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Diffuse Reflectance Spectroscopy (DRS) can provide tissue feedback for pedicle screw placement in spine surgery, yet the integration of fiber optics into the tip of the pedicle probe, a device used to pierce through bone, is challenging, since the optical probing depth and signal-to-noise ratio (SNR) are affected negatively compared to those of a blunt DRS probe. Through Monte Carlo simulations and optical phantom experiments, we show how differences in the shape of the instrument tip influence the acquired spectrum. Our findings demonstrate that a single bevel with an angle of 30∘ offers a solution to anticipate cortical breaches during pedicle screw placement. Compared to a blunt probe, the optical probing depth and SNR of a cone tip are reduced by 50%. The single bevel tip excels with 75% of the optical probing depth and a SNR remaining at approximately ⅔, facilitating the construction of a surgical instrument with integrated DRS.

Abstract Background The increased popularity of minimally invasive spinal surgery calls for a revision of guidance techniques to prevent injuries of nearby neural and vascular structures. Lipid content has previously been proposed as a distinguishing criterion for different bone tissues to provide guidance along the interface of cancellous and cortical bone. This study aims to investigate how fat is distributed throughout the spinal column to confirm or refute the suitability of lipid content for guidance purposes. Results Proton density fat fraction (PDFF) was assessed over all vertebral levels for six human cadavers between 53 and 92 years of age, based on fat and water MR images. According to their distance to the vertebra contour, the data points were grouped in five regions of interest (ROIs): cortical bone (−1 mm to 0 mm), pre-cortical zone (PCZ) 1–3 (0–1 mm; 1–2 mm; 2–3 mm), and cancellous bone ( $$\ge $$ ≥ 3 mm). For PCZ1 vs. PCZ2, a significant difference in mean PDFF of between −7.59 pp and −4.39 pp on average was found. For cortical bone vs. PCZ1, a significant difference in mean PDFF of between −27.09 pp and −18.96 pp on average was found. Conclusion A relationship between distance from the cortical bone boundary and lipid content could be established, paving the way for guidance techniques based on fat fraction detection for spinal surgery.

A standardised monitoring is indispensable to identify trends of insect populations. However, until recently, a systematic monitoring of insects in Germany was missing. Therefore, the German federal ministry for the environment funded the conceptualisation of an insect monitoring scheme.Here, we inform about the general concept and structure of the German insect monitoring scheme (GIMS) and the steps taken and still to be taken for the implementation of the scheme. A first step was the development of the objectives, general concept und structure of the GIMS in close collaboration with the nature conservation authorities at the national and federal state levels, as the latter are responsible for the implementation of nature conservation-related monitoring schemes. The GIMS is structured into two sections: section 1 ‘Monitoring of common insects’ and section 2 ‘Monitoring of rare insects’. Both sections contain modules that focus on selected aspects of insect diversity. In section 1, insect communities of the wider countryside will be monitored. Section 2 focuses on insect communities in rare habitats and species of high conservation value (e.g. threatened species). The next step was to develop standardised sampling methods for the modules in collaboration with experts and the nature conservation authorities. Wherever appropriate, synergies with other monitoring schemes were created, e.g. for combined analyses with environmental variables.Parallel to the development of the concept, several federal states have already implemented selected modules of the GIMS. Furthermore, the module ‘Grasshoppers in grasslands’ was tested during a pilot phase. By using the data from the pilot phase and the High Nature Value Farmland Monitoring scheme the relationship between high nature value farmland and grasshopper diversity was evaluated. This indicated the great potential of using synergies among monitoring schemes for joint data analyses and showed that it is worth exploring such approaches in greater depth.

Abstract Background Schools are a prime setting for the delivery of universal and targeted mental health interventions. Current school-based mental health interventions may not be developed to fully meet student mental health needs and co-production is needed to understand what young people really want. Despite this, research on school-based mental health interventions does not consistently engage in co-production, involving stakeholders, such as young people and schools, in the decision-making, development, evaluation and/or implementation stages. This highlights that transforming the development of school-based mental health interventions is crucial to meeting all stakeholders’ needs. In this paper, we aim to briefly review an approach to co-production that can be used when conducting research on school-based mental health interventions that centre stakeholder voices to drive meaningful change. We describe a case study to showcase this approach. Main body We highlight recommendations and important elements to consider for each stakeholder when engaging in different levels of co-production, including young people, teachers, and schools. We provide practical examples of how this may look like in practice, theoretical underpinnings, and impact on outcomes. Our case study of co-producing a talk to improve mental health literacy in secondary school students is highlighted to demonstrate how a group of young people, teachers, epidemiologist, psychiatrist, and researchers can work together to develop school-based mental health interventions. Conclusion Co-production can be successfully conducted amongst researchers and stakeholders to develop school-based mental health interventions. Changes made to the talk were guided by synthesis of feedback that aligned with the balanced needs, perspectives, and opinions of all stakeholders. The use of this co-production approach in research on school-based mental health interventions with young people, teachers, and schools has important implications for research, service provision, and stakeholder empowerment.

Summary: The development of broadly neutralizing antibody (bnAb)-based therapeutic HIV-1 vaccines and cure concepts depends on monitoring bnAb plasma activity in people with HIV (PWH) on suppressive antiretroviral therapy (ART). To enable this, analytical strategies must be defined to reliably distinguish antibody-based neutralization from drug inhibition. Here, we explore strategies that either utilize drug-resistant viruses or remove drugs from plasma. We develop ART-DEX (ART dissociation and size exclusion), an approach which quantitatively separates drugs from plasma proteins following pH-triggered release allowing accurate definition of antibody-based neutralization. We demonstrate that ART-DEX, alone or combined with ART-resistant viruses, provides a highly effective and scalable means of assessing antibody neutralization during ART. Implementation of ART-DEX in standard neutralization protocols should be considered to enhance the analytical capabilities of studies evaluating bnAb therapeutics and therapeutic vaccines, furthering the development of advanced ART and HIV-1 cure strategies.

Objective: The aim of this study was to evaluate alternative measurement points to assess stress levels during surgery, given that taking electrodermal activity (EDA) measurements from the palms, a commonly used standard, is impractical in surgical contexts. Methods: A combination of mentally challenging tasks on a laparoscopy trainer (LapSim) and physically challenging sports exercises were performed by a group of participants. During these tasks, EDA was measured at three different locations: the fingers, toes, and shoulder/neck area. Additionally, an electrocardiogram was used as an objective measure of stress levels. Results: The findings indicated that EDA measurements taken at the toes produced similar high skin conductance levels to measurements taken at the palms. However, significantly lower skin conductance levels were observed at the shoulder. Despite this, the cross-correlation of EDA data revealed high correlation coefficients (above 0.96) between both the toe and shoulder measurements when compared to the palm data. Conclusions: The study concludes that both the toes and the shoulder/neck area serve as viable alternative locations for assessing occupational stress levels in surgical personnel. This assertion is supported by the similarity of the data produced by these methods to that of the standard finger-based technique, with the latter still being identified as the most sensitive method for capturing EDA. Subsequently, these findings attest to the potential for practical adaptation of this technique in surgical contexts.

Defendants accused of willful patent infringement are currently put to a Hobson's choice: waive attorney-client privilege, or risk a jury verdict of willfulness and potentially trebled damages. In nearly every [...]

Despite multiple recent advances in systemic therapy for metastatic breast cancer, cases which display suboptimal response to guideline-driven treatment are frequently seen in the clinic. Effective options for such patients are limited, particularly in later line of therapy, and selection of optimal treatment options is essentially empirical and based largely on considerations of previous regimens received. Comprehensive cancer profiling includes detection of genetic alterations in tissue and circulating tumor DNA (ctDNA), immunohistochemistry (IHC) from re-biopsied metastatic disease, circulating tumor cells (CTCs), gene expression analysis and pharmacogenomics. The advent of this methodology and application to metastatic breast cancer, facilitates a more scientifically informed approach to identification of optimal systemic therapy approaches independent of the restrictions implied by clinical guidelines. Here we describe a case of metastatic breast cancer where consecutive comprehensive tumor profiling reveals ongoing tumor evolution, guiding the identification of novel effective therapeutic strategies.

Background Sexually transmitted infections disproportionately affect young people and men who have sex with men. Chlamydia is Britain’s most common sexually transmitted infection. Partner notification is a key intervention to reduce transmission of sexually transmitted infections and human immunodeficiency virus but is hard to implement. Accelerated partner therapy is a promising new approach. Objectives determine the effectiveness, costs and acceptability of accelerated partner therapy for chlamydia in heterosexual people model the cost effectiveness of accelerated partner therapy and impact on chlamydia transmission develop and cost partner notification interventions for men who have sex with men. Design Mixed-methods study to develop a new sex partner classification and optimise accelerated partner therapy; cluster crossover randomised controlled trial of accelerated partner therapy, with process and cost-consequence evaluation; dynamic modelling and health economic evaluation; systematic review of economic studies of partner notification for sexually transmitted infections in men who have sex with men; qualitative research to co-design a novel partner notification intervention for men who have sex with men with bacterial sexually transmitted infections. Settings Sexual health clinics and community services in England and Scotland. Participants Women and men, including men who have sex with men and people with mild learning disabilities. Interventions Accelerated partner therapy offered as an additional partner notification method. Main outcome measures Proportion of index patients with positive repeat chlamydia test (primary outcome); proportion of sex partners treated; costs per major outcome averted and quality-adjusted life-year; predicted chlamydia prevalence; experiences of accelerated partner therapy. Data sources Randomised controlled trial: partnership type, resource use, outcomes, qualitative data: economic analysis, modelling and systematic review: resource use and unit costs from the randomised controlled trial, secondary sources. Results The sex partner classification defined five types. Accelerated partner therapy modifications included simplified self-sampling packs and creation of training films. We created a clinical management and partner notification data collection system. In the randomised controlled trial, all 17 enrolled clinics completed both periods; 1536 patients were enrolled in the intervention phase and 1724 were enrolled in the control phase. Six hundred and sixty-six (43%) of 1536 index patients in the intervention phase and 800 (46%) of 1724 in the control phase were tested for Chlamydia trachomatis at 12–24 weeks after contact tracing consultation; 31 (4.7%) in the intervention phase and 53 (6.6%) in the control phase had a positive Chlamydia trachomatis test result [adjusted odds ratio 0.66 (95% confidence interval 0.41 to 1.04); p = 0.071]. The proportion of index patients with ≥ 1 sex partner treated was 88.0% (775/881) in intervention and 84.6% (760/898) in control phase, adjusted odds ratio 1.27 (95% confidence interval 0.96 to 1.68; p = 0.10). Overall, 293/1536 (19.1%) index patients chose accelerated partner therapy for 305 partners, of which partner types were: committed/established, 166/305 (54.4%); new, 85/305 (27.9%); occasional, 45/305 (14.8%); and one-off, 9/305 (3.0%). Two hundred and forty-eight accepted accelerated partner therapy and 241 partners were sent accelerated partner therapy packs, 120/241 (49.8%) returned chlamydia/gonorrhoea samples (78/119, 65.5%, positive for chlamydia, no result in one), but only 60/241 (24.9%) human immunodeficiency virus and syphilis samples (all negative). The primary outcomes of the randomised trial were not statistically significantly different at the 5% level. However, the economic evaluation found that accelerated partner therapy could be less costly compared with routine care, and mathematical modelling of effects and costs extrapolated beyond the trial end points suggested that accelerated partner therapy could be more effective and less costly than routine care in terms of major outcome averted and quality-adjusted life-years’. Healthcare professionals did not always offer accelerated partner therapy but felt that a clinical management and partner notification data collection system enhanced data recording. Key elements of a multilevel intervention supporting men who have sex with men in partner notification included: modifying the cultural and social context of men who have sex with men communities; improving skills and changing services to facilitate partner notification for one-off partners; and working with dating app providers to explore digital partner notification options. The systematic review found no evaluations of partner notification for men who have sex with men. Modelling of gonorrhoea and human immunodeficiency virus co-infection in men who have sex with men was technically challenging. Limitations In the randomised controlled trial, enrolment, follow-up and repeat infections were lower than expected, so statistical power was lower than anticipated. We were unable to determine whether accelerated partner therapy sped up partner treatment. Mathematical modelling of gonorrhoea/human immunodeficiency virus co-infection in men who have sex with men remained at an experimental stage. It was not feasible to include healthcare professionals in the men who have sex with men intervention development due to the COVID-19 pandemic. Conclusions Although the evidence that the intervention reduces repeat infection was not conclusive, the trial results suggest that accelerated partner therapy can be safely offered as a contact tracing option and is also likely to be cost saving, but is best suited to sex partners with emotional connection to the index patient. The Programme’s findings about classification of sexual partner types can be implemented in sexual health care with auditable outcomes. Future work Further research is needed on how to increase uptake of accelerated partner therapy and increase sexually transmitted infections self-sampling by partners; understand how services can use partnership-type information to improve partner notification, especially for those currently underserved; overcome challenges in modelling sexually transmitted infections and human immunodeficiency virus co-infection in men who have sex with men; develop and evaluate an intervention to optimise partner notification among men who have sex with men, focusing on one-off partnerships. Trial registration This trial is registered as ISRCTN15996256. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-0614-20009) and is published in full in Programme Grants for Applied Research; Vol. 12, No. 2. See the NIHR Funding and Awards website for further award information. Plain language summary We aimed to improve the sexual health of people most impacted by sexually transmitted infections and human immunodeficiency virus (young people and men who have sex with men), by preventing transmission and reducing undiagnosed infection. We focused on partner notification (contact tracing and management), particularly accelerated partner therapy. Our research included: a clinical trial interview/focus group studies literature reviews mathematical modelling and health economic evaluations. Firstly, we improved accelerated partner therapy by finding out what people did/didn’t like about it and which types of sex partners might use it. We included some people with mild learning difficulties to see if they could help us improve accelerated partner therapy for people who might find self-managed care tricky. Then, we measured accelerated partner therapy’s value for money in a large clinical trial in people with chlamydia, Britain’s commonest sexually transmitted infection. Finally, we worked with men who have sex with men, sexual healthcare professionals, public health and health planners to make recommendations for new partner notification methods to suit their needs. We found accelerated partner therapy could be less costly than current practices and likely reduce transmission of chlamydia in the population. Our new classification of partnership types showed that accelerated partner therapy suited ‘emotionally connected’, rather than one-off, partners. These partners are important for controlling onward transmission but are traditionally harder to reach. Findings from our stakeholder event suggest that partner notification approaches for men who have sex with men are likely to work best by involving communities as well as clinics, but we were only able to focus on sexually transmitted infections other than human immunodeficiency virus due to COVID-19 impacts. Future research should aim to improve partner notification for one-off partners, simplify the sexually transmitted infection and human immunodeficiency virus self-testing kits used in accelerated partner therapy, explore the pros and cons of immediate antibiotics, and develop and evaluate a system-wide partner notification approach for men who have sex with men, guided by health economics evaluation. Scientific summary Background Sexually transmitted infection (STI) diagnoses have increased since 2010. Young people and men who have sex with men (MSM) are disproportionately affected. Chlamydia is the most commonly reported STI in Britain. Two-thirds of chlamydia infections are diagnosed in heterosexual people under 25 years, while gonorrhoea, syphilis and human immunodeficiency virus (HIV) infections are more common in MSM. Preventing onward transmission is essential to STI and HIV control. Partner notification (PN), also known as contact tracing and management, is a key intervention in which sex partners (SPs) of people with diagnosed infections are identified, tested and treated. PN also provides opportunities to engage people at high risk of infection who might not present for care. Better PN for MSM with infections such as gonorrhoea could enable earlier HIV diagnosis in partners because co-infection is common in this group. However, PN is challenging, and monitoring of performance is limited by the lack of standardised outcome measures and blunt classifications of sex partnership types. Accelerated partner therapy (APT) is a promising new PN method, but its role in preventing transmission is unknown. Aims and objectives The Limiting Undetected Sexually Transmitted infections to RedUce Morbidity (LUSTRUM) Programme aimed to improve the sexual health of people at high risk of STIs and HIV by improving PN outcomes. The Programme had three interconnecting streams: STREAM A: Accelerated partner therapy trial preparation and implementation Specific objectives: Develop a clinically useful SP classification. Optimise the acceptability of the APT intervention. Determine the effectiveness and costs of APT and understand how APT worked in practice. STREAM B: Mathematical modelling and health economic analysis Specific objectives: Quantify the effects of APT on chlamydia transmission and re-infection. Estimate the cost effectiveness of APT, compared with standard PN. STREAM C: Development of partner notification interventions for men who have sex with men Specific objectives: Explore costs and outcomes of PN and testing for HIV. Investigate PN for gonorrhoea in MSM to identify undiagnosed HIV infection using mathematical modelling. Explore barriers and facilitators to PN for bacterial STIs and develop a PN intervention. Methods A1. Development of a clinically usable sex partner classification We synthesised evidence about partnership types from: the third British National Survey of Sexual Attitudes and Lifestyles, 259 dating applications and published literature. Then, we conducted qualitative interviews with members of the public and patients (n = 57), and health professionals (n = 27). We developed definitions for partnership types through external multidisciplinary expert consultation. A2. Optimisation of the accelerated partner therapy intervention We analysed videos of APT role-play consultations and synthesised published evidence about relevant behaviours; explored barriers and facilitators to receiving or delivering APT, including focused work with 25 people with mild learning disabilities, 56 members of the public and patients and 30 healthcare professionals (HCPs); modified and specified key components of APT, wrote a manual and training package, and created online videos. A3. Randomised controlled trial of accelerated partner therapy We conducted a cluster crossover randomised controlled trial with a process and cost-consequence evaluation. Dynamic modelling is described in Stream B. Clusters were 17 sexual health clinics in diverse areas of England and Scotland. Participants [index patients (IPs)] were heterosexual women and men, aged ≥ 16 years with a positive test for Chlamydia trachomatis and/or a clinical diagnosis of pelvic inflammatory disease or cervicitis (women) or non-gonococcal urethritis or epididymo-orchitis (men) and reporting at least one contactable sexual partner in the past 6 months. Intervention: APT was offered as an additional partner notification method for IPs. A HCP assessed their SP(s) by telephone, then sent or gave the IP antibiotics and STI and HIV self-sampling kits for their partner(s). The control arm received standard PN alone. The intervention was implemented at the level of the sexual health clinic, with clinics randomised to intervention or control arm in the first phase by random permutation. The primary outcome was the proportion of IPs testing positive for C. trachomatis 12–24 weeks after the PN consultation. Secondary outcomes included: the proportion of SPs treated; the proportion of partners notified; costs; cost effectiveness; model-predicted chlamydia prevalence. The primary outcome analysis was by intention to treat, fitting random-effects logistic regression models that account for clustering of IPs within clinics and trial periods. Process evaluation: We collected qualitative data through six focus groups and individual interviews (n = 10) with purposively sampled HCPs (n = 34 from 14 sites), IPs (n = 15) and SPs who received APT (n = 17). Quantitative data were collected within a clinical management and PN data collection system (RELAY). Cost-consequence analysis (CCA): We collected data on costs and resource use during the trial and used unit costs from the trial and the Personal Social Services Research Unit. B1 and B2. Modelling the effects of accelerated partner therapy on Chlamydia trachomatis transmission We developed a new deterministic transmission model with a dedicated PN module, which allowed us to identify the effects of different index-partner combinations on chlamydia prevalence. We considered a population aged 16–34 years and calibrated the model to data from the third British National Survey of Sexual Attitudes and Lifestyles. We then extended a previous modelling framework, informed by data from the C. trachomatis transmission model and the trial, to quantify expected rates of chlamydia reinfection (Estcourt CS, Stirrup O, Copas A, Low N, Mapp F, Saunders J, et al. Accelerated partner therapy contact tracing for people with chlamydia (LUSTRUM): a crossover cluster-randomised controlled trial. Lancet Public Health 2022;7(10):e853–65. https://doi.org/10.1016/S2468-2667(22)00204-3). B3. Cost-effectiveness analysis of accelerated partner therapy compared with standard partner notification We developed a spreadsheet-based model using output from the C. trachomatis transmission model to estimate the impact of APT on healthcare costs, major outcomes averted (MOA) and quality-adjusted life-years (QALYs) in a simulated population of 100,000 adults aged 16–34 years. We calculated incremental cost-effectiveness ratios (ICERs) for APT, compared with standard PN and undertook sensitivity and scenario analyses. C1. Systematic review of economic studies of interventions related to partner notification for sexually transmitted infections in men who have sex with men We searched six electronic databases up to June 2020. We included economic evaluation and cost analysis studies if participants were MSM with any STI and/or HIV and the intervention was related to PN, testing or treatment and summarised evidence using a narrative synthesis. C2. Partner notification for bacterial sexually transmitted infections in men who have sex with men as a way to detect undiagnosed human immunodeficiency virus infection in partners We reviewed modelling studies of PN and pre-exposure prophylaxis interventions in MSM and attempted to model PN with co-infections with gonorrhoea HIV. C3. Barriers and facilitators of accelerated partner therapy and development of a novel partner notification intervention for men who have sex with men First, we conducted a stakeholder event with 45 participants from across Britain [MSM, public health experts, service commissioners, multidisciplinary sexual HCPs, non-governmental organisations (NGOs), academics and dating app providers]. We explored the diverse and multilevelled social, cultural and healthcare system-level context shaping poor PN outcomes for one-off partners. We conducted qualitative in-depth interview studies with men who had experienced PN (n = 14, Stream A) and focus groups with MSM (n = 28), clinical and other stakeholders (n = 11) to explore barriers and facilitators to PN. We used the behaviour change wheel within co-design of a potential new PN intervention. Results A1. We created usable definitions for five SP types (committed/established, new, occasional, one-off, sex work), broadly predicated on duration of the relationship, likelihood of future sex and degree of emotional connection. A2. Modifications to the APT intervention included simplification of the patient packs, creation of ‘how to’ training films for participants and HCPs. People with mild learning disabilities found APT acceptable but described feeling overwhelmed by the packs. They recommended using photographs instead of diagrams of anatomical sites for self-sampling, and an ‘easy read’ format. The new partner types and APT processes were built into a new clinical management and PN data collection system called RELAY. A3. In the trial, all 17 clinics completed both periods. One thousand five hundred and thirty-six and 1724 IPs provided data in intervention and control phases. In intervention and control phases, 666 (43.4%) and 800 (46.4%) IPs were tested for C. trachomatis; 31 (4.7%) and 53 (6.6%) were positive, adjusted odds ratio (aOR) 0.66 [95% confidence interval (CI) 0.41 to 1.04; p = 0.07]. The proportion with ≥ 1 SP treated was 775/881 (88.0%) in intervention and 760/898 (84.6%) in the control phase, aOR 1.27 (95% CI 0.96 to 1.68; p = 0.10) (Estcourt C, Mapp F, Stirrup O, Copas A, Howarth A, Owusu M, et al. O18.2 Does Accelerated partner therapy improve partner notification outcomes for people with chlamydia? The LUSTRUM cluster cross-over randomised control trial. Sex Transm Infect 2021;97:A57–8. http://doi.org/10.1136/sextrans-2021-sti.153). In total, 4807 SPs were reported, of whom 1636 (34%) were committed/established partners. Overall, 293/1536 (19.1%) of IPs in intervention phase chose APT for a total of 305 partners, of whom 248 accepted. Partner types were committed/established, 166/305 (54.4%); new, 85/305 (27.9%); occasional, 45/305 (14.8%); and one-off, 9/305 (3.0%). Common reasons for IPs to decline APT included: preferred face-to-face conversation 400/1832 (21.8%), partner already in clinic 388/1832 (21.2%), unwilling to engage with partner 206/1832 (11.2%), preferred partner to attend clinic 202/1832 (11.0%) and partner overseas 150/1832 (8.2%). Of 241 partners sent APT packs, 120/241 (49.8%) returned chlamydia and gonorrhoea testing samples, of which 78/119 (65.5%) were positive for chlamydia (no result in one), but only 60/241 (24.9%) HIV and syphilis samples (all negative). In an unplanned analysis, 2/106 (2.0%) IPs, who were offered APT and accepted it for one or more partners, tested positive for chlamydia at 12–24 weeks. Of IPs not selecting APT or whose partners refused, 29/560 (5.2%) had a positive result on repeat testing. The process evaluation showed that overall intervention fidelity was good and APT was well liked by those who delivered and received it. Overall, we found a mixed picture of an intuitive, coherent intervention struggling to gain purchase within already pressured services. HCPs preferred RELAY to their clinic systems because it helped them standardise PN. However, many sites struggled to scale up the trial processes owing to continual external pressures to adapt services to achieve efficiencies. In some services, APT was perceived as time-consuming and without palpable impact. This observation was related to the absence of a reduction in patient numbers in clinic waiting rooms. In this way, the ‘invisibility’ of the effectiveness of APT curtailed the establishment of positive feedback loops driving normalisation within services. In the CCA, APT cost more than standard PN (£91.23 vs. £75.21). Where accepted, it was more effective than standard PN with an absolute effect difference of 5.26%. B1 and B2. In the model, chlamydia positivity was highest for symptomatic index cases of low sexual activity, with infected partners who were typically asymptomatic and highly sexually active. Partner notification for this index–partner combination would prevent the most transmission. Increasing the number of treated partners from current levels in Britain (0.51, 95% credible interval, CI 0.21 to 0.80) by 25% would reduce chlamydia prevalence by 18% (95% CI 5% to 44%) in both women and men within 5 years. Reducing the time to partner treatment alone had a minor effect on reducing prevalence. Together, these results suggest that PN typically identifies sexual partners who are likely to further transmit chlamydia and that APT could further reduce prevalence if PN uptake increases. B3. In the cost-effectiveness analysis, the base-case results showed APT cost less and was more effective than standard PN in terms of MOA and QALYs, and therefore cost-saving. The results were supported by deterministic sensitivity analysis and scenario analysis for most scenarios, with ICERs very low and well within accepted thresholds. C1. There was very little published evidence on health economic aspects of PN in MSM. This supports the need for new interventions with parallel economic evaluation. C2. Published models have not examined the impact on HIV diagnosis of PN for bacterial STIs, and interventions cannot be extrapolated between countries. There were challenges in fitting the model of gonorrhoea/HIV co-infection to data, including issues with parameter identifiability. C3. We considered APT for MSM (and their more emotionally connected partners) and developed recommendations for a multilevel, multistakeholder intervention targeting MSM with other types of partners for whom PN is known to be more challenging. Key intervention elements included: a co-ordinated and coproduced mass and social media intervention to change norms and beliefs to challenge stigma and other barriers to PN; NGO peer-led work reducing STI-related stigma and persuading MSM to participate actively in PN to protect others and their communities; working with MSM to enable them to prepare for PN interactions and encourage HCP action, monitoring systems to directly address one-off PN outcomes; dating app providers promoting appropriate PN messaging. Conclusions The Programme provides findings about APT, which show promise for future PN. RELAY could be added to clinic systems for recording PN outcomes and processes. The Programme identified gaps in research about PN for one-off, and other partnerships with poor outcomes and high potential for onward sexual transmission. Data from the trial also suggested that APT uptake might be lower for people belonging to ethnic minority groups, although it was not powered to formally evaluate any such differences. The process evaluation and the work in Stream C identify a need for interventions that reach beyond sexual health services. Future work Future work should identify PN approaches for one-off partners; determine how to provide real-time or fast feedback for practitioners on the impact of interventions whose value is not obvious; further research is needed on how to increase uptake of APT, explore the pros and cons of immediate antibiotics, and optimise the uptake of self-sampling in partners, particularly people with mild learning disabilities; understand how services can use sex partnership-type information to improve PN methods, especially for hard-to-reach groups; develop and evaluate a system intervention to increase readiness in MSM for and engagement with PN for bacterial STIs, focusing on one-off partnerships and addressing economic factors and partnership type. Trial registration This trial is registered as ISRCTN15996256. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-0614-20009) and is published in full in Programme Grants for Applied Research; Vol. 12, No. 2. See the NIHR Funding and Awards website for further award information.

Abstract Background Mental health acute and crisis care consumes a large share of mental health budgets internationally but is often experienced as unsatisfactory and difficult to access. As a result, there is an increasing move towards developing innovative community crisis services, to improve patient experience and relieve pressure on inpatient and emergency services. This study aims to understand what helps and hinders the implementation of innovative mental health crisis care projects in England. Methods Using a qualitative approach, 18 interviews were conducted with crisis care service managers exploring their experiences and views of the development and implementation of their service developed with support from an English national capital funding programme. A framework analysis was conducted informed by implementation science. Results Key facilitators to implementation of innovative crisis services included bottom-up development, service user involvement, strong collaborative working, and leadership and management buy-in. Key barriers that affected the projects implementation included the complexities of crisis care, workforce challenges and resourcing issues. Conclusion There is a recognised need to improve, update, and innovate current crisis care offers. Results from this study suggest that a range of models can help address the heterogenous needs of local populations and that new approaches can be implemented where they utilise a whole-systems approach, involving service users and relevant professional stakeholders beyond mental health services in planning and developing the service.

Abstract Understanding the balance between epitope shielding and accessibility on HIV-1 envelope (Env) trimers is essential to guide immunogen selection for broadly neutralizing antibody (bnAb) based vaccines. To investigate the antigenic space of Env immunogens, we created a strategy based on synthetic, high diversity, Designed Ankyrin Repeat Protein (DARPin) libraries. We show that DARPin Antigenicity Analysis (DANA), a purely in vitro screening tool, has the capability to extrapolate relevant information of antigenic properties of Env immunogens. DANA screens of stabilized, soluble Env trimers revealed that stronger trimer stabilization led to the selection of highly mutated DARPins with length variations and framework mutations mirroring observations made for bnAbs. By mimicking heterotypic prime-boost immunization regimens, DANA may be used to select immunogen combinations that favor the selection of trimer-reactive binders. This positions DANA as a versatile strategy for distilling fundamental antigenic features of immunogens, complementary to preclinical immunogenicity testing.

Abstract Background Loneliness and social isolation are increasingly recognised as prevalent among people with mental health problems, and as potential targets for interventions to improve quality of life and outcomes, as well as for preventive strategies. Understanding the relationship between quality and quantity of social relationships and a range of mental health conditions is a helpful step towards development of such interventions. Purpose Our aim was to give an overview of associations between constructs related to social relationships (including loneliness and social isolation) and diagnosed mental conditions and mental health symptoms, as reported in systematic reviews of observational studies. Methods For this umbrella review (systematic review of systematic reviews) we searched five databases (PsycINFO, MEDLINE, EMBASE, CINAHL, Web of Science) and relevant online resources (PROSPERO, Campbell Collaboration, Joanna Briggs Institute Evidence Synthesis Journal). We included systematic reviews of studies of associations between constructs related to social relationships and mental health diagnoses or psychiatric symptom severity, in clinical or general population samples. We also included reviews of general population studies investigating the relationship between loneliness and risk of onset of mental health problems. Results We identified 53 relevant systematic reviews, including them in a narrative synthesis. We found evidence regarding associations between (i) loneliness, social isolation, social support, social network size and composition, and individual-level social capital and (ii) diagnoses of mental health conditions and severity of various mental health symptoms. Depression (including post-natal) and psychosis were most often reported on, with few systematic reviews on eating disorders or post-traumatic stress disorder (PTSD), and only four related to anxiety. Social support was the most commonly included social construct. Our findings were limited by low quality of reviews and their inclusion of mainly cross-sectional evidence. Conclusion Good quality evidence is needed on a wider range of social constructs, on conditions other than depression, and on longitudinal relationships between social constructs and mental health symptoms and conditions.

The expression of bone morphogenetic protein-7 (BMP-7) mRNA by in situ hybridization in rats with normal kidneys and those with acute renal failure has been studied cloning a rat BMP-7 cDNA and using it as a probe. BMP-7 is a member of the transforming growth factor-beta superfamily that are found abundantly in the fetal kidney. Results indicated that the BMP-7 mRNA has the highest expression in tubules of the outer medulla. Its expression is also localized to the adventitia of renal arteries, the epithelial cell layer of the renal pelvis and the ureter.

A study was conducted on the mechanism by which hepatic endothelin (ET) production is enhanced during endotoxin exposure. The findings suggest a model of paracrine signaling to describe the mechanism for the elevation of hepatic ET-1 levels following endotoxin exposure. This paracrine signaling mechanism operates between Kupffer cells that release transforming growth factor-Beta on endotoxin challenge and hepatic endothelial cells.

The characterization and partial purification of secretory platelet-activating factor (PAF)-acetylhydrolase of the rat hepatobiliary system were conducted. The objective is to show that both rat hepatocytes and Kupffer cells secrete constitutive pPAF-AH (plasma-type platelet-activating factor-acetylhydrolase) in cultured mediums. Results demonstrate that rat bile contains substantial amounts of PAF-AH exhibiting pPAF-AH properties.

The roles of endothelin A (ETA) and (ETB) B receptors on bone formation was analyzed in primary cultures of rat fetal calvarial cells to characterize osteoblast responsiveness to ET-1. Analysis of the effects of osteogenic protein (OP)-1 on ET-1 receptor expression indicated the presence of downregulated ETA gene expression in the presence of high levels of OP-1. Furthermore, ET-1 modulated osteoblastic function during discrete phases of osteoblast development.

The effects of endotoxemia on endothelin-1 synthesis by hepatic endothelial cells were analyzed in intact livers isolated from endotoxin-treated rats. Analysis of liver cells from endotoxemia-treated rats indicated the presence of elevated ET-1 hepatic messenger RNA expression. Analysis of liver cell types from endotoxin-treated rats also indicated high ET-1 concentrations in the hepatic endothelial cells. Furthermore, endotoxemia elevated the levels of circulating immunoreactive ET-1 in endotoxin-treated rats due to systemic trauma.

A study was conducted to examine the effects of osteogenic protein-1 (OP-1) on the proliferation and maturation of ROS 17/2.8 cells, which are associated with the growth and differentiation of bone osteoblasts. Treatment with OP-1 increased alkaline phosphatase activity, alkaline phosphatase mRNA, parathyroid hormone receptor mRNA and parathyroid hormone-stimulated adenosine 3',5'-cyclic monophosphate. However, OP-1 inhibited [3H]thymidine incorporation. These results suggest that potentiation of osteoblast by treatment with OP-1 affects bone morphogenesis.