs in mice of the 129/SvJ strain, but not in C57Bl/6 inbred or CD1 outbred mice. Despite this, there have been few comparative studies aimed at determining the similarities and differences between teratoma susceptible and non-susceptible mouse strains. This study examines the entry of fetal germ cells into the male pathway and mitotic arrest in 129T2/SvJ mice. We find that although the entry of fetal germ cells into mitotic arrest is similar between 129T2/SvJ, C57Bl/6 and CD1 mice, there were significant differences in the size and germ cell content of the testis cords in these strains. In 129T2/SvJ mice germ cell mitotic arrest involves upregulation of p27KIP1, p15INK4B, activation of RB, the expression of male germ cell differentiation markers NANOS2, DNMT3L and MILI and repression of the pluripotency network. The germ-line markers DPPA2 and DPPA4 show reciprocal repression and upregulation, respectively, while FGFR3 is substantially enriched in the nucleus of differentiating male germ cells. Further understanding of fetal male germ cell differentiation promises to provide insight into disorders of the testis and germ cell lineage, such as testis tumour formation and infertility

Effect of a 2-week interruption in methotrexate treatment versus continued treatment on COVID-19 booster vaccine immunity in adults with inflammatory conditions (VROOM study): a randomised, open label, superiority trial

BACKGROUND: Immunosuppressive treatments inhibit vaccine-induced immunity against SARS-CoV-2. We evaluated whether a 2-week interruption of methotrexate treatment immediately after the COVID-19 vaccine booster improved antibody responses against the S1 receptor-binding domain (S1-RBD) of the SARS-CoV-2 spike protein compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. METHODS: We did an open-label, prospective, two-arm, parallel-group, multicentre, randomised, controlled, superiority trial in 26 hospitals in the UK. We recruited adults from rheumatology and dermatology clinics who had been diagnosed with an immune-mediated inflammatory disease (eg, rheumatoid arthritis, psoriasis with or without arthritis, axial spondyloarthritis, atopic dermatitis, polymyalgia rheumatica, and systemic lupus erythematosus) and who were taking low-dose weekly methotrexate (≤25 mg per week) for at least 3 months. Participants also had to have received two primary vaccine doses from the UK COVID-19 vaccination programme. We randomly assigned the participants (1:1), using a centralised validated computer randomisation program, to suspend methotrexate treatment for 2 weeks immediately after their COVID-19 booster (suspend methotrexate group) or to continue treatment as usual (continue methotrexate group). Participants, investigators, clinical research staff, and data analysts were unmasked, while researchers doing the laboratory analyses were masked to group assignment. The primary outcome was S1-RBD antibody titres 4 weeks after receiving the COVID-19 booster vaccine dose, assessed in the intention-to-treat population. This trial is registered with ISRCT, ISRCTN11442263; following the pre-planned interim analysis, recruitment was stopped early. FINDINGS: Between Sept 30, 2021 and March 3, 2022, we recruited 340 participants, of whom 254 were included in the interim analysis and had been randomly assigned to one of the two groups: 127 in the continue methotrexate group and 127 in the suspend methotrexate group. Their mean age was 59·1 years, 155 (61%) were female, 130 (51%) had rheumatoid arthritis, and 86 (34%) had psoriasis with or without arthritis. After 4 weeks, the geometric mean S1-RBD antibody titre was 22 750 U/mL (95% CI 19 314-26 796) in the suspend methotrexate group and 10 798 U/mL (8970-12 997) in the continue methotrexate group, with a geometric mean ratio (GMR) of 2·19 (95% CI 1·57-3·04; p<0·0001; mixed-effects model). The increased antibody response in the suspend methotrexate group was consistent across methotrexate dose, administration route, type of immune-mediated inflammatory disease, age, primary vaccination platform, and history of SARS-CoV-2 infection. There were no intervention-related serious adverse events. INTERPRETATION: A 2-week interruption of methotrexate treatment for people with immune-mediated inflammatory diseases resulted in enhanced boosting of antibody responses after COVID-19 vaccination. This intervention is simple, low-cost, and easy to implement, and could potentially translate to increased vaccine efficacy and duration of protection for susceptible groups. FUNDING: National Institute for Health and Care Research

Recovery after spinal cord relapse in multiple sclerosis is predicted by radial diffusivity

Background: The aim of this study was to determine whether the diffusion tensor-derived radial diffusivity and axial diffusivity, measured in the cortico-spinal tract in the cervical cord, predict clinical recovery after a cord relapse in patients with multiple sclerosis, and change over time

Tendinopathy—from basic science to treatment

Chronic tendon pathology (tendinopathy), although common, is difficult to treat. Tendons possess a highly organized fibrillar matrix, consisting of type I collagen and various 'minor' collagens, proteoglycans and glycoproteins. The tendon matrix is maintained by the resident tenocytes, and there is evidence of a continuous process of matrix remodeling, although the rate of turnover varies at different sites. A change in remodeling activity is associated with the onset of tendinopathy. Major molecular changes include increased expression of type III collagen, fibronectin, tenascin C, aggrecan and biglycan. These changes are consistent with repair, but they might also be an adaptive response to changes in mechanical loading. Repeated minor strain is thought to be the major precipitating factor in tendinopathy, although further work is required to determine whether it is mechanical overstimulation or understimulation that leads to the change in tenocyte activity. Metalloproteinase enzymes have an important role in the tendon matrix, being responsible for the degradation of collagen and proteoglycan in both healthy patients and those with disease. Metalloproteinases that show increased expression in painful tendinopathy include ADAM (a disintegrin and metalloproteinase)-12 and MMP (matrix metalloproteinase)-23. The role of these enzymes in tendon pathology is unknown, and further work is required to identify novel and specific molecular targets for therapy

Prospecting environmental mycobacteria: combined molecular approaches reveal unprecedented diversity

Background: Environmental mycobacteria (EM) include species commonly found in various terrestrial and aquatic environments, encompassing animal and human pathogens in addition to saprophytes. Approximately 150 EM species can be separated into fast and slow growers based on sequence and copy number differences of their 16S rRNA genes. Cultivation methods are not appropriate for diversity studies; few studies have investigated EM diversity in soil despite their importance as potential reservoirs of pathogens and their hypothesized role in masking or blocking M. bovis BCG vaccine. Methods: We report here the development, optimization and validation of molecular assays targeting the 16S rRNA gene to assess diversity and prevalence of fast and slow growing EM in representative soils from semi tropical and temperate areas. New primer sets were designed also to target uniquely slow growing mycobacteria and used with PCR-DGGE, tag-encoded Titanium amplicon pyrosequencing and quantitative PCR. Results: PCR-DGGE and pyrosequencing provided a consensus of EM diversity; for example, a high abundance of pyrosequencing reads and DGGE bands corresponded to M. moriokaense, M. colombiense and M. riyadhense. As expected pyrosequencing provided more comprehensive information; additional prevalent species included M. chlorophenolicum, M. neglectum, M. gordonae, M. aemonae. Prevalence of the total Mycobacterium genus in the soil samples ranged from 2.3×107 to 2.7×108 gene targets g−1; slow growers prevalence from 2.9×105 to 1.2×107 cells g−1. Conclusions: This combined molecular approach enabled an unprecedented qualitative and quantitative assessment of EM across soil samples. Good concordance was found between methods and the bioinformatics analysis was validated by random resampling. Sequences from most pathogenic groups associated with slow growth were identified in extenso in all soils tested with a specific assay, allowing to unmask them from the Mycobacterium whole genus, in which, as minority members, they would have remained undetected

Multi-state models and arthroplasty histories after unilateral total hip arthroplasties: Introducing the Summary Notation for Arthroplasty Histories

Background and purpose: An increasing number of patients have several joint replacement procedures during their lifetime. We investigated the use and suitability of multi-state model techniques in providing a more comprehensive analysis and description of complex arthroplasty histories held in arthroplasty registries than are allowed for with traditional survival methods. Patients and methods: We obtained data from the Australian Orthopaedic Association National Joint Replacement Registry on patients (n = 84,759) who had undergone a total hip arthroplasty for osteoarthritis in the period 2002–2008. We set up a multi-state model where patients were followed from their first recorded arthroplasty to several possible states: revision of first arthroplasty, either a hip or knee as second arthroplasty, revision of the second arthroplasty, and death. The Summary Notation for Arthroplasty Histories (SNAH) was developed in order to help to manage and analyze this type of data. Results: At the end of the study period, 12% of the 84,759 patients had received a second hip, 3 times as many as had received a knee. The estimated probabilities of having received a second arthroplasty decreased with age. Males had a lower transition rate for receiving a second arthroplasty, but a higher mortality rate. Interpretation: Multi-state models in combination with SNAH codes are well suited to the management and analysis of arthroplasty registry data on patients who experience multiple joint procedures over time. We found differences in the progression of joint replacement procedures after the initial total hip arthroplasty regarding type of joint, age, and sex.Marianne H Gillam, Philip Ryan, Amy Salter, Stephen E Grave

Statistical process control of mortality series in the Australian and New Zealand Intensive Care Society (ANZICS) adult patient database: implications of the data generating process

for the ANZICS Centre for Outcome and Resource Evaluation (CORE) of the Australian and New Zealand Intensive Care Society (ANZICS)BACKGROUND Statistical process control (SPC), an industrial sphere initiative, has recently been applied in health care and public health surveillance. SPC methods assume independent observations and process autocorrelation has been associated with increase in false alarm frequency. METHODS Monthly mean raw mortality (at hospital discharge) time series, 1995–2009, at the individual Intensive Care unit (ICU) level, were generated from the Australia and New Zealand Intensive Care Society adult patient database. Evidence for series (i) autocorrelation and seasonality was demonstrated using (partial)-autocorrelation ((P)ACF) function displays and classical series decomposition and (ii) “in-control” status was sought using risk-adjusted (RA) exponentially weighted moving average (EWMA) control limits (3 sigma). Risk adjustment was achieved using a random coefficient (intercept as ICU site and slope as APACHE III score) logistic regression model, generating an expected mortality series. Application of time-series to an exemplar complete ICU series (1995-(end)2009) was via Box-Jenkins methodology: autoregressive moving average (ARMA) and (G)ARCH ((Generalised) Autoregressive Conditional Heteroscedasticity) models, the latter addressing volatility of the series variance. RESULTS The overall data set, 1995-2009, consisted of 491324 records from 137 ICU sites; average raw mortality was 14.07%; average(SD) raw and expected mortalities ranged from 0.012(0.113) and 0.013(0.045) to 0.296(0.457) and 0.278(0.247) respectively. For the raw mortality series: 71 sites had continuous data for assessment up to or beyond lag ₄₀ and 35% had autocorrelation through to lag ₄₀; and of 36 sites with continuous data for ≥ 72 months, all demonstrated marked seasonality. Similar numbers and percentages were seen with the expected series. Out-of-control signalling was evident for the raw mortality series with respect to RA-EWMA control limits; a seasonal ARMA model, with GARCH effects, displayed white-noise residuals which were in-control with respect to EWMA control limits and one-step prediction error limits (3SE). The expected series was modelled with a multiplicative seasonal autoregressive model. CONCLUSIONS The data generating process of monthly raw mortality series at the ICU level displayed autocorrelation, seasonality and volatility. False-positive signalling of the raw mortality series was evident with respect to RA-EWMA control limits. A time series approach using residual control charts resolved these issues.John L Moran, Patricia J Solomo