Prospective study of biomechanical risk factors for second and third metatarsal stress fractures in military recruits

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordObjectives This prospective study investigated anatomical and biomechanical risk factors for second and third metatarsal stress fractures in military recruits during training. Design Prospective cohort study. Methods Anatomical and biomechanical measures were taken for 1065 Royal Marines recruits at the start of training when injury-free. Data included passive range of ankle dorsi-flexion, dynamic peak ankle dorsi-flexion and plantar pressures during barefoot running. Separate univariate regression models were developed to identify differences between recruits who developed second (n = 7) or third (n = 14) metatarsal stress fracture and a cohort of recruits completing training with no injury (n = 150) (p < 0.05). A multinomial logistic regression model was developed to predict the risk of injury for the two sites compared with the no-injury group. Multinomial logistic regression results were back transformed from log scale and presented in Relative Risk Ratios (RRR) with 95% confidence intervals (CI). Results Lower dynamic arch index (high arch) (RRR: 0.75, CI: 0.63–0.89, p < 0.01) and lower foot abduction (RRR: 0.87, CI: 0.80–0.96, p < 0.01) were identified as increasing risk for second metatarsal stress fracture, while younger age (RRR: 0.78, CI: 0.61–0.99, p < 0.05) and later peak pressure at the second metatarsal head area (RRR: 1.19, CI: 1.04–1.35, p < 0.01) were identified as risk factors for third metatarsal stress fracture. Conclusions For second metatarsal stress fracture, aspects of foot type have been identified as influencing injury risk. For third metatarsal stress fracture, a delayed forefoot loading increases injury risk. Identification of these different injury mechanisms can inform development of interventions for treatment and prevention.Funding to support this project was provided by University of Exeter and Institute of Naval Medicine

Boot-insole effects on comfort and plantar loading at the heel and fifth metatarsal during running and turning in soccer

Plantar loading may influence comfort, performance and injury risk in soccer boots. This study investigated the effect of cleat configuration and insole cushioning levels on perception of comfort and in-shoe plantar pressures at the heel and fifth metatarsal head region. Nine soccer academy players (age 15.7 ± 1.6 years; height 1.80 ± 0.40 m; body mass 71.9 ± 6.1 kg) took part in the study. Two boot models (8 and 6 cleats) and two insoles (Poron and Poron/gel) provided four footwear combinations assessed using pressure insoles during running and 180° turning. Mechanical and comfort perception tests differentiated boot and insole conditions. During biomechanical testing, the Poron insole generally provided lower peak pressures than the Poron/gel insole, particularly during the braking step of the turn. The boot model did not independently influence peak pressures at the fifth metatarsal, and had minimal influence on heel loads. Specific boot-insole combinations performed differently (P < 0.05). The 8-cleat boot and the Poron insole performed best biomechanically and perceptually, but the combined condition did not. Inclusion of kinematic data and improved control of the turning technique are recommended to strengthen future research. The mechanical, perception and biomechanical results highlight the need for a multi-faceted approach in the assessment of footwear

Baseline study in environmental risk assessment – Escalating need for computer models to be whole-system approach

Despite landfills having the potential to pollute the environment both during their operation and long after they have ceased to receive waste, they remain a dominant waste management option, particularly in the UK. In order to combat the environmental pollution caused by landfills, risk analysis is increasingly being employed through computer models. However, for a risk analysis process to be successful, its foundation has to be well established through a baseline study. This paper aims to identify knowledge gaps in software packages regarding environmental risk assessments in general, and especially those that have been developed specifically for landfills and landfill leachate. The research establishes that there is no holistic computer model for the baseline study of landfills, which risk assessors can use to conduct risk analyses specifically for landfill leachate. This paper also describes a number of factors and features that should be added to the baseline study system in order to render it more integrated – thereby enhancing quantitative risk analysis, and subsequently environmental risk management

Changes in the immune landscape of TNBC after neoadjuvant chemotherapy: correlation with relapse

Introduction: Patients with high-risk, triple negative breast cancer (TNBC) often receive neoadjuvant chemotherapy (NAC) alone or with immunotherapy. Various single-cell and spatially resolved techniques have demonstrated heterogeneity in the phenotype and distribution of macrophages and T cells in this form of breast cancer. Furthermore, recent studies in mice have implicated immune cells in perivascular (PV) areas of tumors in the regulation of metastasis and anti-tumor immunity. However, little is known of how the latter change during NAC in human TNBC or their impact on subsequent relapse, or the likely efficacy of immunotherapy given with or after NAC. Methods: We have used multiplex immunofluorescence and AI-based image analysis to compare the immune landscape in untreated and NAC-treated human TNBCs. We quantified changes in the phenotype, distribution and intercellular contacts of subsets of tumor-associated macrophages (TAMs), CD4+ and CD8+ T cells, and regulatory T cells (Tregs) in PV and non-PV various areas of the stroma and tumor cell islands. These were compared in tumors from patients who had either developed metastases or were disease-free (DF) after a three-year follow up period. Results: In tumors from patients who remained DF after NAC, there was a marked increase in stromal CD163+ TAMs, especially those expressing the negative checkpoint regulator, T-cell immunoglobulin and mucin domain 3 (TIM-3). Whereas CD4+ T cells preferentially located to PV areas in the stroma of both untreated and NAC-treated tumors, specific subsets of TAMs and Tregs only did so only after NAC. Distinct subsets of CD4+ and CD8+ T cells formed PV clusters with CD163+ TAMs and Tregs. These were retained after NAC. Discussion: Quantification of stromal TIM-3+CD163+ TAMs in tumor residues after NAC may represent a new way of identifying patients at high risk of relapse. PV clustering of immune cells is highly likely to regulate the activation and function of T cells, and thus the efficacy of T cell-based immunotherapies administered with or after NAC

Authors’ reply re: painful sex (dyspareunia) in women: prevalence and associated factors in a British population probability survey

No abstract available

Bursting out of our bubble: using creative techniques to communicate within the systematic review process and beyond

This is the final version. Available on open access from BMC via the DOI in this recordBACKGROUND: Increasing pressure to publicise research findings and generate impact, alongside an expectation from funding bodies to go beyond publication within academic journals, has generated interest in alternative methods of science communication. Our aim is to describe our experience of using a variety of creative communication tools, reflect on their use in different situations, enhance learning and generate discussion within the systematic review community. METHODS: Over the last 5 years, we have explored several creative communication tools within the systematic review process and beyond to extend dissemination beyond traditional academic mechanisms. Central to our approach is the co-production of a communication plan with potential evidence users which facilitates (i) the identification of key messages for different audiences, (ii) discussion of appropriate tools to communicate key messages and (iii) exploration of avenues to share them. We aim to involve evidence users in the production of a variety of outputs for each research project cognisant of the many ways in which individuals engage with information. RESULTS: Our experience has allowed us to develop an understanding of the benefits and challenges of a wide range of creative communication tools. For example, board games can be a fun way of learning, may flatten power hierarchies between researchers and research users and enable sharing of large amounts of complex information in a thought provoking way, but they are time and resource intensive both to produce and to engage with. Conversely, social media shareable content can be quick and easy to produce and to engage with but limited in the depth and complexity of shareable information. DISCUSSION: It is widely recognised that most stakeholders do not have time to invest in reading large, complex documents; creative communication tools can be a used to improve accessibility of key messages. Furthermore, our experience has highlighted a range of additional benefits of embedding these techniques within our project processes e.g. opening up two-way conversations with end-users of research to discuss the implications of findings.National Institute for Health Research (NIHR

Consideration of health inequity in systematic reviews and primary studies on risk factors for hearing loss

This is the final version. Available from Wiley via the DOI in this record. DATA AVAILABILITY STATEMENT: The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.Background: Health inequities are systematic, avoidable, and unfair differences in health between populations or population subgroups. There is increased recognition of the need for systematic reviews (SRs) to address health inequities, including drawing out findings relevant to low‐ and middle‐income countries (LMICs). The aim of this study was to determine the extent to which SRs on risk factors for hearing loss reported findings associated with health inequities, and the extent to which this data was captured in the primary studies included within these SRs. Methods: We identified SRs on risk factors for hearing loss from a report on this topic which included a systematic search for relevant SRs. SRs thus identified were inspected for data related to health inequity with reference to PROGRESS‐Plus. We compared how data were reported in SRs versus within primary studies included in the SRs, and the extent to which primary studies from LMICs were represented. Results: We included 17 SRs which reported findings on a variety of physiological, behavioral, demographic, and environmental risk factors for hearing loss. There were 296 unique primary studies included in the SRs, of which 251 (81.49%) were successfully retrieved. Data relating to health inequities was reported relatively infrequently in the SRs and mainly focused on gender and age. Data related to health inequities was more frequently reported in primary studies. However, several PROGRESS‐Plus criteria were only reported in a minority of primary studies. Approximately one‐third of primary studies were from LMICs. Conclusions: There is scope to improve the reporting of data relating to health inequities in primary studies on risk factors for hearing loss. However, SR authors could do more to report health inequities than is currently undertaken, including drawing out findings relevant to LMICs where data are available.National Institute for Health Research (NIHR

What multi-disciplinary delivery models for Occupational Health services are effective for whom? An umbrella review

What did we want to know? In the UK, tens of millions of working days are lost due to work-related ill health every year, costing billions of pounds. Prior to the COVID-19 pandemic, around 8 million working-age people were registered disabled and about half of these were in employment. The role of Occupational Health (OH) services is vital in helping workers to maintain employment when they encounter injury or illness. Part of this role is to advise on prevention of illness and injury at work, but a large part of it is to manage the recovery, rehabilitation and return to work (RTW) of sick-listed employees. The combination of an ageing population, increasing levels of chronic illness, mental health difficulties and disability, and the removal of the default retirement age, means that the demand for occupational health (OH) services is ever increasing. OH providers traditionally rely on a clinical workforce to deliver these services, particularly doctors and nurses with OH qualifications. However, the increasing demand for OH services is unlikely to be met in future using this traditional model, as the number of OH-trained doctors and nurses in the UK is declining. Experts suggest multi-disciplinary models of OH delivery, including a more varied range of healthcare and non-healthcare professionals, can be highly effective. Moving to a more multidisciplinary workforce could also enable OH market capacity to significantly increase to meet new demand with less reliance on OH-trained doctors and nurses. There is a therefore a pressing need to identify effective collaborative models of occupational health service delivery that involve a variety of healthcare and non-healthcare professionals. At this stage, it is necessary to review existing evidence regarding the effectiveness of multi-disciplinary OH-delivered interventions on return-to work outcomes. There is an existing pool of systematic review evidence evaluating OH interventions, but it is difficult to identify which aspects of the delivery of these interventions may be associated with success. The array of interventions and conditions studied across the systematic review evidence base makes it difficult to distil a broader sense of what might be effective. By seeking to evaluate any workplace based multidisciplinary OH intervention that involved the workplace and looking across any health condition leading to sickness absence, we sought to determine which combination of multi-disciplinary professionals are effective for different populations. Aim To review the effectiveness and cost-effectiveness systematic review evidence that evaluates multi-disciplinary OH interventions aiming to improve work outcomes including return to work and reduced sickness absence. Research questions 1. What multi-disciplinary delivery models for OH services are effective, and for whom? 2. What are the characteristics of effective multi-disciplinary delivery models for OH? 3. Which multi-disciplinary models of OH service delivery are cost-effective? Specific research objectives: To identify, critically appraise, and narratively summarise systematic review evidence regarding: 1. The effectiveness of multi-disciplinary interventions intended to improve work outcomes following illness or injury, such as return to work and reduced sickness absence; 2. The cost-effectiveness of multi-disciplinary interventions intended to improve work outcomes following illness or injury. To meet these research objectives, we aimed to: 1. Identify, critically appraise, and map relevant systematic review evidence; 2. Narratively summarise the key findings; 3. Develop a taxonomy of successful interventions. What did we find? Systematic review evidence We identified 89 systematic reviews that contained relevant interventions which involved a variety of professionals and the workplace, and which measured effectiveness in terms of RTW. Of these, we focused on the 24 where the population and intervention characteristics within the systematic reviews were the most relevant to our research questions. The 24 reviews were of varying quality, split evenly between High/Moderate quality and Low/Critically Low-quality ratings. We mapped these 24 reviews in an evidence and gap map (https://eppi.ioe.ac.uk/cms/Portals/35/Maps/MN_Exeter_Feb22.html), providing a visual representation of the evidence. Due to the heterogeneity of the interventions included within the systematic reviews, we were unable to structure the map according to the different types of intervention being evaluated. Instead, using the evidence and gap map, it is possible to view i) the quality and quantity of systematic review evidence for a given health condition, ii) how the review authors rated the effectiveness or cost-effectiveness of the interventions included. Furthermore, by navigating the evidence and gap map, one can see the relevant primary studies within each review. Our umbrella review provides the first point of reference for interventions under the broad remit of multidisciplinary OH services involving the workplace, across any health condition leading to sick leave. However, the body of systematic review evidence about multidisciplinary models of OH services is highly heterogeneous in terms of intervention, health condition, size and quality and we were unable to draw conclusions about the relative effectiveness of different interventions across health conditions from this body of evidence. What are the implications? This umbrella review has highlighted an array of systematic review evidence that exists in relation to the effectiveness or cost-effectiveness of multi-disciplinary OH interventions in supporting RTW. This evidence may be useful for supporting policy makers and commissioners of services to determine which OH interventions may be most useful for supporting different population groups in different contexts. OH professionals may find the content of the evidence and gap map useful in identifying systematic review evidence to support their practice. The evidence and gap map also identifies where systematic review evidence in this area is lacking, or where existing evidence is of poor quality. These may represent areas where it may be particularly useful to conduct further systematic reviews. This umbrella review also highlights the primary studies within these reviews which are specifically relevant to our research aims and objectives. A series of smaller, more specific, systematic reviews, including a search focused on identifying primary studies, quality appraisal and full synthesis, could be conducted using these studies as a starting point/basis to determine the confidence which can be placed in the descriptive findings of this review. How did we get these results? We followed best practice guidance, and our protocol was registered on the Open Science Framework. Our approach was that of an umbrella review, featuring a rigorous search for systematic review evidence, critical appraisal and mapping of evidence. Finding the systematic review evidence The search strategy included search terms that describe returning to work, such as ‘return to work’, ‘re-entering work’ and ‘vocational rehabilitation’, in conjunction with a systematic review study type filter. An historical date limit of 2001 was applied, and the results limited to English language studies. We searched a selection of health and non-health care bibliographic databases and search engines to identify evidence from a variety of sectors of employment. To identify grey literature we searched Google Search, Google Scholar and a selection of topically relevant websites. We also consulted with stakeholders to identify reports already known to them. We sought systematic reviews about adults (16 or over) in employment who have had absence or are absent from work for any medical reason and were receiving an intervention to get them back to work or help them retain work. Interventions needed to be multi-disciplinary (including professionals from different backgrounds in clinical and non-clinical professions) and designed to support employees and employers to manage health conditions in the workplace and/or to help employees with health conditions retain work and/or return to work following medical absence. Effectiveness needed to be measured in terms of return to work, work retention or measures of absence, or economic evaluation outcomes. Data extraction and quality appraisal Summary data for each eligible review was extracted. More detailed data extraction was carried out for the twenty-four reviews rated as being the most relevant to the aims of our umbrella review. Then, details of the primary studies identified within these reviews that met our inclusion criteria, were extracted. This aimed to supplement data which was reported poorly at the level of the review and focused on information about the professionals who delivered the intervention. All data were extracted by one reviewer and checked by a second, with disagreements being settled through discussion. The quality of the systematic reviews rated as high or medium relevance following full-text screening was appraised using the AMSTAR-2 quality appraisal tool. Data analysis and presentation Summary data for all eligible systematic reviews were tabulated and described narratively. The data extracted from reviews of High and Medium relevance was imported into EPPI-Mapper software to create an evidence and gap map (https://eppi.ioe.ac.uk/cms/Portals/35/Maps/MN_Exeter_Feb22.html) The evidence and gap map was structured according to the health condition that led to sick leave, and the main findings relating to the return to work outcome(s) reported at review level. The size and colour of the circles within each segment of the map represent the number and quality of reviews reporting RTW outcomes for interventions conducted with particular health conditions. Each segment can be clicked upon to view the abstracts of the systematic reviews included in that segment, and a link to the included primary studies which were relevant to our umbrella review. Details of the systematic reviews included within the map were tabulated and described narratively. Primary studies which were relevant to the aims of our umbrella review were tagged in the record of the included systematic review within the map. Stakeholder involvement We worked alongside a variety of stakeholders and advisors to ensure our umbrella review reflects the needs of individuals who will use it. Stakeholders included commissioners and policy makers from DHSC and DWP, OH personnel and people with lived experience of accessing OH services themselves and/or supporting employees to access OH services.National Institute for Health Research (NIHR

Targeting a STING agonist to perivascular macrophages in prostate tumors delays resistance to androgen deprivation therapy

Background: Androgen deprivation therapy (ADT) is a front-line treatment for prostate cancer. In some men, their tumors can become refractory leading to the development of castration-resistant prostate cancer (CRPC). This causes tumors to regrow and metastasize, despite ongoing treatment, and impacts negatively on patient survival. ADT is known to stimulate the accumulation of immunosuppressive cells like protumoral tumor-associated macrophages (TAMs), myeloid-derived suppressor cells and regulatory T cells in prostate tumors, as well as hypofunctional T cells. Protumoral TAMs have been shown to accumulate around tumor blood vessels during chemotherapy and radiotherapy in other forms of cancer, where they drive tumor relapse. Our aim was to see whether such perivascular (PV) TAMs also accumulate in ADT-treated prostate tumors prior to CRPC, and, if so, whether selectively inducing them to express a potent immunostimulant, interferon beta (IFNβ), would stimulate antitumor immunity and delay CRPC. Methods: We used multiplex immunofluorescence to assess the effects of ADT on the distribution and activation status of TAMs, CD8+T cells, CD4+T cells and NK cells in mouse and/or human prostate tumors. We then used antibody-coated, lipid nanoparticles (LNPs) to selectively target a STING agonist, 2′3′-cGAMP (cGAMP), to PV TAMs in mouse prostate tumors during ADT. Results: TAMs accumulated at high density around blood vessels in response to ADT and expressed markers of a protumoral phenotype including folate receptor-beta (FR-β), MRC1 (CD206), CD169 and VISTA. Additionally, higher numbers of inactive (PD-1-) CD8+T cells and reduced numbers of active (CD69+) NK cells were present in these PV tumor areas. LNPs coated with an antibody to FR-β selectively delivered cGAMP to PV TAMs in ADT-treated tumors, where they activated STING and upregulated the expression of IFNβ. This resulted in a marked increase in the density of active CD8+T cells (along with CD4+T cells and NK cells) in PV tumor areas, and significantly delayed the onset of CRPC. Antibody depletion of CD8+T cells during LNP administration demonstrated the essential role of these cells in delay in CRPC induced by LNPs. Conclusion: Together, our data indicate that targeting a STING agonist to PV TAMs could be used to extend the treatment window for ADT in prostate cancer