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Tuberculosis (TB) is the most common cause of death in people living with HIV. BCG delivered intradermally (ID) is the only licensed vaccine to prevent TB. However, it offers little protection from pulmonary TB in adults. Intravenous (IV) BCG, but not ID BCG, confers striking protection against Mycobacterium tuberculosis (Mtb) infection and disease in rhesus macaques. We investigated whether IV BCG could protect against TB in macaques with a pre-existing SIV infection. There was a robust influx of airway T cells following IV BCG in both SIV-infected and SIV-naïve animals, with elevated antibody titers in plasma and airways. Following Mtb challenge, all 7 SIV-naïve and 9 out of 12 SIV-infected vaccinated animals were completely protected, without any culturable bacilli in their tissues. PBMC responses post-challenge indicated early clearance of Mtb in vaccinated animals regardless of SIV infection. These data support that IV BCG is immunogenic and efficacious in SIV-infected animals.

Tuberculosis (TB) is the leading infectious cause of death among people living with HIV. People living with HIV are more susceptible to contracting Mycobacterium tuberculosis and often have worsened TB disease. Understanding the immunologic defects caused by HIV and the consequences it has on M. tuberculosis coinfection is critical in combating this global health epidemic. We previously showed in a model of SIV and M. tuberculosis coinfection in Mauritian cynomolgus macaques (MCM) that SIV/M. tuberculosis–coinfected MCM had rapidly progressive TB. We hypothesized that pre-existing SIV infection impairs early T cell responses to M. tuberculosis infection. We infected MCM with SIVmac239, followed by coinfection with M. tuberculosis Erdman 6 mo later. Although similar, TB progression was observed in both SIV+ and SIV-naive animals at 6 wk post–M. tuberculosis infection; longitudinal sampling of the blood (PBMC) and airways (bronchoalveolar lavage) revealed a significant reduction in circulating CD4+ T cells and an influx of CD8+ T cells in airways of SIV+ animals. At sites of M. tuberculosis infection (i.e., granulomas), SIV/M. tuberculosis–coinfected animals had a higher proportion of CD4+ and CD8+ T cells expressing PD-1 and TIGIT. In addition, there were fewer TNF-producing CD4+ T cells in granulomas of SIV/M. tuberculosis–coinfected animals. Taken together, we show that concurrent SIV infection alters T cell phenotypes in granulomas during the early stages of TB disease. As it is critical to establish control of M. tuberculosis replication soon postinfection, these phenotypic changes may distinguish the immune dysfunction that arises from pre-existing SIV infection, which promotes TB progression.

Breast amyloidosis is a rare condition which is mostly associated with hematological disorders or hereditary genetic disorders. Imaging findings of breast amyloidosis can mimic malignancy, which often leads to biopsy or excision of the lesion. Here, we presented a case of localized lactotransferrin-related breast amyloidosis in an elderly female patient. Histologic examination revealed extensive involvement of breast lobules by amorphous amyloid materials, with attenuation of lobular structures and prominent calcifications. Positive immunostains for myoepithelial cells helped to exclude the possibility of invasive carcinoma. The patient had no hematologic malignancy besides immunoglobulin G lambda monoclonal gammopathy of undetermined significance. Mass spectrometry of the breast amyloid identified lactotransferrin and no immunoglobulin or its light chain. On follow-up, the patient showed no recurrence of the breast lesion after local excision nor showed other systematic comorbidities, indicating the benign nature of the lesion. This first report of lactotransferrin-related amyloidosis may represent a special type of localized breast amyloidosis that has no correlation with systematic disorders.

During the decades representing working-age adulthood, most people will experience one or several significant life events or transitions. These may present a challenge to mental health.The primary aim of this rapid systematic review of systematic reviews was to summarise available evidence on the effectiveness of interventions to promote and protect mental health relating to four key life events and transitions: pregnancy and early parenthood, bereavement, unemployment, and housing problems. This review was conducted to inform UK national policy on mental health support.We searched key databases for systematic reviews of interventions for working-age adults (19 to 64 years old) who had experienced or were at risk of experiencing one of four key life events. Titles and abstracts were screened by two reviewers in duplicate, as were full-text manuscripts of relevant records. We assessed the quality of included reviews and extracted data on the characteristics of each literature review. We prioritised high quality, recent systematic reviews for more detailed data extraction and synthesis.The search and screening of 3997 titles/abstracts and 239 full-text papers resulted in 134 relevant studies, 68 of which were included in a narrative synthesis. Evidence was strongest and of the highest quality for interventions to support women during pregnancy and after childbirth. For example, we found benefits of physical activity and psychological therapy for outcomes relating to mental health after birth. There was high quality evidence of positive effects of online bereavement interventions and psychological interventions on symptoms of grief, post-traumatic stress, and depression. Evidence was inconclusive and of lower quality for a range of other bereavement interventions, unemployment support interventions, and housing interventions.Whilst evidence based mental health prevention and promotion is available during pregnancy and early parenthood and for bereavement, it is unclear how best to support adults experiencing job loss, unemployment, and housing problems.

Early intensive applied behaviour analysis-based interventions are intensive interventions for autistic children that are often delivered on a one-to-one basis for 20-50 hours per week.To evaluate the clinical effectiveness and cost-effectiveness of early intensive applied behaviour analysis-based interventions for autistic children, based on current evidence.A systematic review and individual participant data meta-analysis were conducted to evaluate the clinical effectiveness of an early intensive applied behaviour analysis-based intervention for autistic children. An economic analysis included a review of existing analyses and the development of a new model.Twenty studies were included in the clinical review. Individual participant data were retrieved from 15 of these studies. Results favoured the interventions when assessing adaptive behaviour after 2 years compared with treatment as usual/eclectic interventions (mean difference 7.00, 95% confidence interval 1.95 to 12.06). In analyses of cognitive ability (intelligence quotient), results favoured the interventions by approximately 10 points after 1 year (mean difference 9.16, 95% confidence interval 4.38 to 13.93) and 2 years (mean difference 14.13, 95% confidence interval 9.16 to 19.10). Evidence for other outcomes was limited and meta-analyses were generally inconclusive. There was no evidence that the effect of the interventions varied with characteristics of the children, but data were limited. Adopting a £30,000 per quality-adjusted life-year threshold, the results of the cost-effectiveness analysis indicate that early intensive applied behaviour analysis-based interventions would need to generate larger benefits or cost savings to be cost-effective. Adopting a public sector perspective and making pessimistic assumptions about long-term effects, the incremental cost-effectiveness ratio for early intensive applied behaviour analysis-based therapy compared with treatment as usual is £189,122 per quality-adjusted life-year. When optimistic assumptions are made, the incremental cost-effectiveness ratio is £46,768 per quality-adjusted life-year. Scenario analyses indicated that these interventions can potentially be cost-effective if long-term improvements persist into adulthood, or if they have significant impact on educational placement. Care should be taken when interpreting these scenarios owing to the limited data.All included studies were at risk of bias, there was substantial heterogeneity and effects varied considerably across studies. The effect of intervention on autism symptom severity, language development and school placement remains uncertain because of the limited data. The long-term effects are unclear owing to a lack of follow-up data.This review found limited evidence that early intensive applied behaviour analysis-based interventions may improve cognitive ability and adaptive behaviour, but the long-term impact of the interventions remains unknown. The economic analysis is constrained by the limited effectiveness evidence, but suggests that these interventions are unlikely to be cost-effective unless clear long-term benefits, or a substantial change in which schools children attend, can be identified.Further studies into the effectiveness of early intensive applied behaviour analysis-based interventions may be warranted if they include well-defined, alternative interventions as comparators and collect relevant outcomes. Consideration should be given to future studies that not only address whether or not early intensive applied behaviour analysis-based interventions are clinically effective, but also aim to identify which components of early intensive applied behaviour analysis-based interventions might drive effectiveness.This study is registered as PROSPERO CRD42017068303.This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inAutism is a lifelong condition that affects how people understand the world and interact with others. Early intensive applied behaviour analysis-based interventions are an approach designed to help young (preschool) autistic children. This approach is often delivered on a one-to-one basis, for 20–50 hours per week, over a period of several years. This project obtained and analysed the original data from studies of early intensive applied behaviour analysis-based interventions, to determine whether or not these interventions are beneficial. It also investigated whether or not the interventions represent good value for money. The results suggest that early intensive applied behaviour analysis-based interventions may improve children’s intelligence, communication, social and life skills more than standard approaches. However, some results could be inaccurate or incorrect, and there was no evidence about other important outcomes, such as the severity of autism and where children went to school. Most studies lasted for around 2 years, which means that it is not known if early intensive applied behaviour analysis-based interventions have meaningful long-term benefits. It was not possible to fully assess whether or not these interventions provided value for money, as the benefits of early intensive applied behaviour analysis-based interventions were unclear, although the available evidence suggested that they did not. Early intensive applied behaviour analysis-based interventions may, however, provide value for money if their effects were to last into adulthood, or if receiving early intensive applied behaviour analysis had a large impact on the type of school children attended. Future studies of early interventions may be helpful, but should consider looking at which components of early applied behaviour analysis-based interventions are the most important, rather than at whether or not they work better than other interventions. Future studies should also follow best current research practice and evaluate outcomes that matter to autistic people and their families.

Background The health and well-being of staff working in the NHS is a significant issue for UK health care. We sought to identify research relevant to the promotion of healthy lifestyles among NHS staff on behalf of NHS England. Objectives To map existing reviews on workplace-based interventions to promote health and well-being, and to assess the scope for further evidence synthesis work. Design Rapid and responsive scoping search and evidence map. Participants Adult employees in any occupational setting and in any role. Interventions Any intervention aimed at promoting or maintaining physical or mental health and well-being. Early intervention initiatives and those addressing violence against staff, workplace bullying or harassment were also included. Main outcome measures Any outcome related to the effectiveness, cost-effectiveness or implementation of interventions. Data sources A scoping search of nine databases was conducted to identify systematic reviews on health and well-being at work. Searches were limited by publication date (2000 to January/February 2019). Review methods The titles and abstracts of over 8241 records were screened and a total of 408 potentially relevant publications were identified. Information on key characteristics were extracted from the titles and abstracts of all potentially relevant publications. Descriptive statistics (counts and percentages) for key characteristics were generated and data from reviews and ‘reviews of reviews’ were used to produce the evidence map. Results Evidence related to a broad range of physical and mental health issues was identified across 12 ‘reviews of reviews’ and 312 other reviews, including 16 Cochrane reviews. There also exists National Institute for Health and Care Excellence guidance addressing multiple issues of potential relevance. A large number of reviews focused on mental health, changing lifestyle behaviour, such as physical activity, or on general workplace health/health promotion. Most of the reviews that focused only on health-care staff addressed mental health issues, and stress/burnout in particular. Limitations The scoping search process was extensive and clearly effective at identifying relevant publications, but the strategy used may not have identified every potentially relevant review. Owing to the large number of potentially relevant reviews identified from the scoping search, it was necessary to produce the evidence map using information from the titles and abstracts of reviews only. Conclusions It is doubtful that further evidence synthesis work at this stage would generate substantial new knowledge, particularly within the context of the NHS Health and Wellbeing Framework[NHS England. Workforce Health and Wellbeing Framework. 2018. URL: www.nhsemployers.org/-/media/Employers/Publications/Health-and-wellbeing/NHS-Workforce-HWB-Framework_updated-July-18.pdf (accessed 10 January 2019)] published in 2018. Additional synthesis work may be useful if it addressed an identifiable need and it was possible to identify one of the following: (1) a specific and focused research question arising from the current evidence map; it may then be appropriate to focus on a smaller number of reviews only, and provide a more thorough and critical assessment of the available evidence; and (2) a specific gap in the literature (i.e. an issue not already addressed by existing reviews or guidance); it may then be possible to undertake further literature searching and conduct a new evidence review. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 18. See the NIHR Journals Library website for further project information.

Mycobacterium tuberculosis (Mtb) is the leading cause of death from infection worldwide1. The only available vaccine, BCG (Bacillus Calmette–Guerin), is given intradermally and has variable efficacy against pulmonary tuberculosis, the major cause of mortality and disease transmission1,2. Here we show that intravenous administration of BCG profoundly alters the protective outcome of Mtb challenge in non-human primates (Macaca mulatta). Compared with intradermal or aerosol delivery, intravenous immunization induced substantially more antigen-responsive CD4 and CD8 T cell responses in blood, spleen, bronchoalveolar lavage and lung lymph nodes. Moreover, intravenous immunization induced a high frequency of antigen-responsive T cells across all lung parenchymal tissues. Six months after BCG vaccination, macaques were challenged with virulent Mtb. Notably, nine out of ten macaques that received intravenous BCG vaccination were highly protected, with six macaques showing no detectable levels of infection, as determined by positron emission tomography–computed tomography imaging, mycobacterial growth, pathology and granuloma formation. The finding that intravenous BCG prevents or substantially limits Mtb infection in highly susceptible rhesus macaques has important implications for vaccine delivery and clinical development, and provides a model for defining immune correlates and mechanisms of vaccine-elicited protection against tuberculosis. The delivery route and dose of the BCG vaccine profoundly alters the protective outcome after Mycobacterium tuberculosis challenge in non-human primates.

Background The economic and social costs of autism are significant. This study evaluates the cost-effectiveness of early intensive Applied Behaviour Analysis (ABA)-based interventions for autistic pre-school children in the UK. Methods A de novo economic analysis was developed in Microsoft Excel comparing early intensive ABA-based interventions compared with treatment as usual (TAU). The analysis used 15.5-year time horizon, with costs and benefits discounted a 3.5%. The model structure was based on cohort structure to capture changes in adaptive behaviour and cognitive ability over time. The analysis was informed by an individual patient data (IPD) meta-analysis of available evidence. Results Adopting a public sector perspective, early intensive ABA-based therapies were associated with greater incremental costs and greater benefits. When pessimistic assumptions were made regarding the long-term effects of treatment incremental costs were £46,103 and incremental quality-adjusted life years (QALYs) were 0.24, resulting in an incremental cost-effectiveness ratio (ICER) of £189,122 per quality-adjusted life year (QALY). When optimistic assumptions were made about long-term effects, incremental costs were £39,233 with incremental benefits of 0.84 QALYs. The resulting ICER was £46,768 per QALY. Scenario analyses emphasised the importance of assumptions made regarding adult outcomes and type of school attended, both of which significantly affect the results of the analysis. Conclusions The results of this economic analysis suggest that early intensive ABA-based interventions are unlikely to represent value for money, based on a £20,000 to £30,000 per QALY threshold typically adopted to inform UK healthcare funding decisions. However, important gaps in the available evidence, limit the strength of the conclusions that can be drawn from the presented analysis. Further research, focusing on the trajectory of autistic children following intervention is likely to be highly beneficial to resolving some of these uncertainties.

Background Lifestyle risk behaviours are associated with an increased risk of non-communicable disease and mortality. There are socio-economic inequalities in these behaviours, with some behaviours being more prevalent in particular groups, such as prisoners, homeless people and Gyspies, Travellers and Roma. The aim of this scoping review was to identify and bring together existing evidence from systematic reviews on reducing risk behaviours in disadvantaged groups and highlight where there is insufficient evidence to inform policy. Methods MEDLINE and Embase were searched up to October 2020 for English language reviews, with supplementary searching in Epistemonikos and Health Systems Evidence. Systematic reviews reporting behavioural outcomes of interventions targeting smoking, excessive alcohol use, unhealthy diet or physical inactivity in low income or socio-economic status (SES), unemployed people, homeless people, care leavers, prisoners, refugees or asylum seekers, Travellers, Gypsies or Roma, people with learning disabilities or deprived areas or communities were eligible. Reviews of population-level policies reporting differential effects for disadvantaged groups and qualitative reviews exploring barriers or facilitators to behaviour change were also included. The literature was mapped based on the group and behaviour targeted. Results In total 9,336 records were screened, 262 full texts retrieved and 92 systematic reviews included. The majority of reviews included studies of people with low income or SES (n=68), with diet and low income the most frequently addressed combination. There were fourteen reviews on prisoners, 12 on deprived areas, ten on homeless people and nine on people with learning disabilities. Only three reviews included unemployed people and two included refugees or asylum seekers (both focusing on barriers and facilitators to healthy eating). No reviews were identified on care leavers or Gypsies, Travellers and Roma. In total there were 11 reviews targeting alcohol use. Sixteen qualitative reviews explored participants’ perceptions of barriers and facilitators to changing their behaviour. Conclusion A large number of systematic reviews were identified but we found some evidence gaps where new syntheses or primary studies may be needed to guide policy, for example on care leavers, Gypsies, Travellers and Roma and refugees and asylum seekers. Other useful contributions might include an overview bringing together different interventions in low-income populations and an overview of the perceptions of disadvantaged groups about behaviour change, allowing common barriers to be identified as well as factors that are unique to specific groups.

Background For systematic reviews to be rigorous, deliverable and useful, they need a well-defined review question. Scoping for a review also requires the specification of clear inclusion criteria and planned synthesis methods. Guidance is lacking on how to develop these, especially in the context of undertaking rapid and responsive systematic reviews to inform health services and health policy. Objective This report describes and discusses the experiences of review scoping of three commissioned research centres that conducted evidence syntheses to inform health and social care organisation, delivery and policy in the UK, between 2017 and 2020. Data sources Sources included researcher recollection, project meeting minutes, e-mail correspondence with stakeholders and scoping searches, from allocation of a review topic through to review protocol agreement. Methods We produced eight descriptive case studies of selected reviews from the three teams. From case studies, we identified key issues that shape the processes of scoping and question formulation for evidence synthesis. The issues were then discussed and lessons drawn. Findings Across the eight diverse case studies, we identified 14 recurrent issues that were important in shaping the scoping processes and formulating a review’s questions. There were ‘consultative issues’ that related to securing input from review commissioners, policy customers, experts, patients and other stakeholders. These included managing and deciding priorities, reconciling different priorities/perspectives, achieving buy-in and engagement, educating the end-user about synthesis processes and products, and managing stakeholder expectations. There were ‘interface issues’ that related to the interaction between the review team and potential review users. These included identifying the niche/gap and optimising value, assuring and balancing rigour/reliability/relevance, and assuring the transferability/applicability of study evidence to specific policy/service user contexts. There were also ‘technical issues’ that were associated with the methods and conduct of the review. These were choosing the method(s) of synthesis, balancing fixed and fluid review questions/components/definitions, taking stock of what research already exists, mapping versus scoping versus reviewing, scoping/relevance as a continuous process and not just an initial stage, and calibrating general compared with specific and broad compared with deep coverage of topics. Limitations As a retrospective joint reflection by review teams on their experiences of scoping processes, this report is not based on prospectively collected research data. In addition, our evaluations were not externally validated by, for example, policy and service evidence users or patients and the public. Conclusions We have summarised our reflections on scoping from this programme of reviews as 14 common issues and 28 practical ‘lessons learned’. Effective scoping of rapid, responsive reviews extends beyond information exchange and technical procedures for specifying a ‘gap’ in the evidence. These considerations work alongside social processes, in particular the building of relationships and shared understanding between reviewers, research commissioners and potential review users that may be reflective of consultancy, negotiation and co-production models of research and information use. Funding This report has been based on work commissioned by the National Institute for Health Research (NIHR) Health Services and Delivery Research (HSDR) programme as three university-based evidence synthesis centres to inform the organisation, delivery and commissioning of health and social care; at the University of Exeter (NIHR 16/47/22), the University of Sheffield (NIHR 16/47/17) and the University of York (NIHR 16/47/11). This report was commissioned by the NIHR HSDR programme as a review project (NIHR132708) within the NIHR HSDR programme. This project was funded by the NIHR HSDR programme and will be published in full in Health Services and Delivery Research; Vol. 9, No. 15. See the NIHR Journals Library website for further project information.

Tuberculosis (TB) is the leading cause of death from infection worldwide. The only approved vaccine, BCG, has variable protective efficacy against pulmonary TB, the transmissible form of the disease. Therefore, improving this efficacy is an urgent priority. This study assessed whether heterologous prime-boost vaccine regimens in which BCG priming is boosted with either (i) protein and adjuvant (M72 plus AS01E or H56 plus CAF01) delivered intramuscularly (IM), or (ii) replication-defective recombinant adenovirus serotype 5 (Ad5) expressing various Mycobacterium tuberculosis (Mtb) antigens (Ad5(TB): M72, ESAT-6/Ag85b, or ESAT-6/Rv1733/Rv2626/RpfD) administered simultaneously by IM and aerosol (AE) routes, could enhance blood- and lung-localized T-cell immunity and improve protection in a nonhuman primate (NHP) model of TB infection. Ad5(TB) vaccines administered by AE/IM routes following BCG priming elicited ~10–30% antigen-specific CD4 and CD8 T-cell multifunctional cytokine responses in bronchoalveolar lavage (BAL) but did not provide additional protection compared to BCG alone. Moreover, AE administration of an Ad5(empty) control vector after BCG priming appeared to diminish protection induced by BCG. Boosting BCG by IM immunization of M72/AS01E or H56:CAF01 elicited ~0.1–0.3% antigen-specific CD4 cytokine responses in blood with only a transient increase of ~0.5–1% in BAL; these vaccine regimens also failed to enhance BCG-induced protection. Taken together, this study shows that boosting BCG with protein/adjuvant or Ad-based vaccines using these antigens, by IM or IM/AE routes, respectively, do not enhance protection against primary infection compared with BCG alone, in the highly susceptible rhesus macaque model of tuberculosis., Tuberculosis vaccination: Multi-platform/route BCG boosting in rhesus macaques BCG is the only clinically-approved tuberculosis (TB) vaccine but has highly variable protection against pulmonary manifestations of the disease. JoAnne Flynn and colleagues at the University of Pittsburgh investigate whether heterologous boosting can improve the efficacy of BCG vaccination in a highly susceptible rhesus macaque model. The boosting is performed using a variety of vaccination routes (intramuscular, aerosol) and platforms including multiple Mycobacterium tuberculosis (Mtb) protein subunits in adjuvant and/or expressed in adenovirus vectors. The various platforms and routes are designed to enhance immune responses thought to be involved in protection from Mtb. Despite in certain cases (e.g., aerosol) being able to enhance lung T cell cytokine responses, none of the boosting regimens showed any improved protection over standard intradermal BCG vaccination. This study highlights the formidable challenges facing attempts to elicit robust pulmonary protection against pulmonary Mtb infection.

Individuals infected with both HIV and Mycobacterium tuberculosis (Mtb) are more likely to develop severe Tuberculosis (TB) disease than HIV-naïve individuals. To understand how a chronic pre-existing Simian immunodeficiency virus (SIV) infection impairs the early immune response to Mtb, we used the Mauritian cynomolgus macaque (MCM) model of SIV/Mtb co-infection. We examined the relationship between peripheral viral control and Mtb burden, Mtb dissemination, and immunological function between SIV+ spontaneous controllers, SIV+ non-controllers, and SIV-naïve MCM who were challenged with a barcoded Mtb Erdman strain and necropsied six weeks post infection. Mycobacterial burden was highest in the SIV+ non-controllers in all assessed tissues. In lung granulomas, we found the frequency of CD4+ T cells producing TNFα was reduced in all SIV+ MCM, but CD4+ T cells producing IFNγ were only lower in the SIV+ non-controllers. Further, while all SIV+ MCM had more PD1+ and TIGIT+ T cells in the lung granulomas relative to SIV-naïve MCM, SIV+ controllers exhibited the highest frequency of cells expressing these markers. To measure the effect of SIV infection on within-host bacterial dissemination, we sequenced the molecular barcodes of Mtb present in each tissue and characterized the complexity of the Mtb populations. While Mtb population complexity was not associated with infection group, lymph nodes had increased complexity when compared to lung granulomas across all groups. These results provide evidence SIV+ animals, independent of viral control, exhibit dysregulated immune responses and enhanced dissemination of Mtb, likely contributing to the poor TB disease course across all SIV/Mtb co-infected animals.ImportanceHIV and TB remain significant global health issues, despite the availability of treatments. Individuals with HIV, including those who are virally suppressed, are at an increased risk to develop and succumb to severe TB disease when compared to HIV-naïve individuals. Our study aims to understand the relationship between SIV replication, mycobacterial growth, and immunological function in the tissues of co-infected Mauritian cynomolgus macaques during the early phase of Mtb infection. Here we demonstrate that increased viral replication is associated with increased bacterial burden in the tissues and impaired immunologic responses, and that the damage attributed to virus infection is not fully eliminated when animals spontaneously control virus replication.

This individual participant data meta-analysis is the most intensive possible evaluation of the effectiveness of early intensive applied behaviour analysis–based interventions for pre-school autistic children compared with treatment as usual/eclectic interventions. Data from 491 participants (originally collected in 10 studies) were included. Children receiving early intensive applied behaviour analysis–based interventions improved more on the Vineland adaptive behaviour scale (MD = 7.00; 95% confidence interval = 1.95–12.06) and cognitive ability (intelligence quotient) (MD = 14.13; 95% confidence interval = 9.16–19.10) relative to comparators at 2 years; though effects varied considerably across studies. Evidence for other outcomes was inconclusive due to insufficient evidence and there were few data on longer-term effects. All studies were at risk of bias across several domains, often due to the lack of randomisation or blinding of outcome assessors. Given the emerging evidence of modest, albeit short term, effects of a range of pre-school autism interventions and the limitations of the quality of evaluation studies to date, future research should investigate which supports and interventions are most effective for children and families prioritising outcomes measures that are meaningful for the autism community and longer-term follow-up. Further systematic reviews of the existing evidence are unlikely to add to the findings presented here. Lay abstract Early intensive applied behaviour analysis–based interventions are designed to support young autistic children’s learning and development. Unfortunately, the available evidence about the effectiveness of these interventions remains unclear. Several reviews have focused on the published findings rather than contacting the authors to collect and analyse data about the individual participants in the original studies. Also, most of the studies were carried out by groups involved in delivering the interventions leading to the potential bias in interpreting the results. Our research team (supported by an international advisory group) carried out an independent individual patient data review by collecting the original participant data from the authors of the studies, to examine the effectiveness of these interventions. The results suggested that early intensive applied behaviour analysis–based interventions might lead to some changes in children’s cognitive ability (intelligence quotient) and everyday life skills after 2 years, compared with standard treatments. However, all the studies had problems with the way they were designed. Also, few of the studies looked at outcomes that have been described as most important to autistic people or followed children beyond 2 years. We think that further systematic reviews of the existing evidence are unlikely to add to the findings of our review. Furthermore, we recommend that future research should investigate which types of supports and interventions are most effective for children and families, prioritising outcomes measures that are meaningful for the autism community and include, wherever possible, longer-term follow-up.

Tuberculosis (TB) is the leading infectious cause of death among people living with HIV (PLHIV). PLHIV are more susceptible to contracting Mycobacterium tuberculosis (Mtb) infection and often have worsened TB disease. Understanding the immunologic defects caused by HIV and the consequences it has on Mtb co-infection is critical in combating this global health epidemic. We previously established a model of simian immunodeficiency virus (SIV) and Mtb co-infection in Mauritian cynomolgus macaques (MCM), and showed that SIV/Mtb co-infected MCM had rapidly progressive TB. We hypothesized that pre-existing SIV infection impairs early T cell responses to Mtb infection. To test our hypothesis, we infected MCM with SIVmac239 intrarectally followed by co-infection with a low dose of Mtb Erdman 6 months later. SIV-naïve MCM were infected with Mtb alone as controls. Six weeks after Mtb infection, animals were necropsied and immune responses were measured by multiparameter flow cytometry. While the two groups exhibited similar TB progression at time of necropsy (Nx), longitudinal sampling of the blood (PBMC) and airways (BAL) revealed a significant reduction in circulating CD4+ T cells and an influx of CD8+ T cells in airways following Mtb co-infection of SIV+ animals. Differences in the activation markers CD69, PD-1, and TIGIT were observed. At sites of Mtb infection (i.e. granulomas), SIV/Mtb co-infected animals had a higher proportion of CD4+ and CD8+ T cells expressing PD-1 and TIGIT. In addition, there were fewer TNF-producing CD4+ and CD8+ T cells in granulomas and airways of SIV/Mtb co-infected animals. Taken together, we show that concurrent SIV infection alters T cell phenotypes in granulomas during the early stages of TB disease. As it is critical to establish control of Mtb replication soon after infection, these phenotypic changes may distinguish the immune dysfunction that arises from pre-existing SIV infection which promotes TB progression.Author SummaryPeople living with HIV are incredibly susceptible to TB and, when co-infected with Mtb, often develop serious TB disease. We do not yet understand precisely how HIV infection impairs the early stages of the adaptive immune response against Mtb bacilli. We employed a non-human primate model of HIV, using SIV as a surrogate for HIV, followed by Mtb co-infection to investigate the immunologic defects associated with pre-existing SIV infection over the first six weeks of Mtb co-infection. Our study focused on CD4+ and CD8+ T cells as these cells are known to play an important role in Mtb control. We found more CD8+ T cells in granulomas, the sites of Mtb infection, from SIV/Mtb co-infected animals, with little difference in CD4+ T cells. SIV/Mtb co-infected animals and animals infected with SIV alone had a higher proportion of both CD4+ and CD8+ T cells expressing activation markers compared to SIV-naïve animals, consistent with SIV-dependent immune activation. Notably, we observed a lower proportion of TNF-producing T cells, a cytokine critical for Mtb control, in granulomas and airways of SIV/Mtb co-infected animals. Taken together, these data show that pre-existing SIV alters T cell phenotypes and reduces TNF responses early in Mtb infection.

Background: The integration of care, particularly across the health and social care sectors, has been a long-standing policy objective in the UK. We sought to scope the evidence related to the regulation and inspection of integrated care. Objective(s): To identify and classify published material that could potentially address four key questions: 1. What models of regulation and inspection of integrated care have been proposed? (Including approaches taken in other countries) 2. What evidence is available on the effectiveness of such models? 3. What are the barriers and enablers of effective regulation and inspection of integrated care? 4. Can barriers to effective regulation and inspection be overcome without legislative change? Design: Rapid scoping review. Publication type and focus: Both empirical and non-empirical publications related to the regulation and inspection of integrated care were included. Setting: Publications focused on the integration of health and social care services, or provision delivered across other settings/sectors by different professional groups working together. Outcomes: Empirical studies reporting on any outcome relevant to the regulation and/or inspection of integrated care. Non-empirical publications focusing on any relevant issue including proposed models of regulation or outcome frameworks. Data sources: A targeted search of five databases was undertaken. Additionally, we conducted supplementary searches of the websites of key organisations and searched for other grey literature using the advanced search function of Google. Key contacts were also approached, and a request made for relevant documents. Review methods: The title and abstracts of 5380 records were screened and a total of 166 publications were included. Documents were coded based on key characteristics, and a descriptive summary of the literature produced. No attempt was made to assess the quality or synthesise the findings of the retrieved evidence. Results Out of the 166 included publications, 71 were identified from database searches and 95 were included from supplementary website searches. While there were records that could be classified as relevant to one or more of the research questions identified through the stakeholder consultation, there was a notable absence of evidence relating to (a) effectiveness of regulatory/inspection strategies and (b) professional regulation. Conclusions and future work The evidence base relating to the regulation or inspection of integrated care is relatively small. There may be an opportunity to synthesise some of the existing views and experience data on system regulation and inspection identified in a more formal systematic review. However, before a useful evidence base can be developed, policy makers and researchers need to agree what constitutes ‘effective’ regulation, how this can be measured, and which study designs are most appropriate for evaluation. Related questions about what constitutes ‘successful’ integration of care should also be taken into account when planning such research. While potentially useful reforms have been proposed, empirical evidence in relation to professional regulation appears particularly scarce. Organisations responsible for regulating professionals might therefore consider incorporating some form of evaluation into any planned strategic reforms. Limitations The degree of focus on integration or regulation was a difficult criterion to apply with strict consistency.

Mucosal-associated invariant T (MAIT) cells can recognize and respond to some bacterially infected cells. Several in vitro and in vivo models of Mycobacterium tuberculosis (Mtb) infection suggest that MAIT cells can contribute to control of Mtb, but these studies are often cross-sectional and use peripheral blood cells. Whether MAIT cells are recruited to Mtb-affected granulomas and lymph nodes (LNs) during early Mtb infection and what purpose they might serve there is less well understood. Furthermore, whether HIV/SIV infection impairs MAIT cell frequency or function at the sites of Mtb replication has not been determined. Using Mauritian cynomolgus macaques (MCM), we phenotyped MAIT cells in the peripheral blood and bronchoalveolar lavage (BAL) before and during infection with SIVmac239. To test the hypothesis that SIV co-infection impairs MAIT cell frequency and function within granulomas, SIV+ and -naïve MCM were infected with a low dose of Mtb Erdman, and necropsied at 6 weeks post Mtb-challenge. MAIT cell frequency and function were examined within the peripheral blood, BAL, and Mtb-affected lymph nodes (LN) and granulomas. MAIT cells did not express markers indicative of T cell activation in response to Mtb in vivo within granulomas in animals infected with Mtb alone. SIV and Mtb co-infection led to increased expression of the activation/exhaustion markers PD-1 and TIGIT, and decreased ability to secrete TNFα when compared to SIV-naïve MCM. Our study provides evidence that SIV infection does not prohibit the recruitment of MAIT cells to sites of Mtb infection, but does functionally impair those MAIT cells. Their impaired function could have impacts, either direct or indirect, on the long-term containment of TB disease., Author summary MAIT cells are a population of immune cells that can directly detect and destroy some bacterially infected cells. Evidence suggests that MAIT cells may play a role in control of Mycobacterium tuberculosis (Mtb) infection, but few studies have examined MAIT cell activity within granulomas, which are the sites of Mtb replication. In addition, chronic HIV infection has been shown to impair the frequency and function of MAIT cells in humans, but these studies focus on peripheral blood and not the sites of Mtb infection. Here, we used a macaque model of SIV and Mtb co-infection to determine whether SIV, as a model for HIV, could dysregulate MAIT cells in tissues where Mtb replication is occurring. SIV co-infection did not affect the absolute numbers of MAIT cells present within granulomas but did impair the ability of the MAIT cells to respond to mycobacteria both in vivo and in vitro. Overall, our study provides evidence that SIV infection alters MAIT cells phenotypically, and impairs MAIT cell function. What effect this might have on antimycobacterial immunity is an avenue for future exploration.

Mucosal associated invariant T (MAIT) cells recognize and can directly destroy bacterially infected cells. While a role for MAIT cells has been suggested in several in vitro and in vivo models of M.tuberculosis (Mtb) infection, these studies have often focused on MAIT cells within the peripheral blood or are cross-sectional studies rather than longitudinal studies. The role of MAIT cells within granulomas and other sites of Mtb infection is relatively unknown. Furthermore, how HIV/SIV infection might impair MAIT cells at the sites of Mtb infection has not been determined. Using a Mauritian cynomolgus macaque (MCM) model system, we phenotyped MAIT cells in the peripheral blood and BAL prior to and during infection with SIVmac239. To characterize the role of MAIT cells within granulomas, SIV+ and -naïve MCM were infected with a low dose of Mtb for 6 weeks. MAIT cell frequency and function was examined within the peripheral blood, distal airways, as well as within Mtb-affected lymph nodes (LN) and tissues. Surprisingly, we found no evidence of MAIT cell responsiveness to Mtb within granulomas. Additionally, MAIT cells only minimally responded to mycobacterial stimulus in ex vivo functional assays. In contrast, most MAIT cell activation seemed to occur in samples with highly active SIV replication, including blood and SIV-infected LN. Finally, the ability of MAIT cells to secrete TNFα (TNF) was impaired during SIV and Mtb co-infection, indicating that the two pathogens together could have a synergistically deleterious effect on MAIT cell function. The effect of this functional impairment on overall TB disease burden was unclear, but might be deleterious if MAIT cells are needed to fully activate antimycobacterial immune cells within the granulomas.

Background Public injecting of recreational drugs has been documented in a number of cities worldwide and was a key risk factor in a HIV outbreak in Glasgow, Scotland during 2015. We investigated the characteristics and health needs of people involved in this practice and explored stakeholder attitudes to new harm reduction interventions. Methods We used a tripartite health needs assessment framework, comprising epidemiological, comparative, and corporate approaches. We undertook an analysis of local and national secondary data sources on drug use; a series of rapid literature reviews; and an engagement exercise with people currently injecting in public places, people in recovery from injecting drug use, and staff from relevant health and social services. Results Between 400 and 500 individuals are estimated to regularly inject in public places in Glasgow city centre: most experience a combination of profound social vulnerabilities. Priority health needs comprise addictions care; prevention and treatment of blood-borne viruses; other injecting-related infections and injuries; and overdose and drug-related death. Among people with lived experience and staff from relevant health and social care services, there was widespread – though not unanimous – support for the introduction of safer injecting facilities and heroin-assisted treatment services. Conclusions The environment and context in which drug consumption occurs is a key determinant of harm, and is inextricably linked to upstream social factors. Public injecting therefore requires a multifaceted response. Though evidence-based interventions exist, their implementation internationally is variable: understanding the attitudes of key stakeholders provides important insights into local facilitators and barriers. Following this study, Glasgow plans to establish the world’s first co-located safer injecting facility and heroin-assisted treatment service. Electronic supplementary material The online version of this article (10.1186/s12889-018-5718-9) contains supplementary material, which is available to authorized users.

Background In ‘digital-first primary care’ models of health-care delivery, a patient’s first point of contact with a general practitioner or other health professional is through a digital channel, rather than a face-to-face consultation. Patients are able to access advice and treatment remotely from their home or workplace via a number of different technologies. Objectives This rapid responsive evidence synthesis was undertaken to inform NHS England policy in ‘digital-first primary care’. It was conducted in two stages: (1) scoping the published evidence and (2) addressing a refined set of questions produced by NHS England from the evidence retrieved during the scoping stage. Data sources Searches were conducted of five electronic databases (MEDLINE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, the Health Technology Assessment database and PROSPERO were searched in July 2018) and relevant research/policy and government websites, as well as the National Institute for Health Research Health Service and Delivery Research programme database of ongoing and completed projects. No date or geographical limitations were applied. Review methods After examining the initial scoping material, NHS England provided a list of questions relating to the potential effects of digital modes and models of engagement, and the contracting and integration of these models into primary care. Systematic reviews and evidence syntheses, including evidence on the use of digital (online) modes and models of engagement between patients and primary care, were examined more closely, as was ongoing research and any incidentally identified primary studies focused on the use of digital (online) modes and models of engagement. All records were screened by two reviewers, with disagreements resolved by consensus or consulting a third reviewer. Results Evidence suggests that uptake of existing digital modes of engagement is currently low. Patients who use digital alternatives to face-to-face consultations are likely to be younger, female and have higher income and education levels. There is some evidence that online triage tools can divert demand away from primary care, but results vary between interventions and outcome measures. A number of potential barriers exist to using digital alternatives to face-to-face consultations, including inadequate NHS technology and staff concerns about workload and confidentiality. There are currently insufficient empirical data to either substantiate or allay such concerns. Very little evidence exists on outcomes related to quality of care, service delivery, benefits or harms for patients, or on financial costs/cost-effectiveness. No studies examining how to contract and commission alternatives to face-to-face consultations were identified. Limitations The quality of the included reviews was variable. Poor reporting of methodology and a lack of adequate study details were common issues. Much of the evidence focused on exploring stakeholder views rather than on objective measurement of potential impacts. The current evidence synthesis is based on a rapid scoping exercise and cannot provide the breadth or depth of insight that might have been achieved with a full systematic review. Conclusions Rapid scoping of the literature suggests that there is little high-quality evidence relating to ‘digital-first primary care’ as defined by NHS England. The broader evidence on alternatives to face-to-face consultation addresses certain policy-maker concerns, such as the possible impact of new technologies on workload and workforce, inequalities, local implementation and integration with existing services. However, although this evidence gives an insight into the views and experiences of health professionals in relation to such concerns, quantitative empirical data are lacking. Funding The National Institute for Health Research Health Service and Delivery Research programme.

Background Police officers are often the first responders to mental health-related incidents and, consequently, can become a common gateway to care. The volume of such calls is an increasing challenge. Objective What is the evidence base for models of police-related mental health triage (often referred to as ‘street triage’) interventions? Design Rapid evidence synthesis. Participants Individuals perceived to be experiencing mental ill health or in a mental health crisis. Interventions Police officers responding to calls involving individuals experiencing perceived mental ill health or a mental health crisis, in the absence of suspected criminality or a criminal charge. Main outcome measures Inclusion was not restricted by outcome. Data sources Eleven bibliographic databases (i.e. Applied Social Sciences Index and Abstracts, Criminal Justice Abstracts, EMBASE, MEDLINE, PAIS® Index, PsycINFO, Scopus, Social Care Online, Social Policy & Practice, Social Sciences Citation Index and Social Services Abstracts) and multiple online sources were searched for relevant systematic reviews and qualitative studies from inception to November 2017. Additional primary studies reporting quantitative data published from January 2016 were also sought. Review methods The three-part rapid evidence synthesis incorporated metasynthesis of the effects of street triage-type intervention models, rapid synthesis of UK-relevant qualitative evidence on implementation and the overall synthesis. Results Five systematic reviews, eight primary studies reporting quantitative data and eight primary studies reporting qualitative data were included. Most interventions involved police officers working in partnership with mental health professionals. These interventions were generally valued by staff and showed some positive effects on procedures (such as rates of detention) and resources, although these results were not entirely consistent and not all important outcomes were measured. Most of the evidence was at risk of multiple biases caused by design flaws and/or a lack of reporting of methods, which might affect the results. Limitations All primary research was conducted in England, so may not be generalisable to the whole of the UK. Discussion of health equity issues was largely absent from the evidence. Conclusions Most published evidence that aims to describe and evaluate various models of street triage interventions is limited in scope and methodologically weak. Several systematic reviews and recent studies have called for a prospective, comprehensive and streamlined collection of a wider variety of data to evaluate the impact of these interventions. This rapid evidence synthesis expands on these recommendations to outline detailed implications for research, which includes clearer articulation of the intervention’s objectives, measurement of quantitative outcomes beyond section 136 of the Mental Health Act 1983 [Great Britain. Mental Health Act 1983. Section 136. London: The Stationery Office; 1983 URL: www.legislation.gov.uk/ukpga/1983/20/section/136 (accessed October 2017)] (i.e. rates, places of safety and processing data) and outcomes that are most important to the police, mental health and social care services and service users. Evaluations should take into consideration shorter-, medium- and longer-term effects. Whenever possible, study designs should have an appropriate concurrent comparator, for example by comparing the pragmatic implementation of collaborative street triage models with models that emphasise specialist training of police officers. The collection of qualitative data should capture dissenting views as well as the views of advocates. Any future cost-effectiveness analysis of these interventions should evaluate the impact across police, health and social services. Funding The National Institute for Health Research Health Services and Delivery Research programme.

Intracranial ectopic salivary gland rests within dural-based lesions are reported very infrequently in the literature. The authors report the unique case of a 12-year-old boy with a cerebellar medulloblastoma positive for sonic hedgehog (Shh) that contained intraaxial mature ectopic salivary gland rests. The patient underwent clinical and radiological monitoring postoperatively, until he died of disseminated disease. An autopsy showed no evidence of salivary glands within disseminated lesions. The intraaxial presence of salivary gland rests and concomitant Shh positivity of the described tumor point to a disorder in differentiation as opposed to ectopic developmental foci, which are uniformly dural based in the described literature. The authors demonstrate the characteristic “papilionaceous” appearance of the salivary glands with mucicarmine stain and highlight the role of Shh signaling in explaining the intraaxial presence of seromucous gland analogs. This article reports the first intraaxial posterior fossa tumor with heterotopic salivary gland rests, and it provides molecular and embryopathological insights into the development of these lesions.

BackgroundPeople with mental health conditions have a lower life expectancy and poorer physical health outcomes than the general population. Evidence suggests that this discrepancy is driven by a combination of clinical risk factors, socioeconomic factors and health system factors.Objective(s)To explore current service provision and map the recent evidence on models of integrated care addressing the physical health needs of people with severe mental illness (SMI) primarily within the mental health service setting. The research was designed as a rapid review of published evidence from 2013–15, including an update of a comprehensive 2013 review, together with further grey literature and insights from an expert advisory group.SynthesisWe conducted a narrative synthesis, using a guiding framework based on nine previously identified factors considered to be facilitators of good integrated care for people with mental health problems, supplemented by additional issues emerging from the evidence. Descriptive data were used to identify existing models, perceived facilitators and barriers to their implementation, and any areas for further research.Findings and discussionThe synthesis incorporated 45 publications describing 36 separate approaches to integrated care, along with further information from the advisory group. Most service models were multicomponent programmes incorporating two or more of the nine factors: (1) information sharing systems; (2) shared protocols; (3) joint funding/commissioning; (4) colocated services; (5) multidisciplinary teams; (6) liaison services; (7) navigators; (8) research; and (9) reduction of stigma. Few of the identified examples were described in detail and fewer still were evaluated, raising questions about the replicability and generalisability of much of the existing evidence. However, some common themes did emerge from the evidence. Efforts to improve the physical health care of people with SMI should empower people (staff and service users) and help remove everyday barriers to delivering and accessing integrated care. In particular, there is a need for improved communication between professionals and better information technology to support them, greater clarity about who is responsible and accountable for physical health care, and awareness of the effects of stigmatisation on the wider culture and environment in which services are delivered.Limitations and future workThe literature identified in the rapid review was limited in volume and often lacked the depth of description necessary to acquire new insights. All members of our advisory group were based in England, so this report has limited information on the NHS contexts specific to Scotland, Wales and Northern Ireland. A conventional systematic review of this topic would not appear to be appropriate in the immediate future, although a more interpretivist approach to exploring this literature might be feasible. Wherever possible, future evaluations should involve service users and be clear about which outcomes, facilitators and barriers are likely to be context-specific and which might be generalisable.FundingThe research reported here was commissioned and funded by the Health Services and Delivery Research programme as part of a series of evidence syntheses under project number 13/05/11. For more information visitwww.nets.nihr.ac.uk/projects/hsdr/130511.

BackgroundOrganisational case study proposals can be poorly articulated and methodologically weak, raising the possible need for publication standards in this area.ObjectivesTo develop reporting standards for organisational case study research, with particular application to the UK National Health Service.DesignRapid evidence synthesis and Delphi consensus process.Data sourcesRelevant case studies and methods texts were identified through searches of library catalogues, key text and author searches, focused searching of health and social science databases and some targeted website searching.Review methodsThe reporting standards were developed in three stages: (1) a rapid review of the existing literature to identify items; (2) a modified Delphi consensus process to develop and refine content and structure; and (3) application of the high-consensus Delphi items to two samples of organisational case studies to assess their feasibility as reporting standards. Items for the Delphi consultation were identified from published organisational case studies and related methodological texts. Identified items were sent to a Delphi expert panel for rating over two rounds. Participants were also asked whether or not the provisional framework in which items were presented was appropriate, and were given the opportunity to adapt this alongside the content. In both rounds, the high-consensus threshold was set at 70% agreement among respondents for each item. High-consensus items from the Delphi consultation were then applied to previously identified case study publications to determine their relevance to the reporting of real-world organisational case studies and to better understand how the results of the Delphi consultation might best be implemented as a reporting standard.ResultsOne hundred and three unique reporting items were identified from 25 methodological texts; eight example case studies and 12 exemplar case studies did not provide any additional unique items. Thirteen items were ultimately rated as ‘Should be reported for all organisational case studies’ by at least 70% of respondents, with the degree of consensus ranging from 73% to 100%. As a whole, exemplar case studies [which had been provided by the National Institute for Health Research (NIHR)’s Health Services and Delivery Research (HSDR) programme as examples of methodologically strong projects] more consistently reported the high-consensus Delphi items than did case studies drawn from the literature more broadly.LimitationsTime and resource constraints prevented an initial ‘item-generation’ round in the Delphi consensus process. Items are therefore likely to have been influenced by the content, wording and assumptions of available literature.ConclusionsThe high-consensus items were translated into a set of 13 reporting standards that aim to improve the consistency, rigour and reporting of organisational case study research, thereby making it more accessible and useful to different audiences. The reporting standards themselves are intended primarily as a tool for authors of organisational case studies. They briefly outline broad requirements for rigorous and consistent reporting without constraining methodological freedom.Future workThese reporting standards should be included as part of the submission requirements for all organisational case studies seeking funding. Though these reporting standards do not mandate specific methods, if a reporting item is not reported for legitimate methodological reasons, the onus is on the author to outline their rationale for the reader.FundingThe NIHR HSDR programme.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is the leading cause of death among human immunodeficiency virus (HIV)-positive patients. The precise mechanisms by which HIV impairs host resistance to a subsequent M. tuberculosis infection are unknown. We modeled this coinfection in Mauritian cynomolgus macaques (MCM) using simian immunodeficiency virus (SIV) as an HIV surrogate. We infected seven MCM with SIVmac239 intrarectally and 6 months later coinfected them via bronchoscope with ∼10 CFU of M. tuberculosis. Another eight MCM were infected with M. tuberculosis alone. TB progression was monitored by clinical parameters, by culturing bacilli in gastric and bronchoalveolar lavages, and by serial [18F]fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging. The eight MCM infected with M. tuberculosis alone displayed dichotomous susceptibility to TB, with four animals reaching humane endpoint within 13 weeks and four animals surviving >19 weeks after M. tuberculosis infection. In stark contrast, all seven SIV+ animals exhibited rapidly progressive TB following coinfection and all reached humane endpoint by 13 weeks. Serial PET/CT imaging confirmed dichotomous outcomes in MCM infected with M. tuberculosis alone and marked susceptibility to TB in all SIV+ MCM. Notably, imaging revealed a significant increase in TB granulomas between 4 and 8 weeks after M. tuberculosis infection in SIV+ but not in SIV-naive MCM and implies that SIV impairs the ability of animals to contain M. tuberculosis dissemination. At necropsy, animals with preexisting SIV infection had more overall pathology, increased bacterial loads, and a trend towards more extrapulmonary disease than animals infected with M. tuberculosis alone. We thus developed a tractable MCM model in which to study SIV-M. tuberculosis coinfection and demonstrate that preexisting SIV dramatically diminishes the ability to control M. tuberculosis coinfection.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is the leading cause of death among HIV positive patients. The precise mechanisms by which HIV impairs host resistance to a subsequent M.tb infection are unknown. We modeled this co-infection in Mauritian cynomolgus macaques (MCM) using SIV as an HIV surrogate. We infected seven MCM with SIVmac239 intrarectally and six months later co-infected them via bronchoscope with ~10 CFU M.tb. Another eight MCM were infected with M.tb alone. TB progression was monitored by clinical parameters, by culturing bacilli in gastric and bronchoalveolar lavages, and by serial 18F-FDG PET/CT imaging. The eight MCM infected with M.tb alone displayed dichotomous susceptibility to TB, with four animals reaching humane endpoint within 13 weeks and four animals surviving >19 weeks post M.tb infection. In stark contrast, all seven SIV+ animals exhibited rapidly progressive TB following co-infection and all reached humane endpoint by 13 weeks. Serial PET/CT imaging confirmed dichotomous outcomes in MCM infected with M.tb alone and marked susceptibility to TB in all SIV+ MCM. Notably, imaging revealed a significant increase in TB granulomas between four and eight weeks post M.tb infection in SIV+, but not in SIV-naive MCM and implies that SIV impairs the ability of animals to contain M.tb dissemination. At necropsy, animals with pre-existing SIV infection had more extrapulmonary TB disease, more overall pathology, and increased bacterial loads than animals infected with M.tb alone. We thus developed a tractable MCM model in which to study SIV-M.tb co-infection and demonstrate that pre-existing SIV dramatically diminishes the ability to control M.tb co-infection.Author summaryMycobacterium tuberculosis (M.tb) is the etiologic agent of tuberculosis (TB) and infects a tremendous number of individuals. TB causes millions of deaths each year and is the leading cause of death in human immunodeficiency virus (HIV)-positive individuals. Currently, the mechanisms by which pre-existing HIV infection increases susceptibility to subsequent M.tb infection and predisposes an individual to TB disease are poorly understood. We developed a simian immunodeficiency virus (SIV) - M.tb co-infection model in Mauritian cynomolgus macaques (MCM) to investigate how SIV impairs the immune response to a subsequent M.tb infection. We show that naive MCM display variable resistance to TB while all SIV-infected MCM failed to control M.tb infection. Using quantitative measures of disease and serial PET/CT imaging, we show that SIV+ co-infected animals uniformly exhibit rapid TB progression, more tuberculosis disease dissemination, and increased mortality. This coinfection model will facilitate studies, provide unique insights into the defects underlying TB susceptibility in HIV+ individuals and will help us develop approaches to overcome these defects.

People with mental health conditions have a lower life expectancy and poorer physical health outcomes than the general population. Evidence suggests this is due to a combination of clinical risk factors, socioeconomic factors, and health system factors, notably a lack of integration when care is required across service settings.\ud \ud \ud \ud Several recent reports have looked at ways to better integrate physical and mental health care for people with severe mental illness (SMI). We built on these by conducting a mapping review that looked for the most recent evidence and service models in this area. This involved searching the published literature and speaking to people involved in providing or using current services.\ud \ud \ud \ud Few of the identified service models were described adequately and fewer still were evaluated, raising questions about the replicability and generalisability of much of the existing evidence. However, some common themes did emerge. Efforts to improve the physical health care of people with SMI should empower staff and service users and help remove everyday barriers to delivering and accessing integrated care. In particular, there is a need for improved communication among professionals and better information technology to support them, greater clarity about who is responsible and accountable for physical health care, and greater awareness of the effects of stigmatisation on the wider culture and environment in which services are delivered.

In the past 2 decades, it has become increasingly clear that nonhuman primates, specifically macaques, are useful models for human tuberculosis (TB). Several macaque species have been used for TB studies, and questions remain about the similarities and differences in TB pathogenesis among macaque species, which can complicate decisions about the best species for a specific experiment. Here we provide a quantitative assessment, using serial positron emission tomography and computed tomography (PET-CT) imaging and precise quantitative determination of bacterial burdens of low-dose Mycobacterium tuberculosis infection in cynomolgus macaques of Chinese origin, rhesus macaques of Chinese origin, and Mauritian cynomolgus macaques. This comprehensive study demonstrates that there is substantial variability in the outcome of infection within and among species. Overall, rhesus macaques have higher rates of disease progression, more lung, lymph node, and extrapulmonary involvement, and higher bacterial burdens than Chinese cynomolgus macaques. The small cohort of Mauritian cynomolgus macaques assessed here indicates that this species is more similar to rhesus macaques than to Chinese cynomolgus macaques in terms of M. tuberculosis infection outcome. These data provide insights into the differences among species, providing valuable data to the field for assessing macaque studies of TB.

Non-human primate (NHP) models of tuberculosis (TB) immunity and pathogenesis, especially rhesus and cynomolgus macaques, are particularly attractive because of the high similarity of the human and macaque immune systems. However, little is known about the MHC class II epitopes recognized in macaques, thus hindering the establishment of immune correlates of immunopathology and protective vaccination. We characterized immune responses in rhesus macaques vaccinated against and/or infected with Mycobacterium tuberculosis (Mtb), to a panel of antigens currently in human vaccine trials. We defined 54 new immunodominant CD4(+) T cell epitopes, and noted that antigens immunodominant in humans are also immunodominant in rhesus macaques, including Rv3875 (ESAT-6) and Rv3874 (CFP10). Pedigree and inferred restriction analysis demonstrated that this phenomenon was not due to common ancestry or inbreeding, but rather presentation by common alleles, as well as, promiscuous binding. Experiments using a second cohort of rhesus macaques demonstrated that a pool of epitopes defined in the previous experiments can be used to detect T cell responses in over 75% of individual monkeys. Additionally, 100% of cynomolgus macaques, irrespective of their latent or active TB status, responded to rhesus and human defined epitope pools. Thus, these findings reveal an unexpected general repertoire overlap between MHC class II epitopes recognized in both species of macaques and in humans, showing that epitope pools defined in humans can also be used to characterize macaque responses, despite differences in species and antigen exposure. The results have general implications for the evaluation of new vaccines and diagnostics in NHPs, and immediate applicability in the setting of macaque models of TB.

Jonathan J Streit,1 Yousef Shishani,1 Mark Rodgers,2 Reuben Gobezie1 1The Cleveland Shoulder Institute, 2Department of Pathology, University Hospitals of Cleveland, Cleveland, OH, USA Background: Bicipital tendinitis is a common cause of anterior shoulder pain, but there is no evidence that acute inflammation of the extra-articular long head of the biceps (LHB) tendon is the root cause of this condition. We evaluated the histologic findings of the extra-articular portion of the LHB tendon and synovial sheath in order to compare those findings to known histologic changes seen in other tendinopathies. Methods: Twenty-six consecutive patients (mean age 45.4±13.7 years) underwent an open subpectoral biceps tenodesis for anterior shoulder pain localized to the bicipital groove. Excised tendons were sent for histologic analysis. Specimens were graded using a semiquantitative scoring system to evaluate tenocyte morphology, the presence of ground substance, collagen bundle characteristics, and vascular changes. Results: Chronic inflammation was noted in only two of 26 specimens, and no specimen demonstrated acute inflammation. Tenocyte enlargement and proliferation, characterized by increased roundness and size of the cell and nucleus with proteoglycan matrix expansion and myxoid degenerative changes, was found in all 26 specimens. Abundant ground substance, collagen bundle changes, and increased vascularization were visualized in all samples. Conclusion: Anterior shoulder pain attributed to the biceps tendon does not appear to be due to an inflammatory process in most cases. The histologic findings of the extra-articular portion of the LHB tendon and synovial sheath are similar to the pathologic findings in de Quervain tenosynovitis at the wrist, and may be due to a chronic degenerative process similar to this and other tendinopathies of the body. Keywords: biceps tendinitis, biceps tendinopathy, tenosynovium, anterior shoulder pain, long head biceps tendon, histologic analysis

Adults with autism spectrum disorder without intellectual impairment may benefit from a range of support services. This article presents the results of a systematic review assessing the effectiveness of supportive interventions for adults with autism spectrum disorder without intellectual impairment. A total of 32 studies were included; most focused on younger male participants. Although evidence was lacking for most types of intervention, employment programmes and social skills training were found to be effective for more proximal outcomes such as social skills. Evidence that any intervention improves mental health or well-being was very limited. Most interventions focused on mitigating specific deficits, rather than on providing broader support. Further research is needed on the effectiveness of supportive interventions such as advocacy and mentoring.