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A Unified Metric of Human Immune Health?

IFNγ Production by Functionally Reprogrammed Tregs Promotes Antitumor Efficacy of OX40/CD137 Bispecific Agonist Therapy.

UNLABELLED: Regulatory T cells (Treg) are highly enriched within many tumors and suppress immune responses to cancer. There is intense interest in reprogramming Tregs to contribute to antitumor immunity. OX40 and CD137 are expressed highly on Tregs, activated and memory T cells, and NK cells. In this study, using a novel bispecific antibody targeting mouse OX40 and CD137 (FS120m), we show that OX40/CD137 bispecific agonism induces potent antitumor immunity partially dependent upon IFNγ production by functionally reprogrammed Tregs. Treatment of tumor-bearing animals with OX40/CD137 bispecific agonists reprograms Tregs into both fragile Foxp3+ IFNγ+ Tregs with decreased suppressive function and lineage-instable Foxp3- IFNγ+ ex-Tregs. Treg fragility is partially driven by IFNγ signaling, whereas Treg instability is associated with reduced IL2 responsiveness upon treatment with OX40/CD137 bispecific agonists. Importantly, conditional deletion of Ifng in Foxp3+ Tregs and their progeny partially reverses the antitumor efficacy of OX40/CD137 bispecific agonist therapy, revealing that reprogramming of Tregs into IFNγ-producing cells contributes to the anti-tumor efficacy of OX40/CD137 bispecific agonists. These findings provide insights into mechanisms by which bispecific agonist therapies targeting costimulatory receptors highly expressed by Tregs potentiate antitumor immunity in mouse models. SIGNIFICANCE: The bispecific antibody FS120, an immunotherapy currently being tested in the clinic, partially functions by inducing anti-tumor activity of Tregs, which results in tumor rejection.

GS-TCGA: Gene Set-Based Analysis of The Cancer Genome Atlas.

Most tools for analyzing large gene expression datasets, including The Cancer Genome Atlas (TCGA), have focused on analyzing the expression of individual genes or inference of the abundance of specific cell types from whole transcriptome information. While these methods provide useful insights, they can overlook crucial process-based information that may enhance our understanding of cancer biology. In this study, we describe three novel tools incorporated into an online resource; gene set-based analysis of The Cancer Genome Atlas (GS-TCGA). GS-TCGA is designed to enable user-friendly exploration of TCGA data using gene set-based analysis, leveraging gene sets from the Molecular Signatures Database. GS-TCGA includes three unique tools: GS-Surv determines the association between the expression of gene sets and survival in human cancers. Co-correlative gene set enrichment analysis (CC-GSEA) utilizes interpatient heterogeneity in cancer gene expression to infer functions of specific genes based on GSEA of coregulated genes in TCGA. GS-Corr utilizes interpatient heterogeneity in cancer gene expression profiles to identify genes coregulated with the expression of specific gene sets in TCGA. Users are also able to upload custom gene sets for analysis with each tool. These tools empower researchers to perform survival analysis linked to gene set expression, explore the functional implications of gene coexpression, and identify potential gene regulatory mechanisms.

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

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

Understanding the leading indicators of hospital admissions from COVID-19 across successive waves in the UK

Abstract Following the end of universal testing in the UK, hospital admissions are a key measure of COVID-19 pandemic pressure. Understanding leading indicators of admissions at the National Health Service (NHS) Trust, regional and national geographies help health services plan for ongoing pressures. We explored the spatio-temporal relationships of leading indicators of hospitalisations across SARS-CoV-2 waves in England. This analysis includes an evaluation of internet search volumes from Google Trends, NHS triage calls and online queries, the NHS COVID-19 app, lateral flow devices (LFDs), and the ZOE app. Data sources were analysed for their feasibility as leading indicators using Granger causality, cross-correlation, and dynamic time warping at fine spatial scales. Google Trends and NHS triages consistently temporally led admissions in most locations, with lead times ranging from 5 to 20 days, whereas an inconsistent relationship was found for the ZOE app, NHS COVID-19 app, and LFD testing, which diminished with spatial resolution, showing cross-correlation of leads between –7 and 7 days. The results indicate that novel surveillance sources can be used effectively to understand the expected healthcare burden within hospital administrative areas though the temporal and spatial heterogeneity of these relationships is a key determinant of their operational public health utility.

Retrospective analysis of Schlafen11 (SLFN11) to predict the outcomes to therapies affecting the DNA damage response

Schlafen 11 (SLFN11) is a gene encoding for a protein involved in the irreversible arrest of cell replication under DNA-damaging stress. SLFN11 is expressed differently across various cancers. When overexpressed, SLFN11 inhibits tumor replication and growth by early recruitment to stressed replication forks, making tumors more sensitive to a range of anti-cancer treatments, including topoisomerase I–II inhibitors, DNA alkylating agents, platinum salts, anti-metabolites, anti-tumor antibiotics, poly ADP-ribose polymerase (PARP) inhibitors and immunotherapies. SLFN11 expression can be silenced in cancer cells through different epigenetic mechanisms, resulting in SLFN11 downregulation and resistance to anti-cancer treatments. In this context, SLFN11 is increasingly being recognized as a promising biomarker for predicting cancer treatment responses. Its expression levels can inform clinical decisions, helping to identify patients most likely to benefit from therapies that exploit replication stress and to select new drug combinations that specifically aim to overcome SLFN11 deficiency.

SLFN11 informs on standard of care and novel treatments in a wide range of cancer models.

BACKGROUND: Schlafen 11 (SLFN11) has been linked with response to DNA-damaging agents (DDA) and PARP inhibitors. An in-depth understanding of several aspects of its role as a biomarker in cancer is missing, as is a comprehensive analysis of the clinical significance of SLFN11 as a predictive biomarker to DDA and/or DNA damage-response inhibitor (DDRi) therapies. METHODS: We used a multidisciplinary effort combining specific immunohistochemistry, pharmacology tests, anticancer combination therapies and mechanistic studies to assess SLFN11 as a potential biomarker for stratification of patients treated with several DDA and/or DDRi in the preclinical and clinical setting. RESULTS: SLFN11 protein associated with both preclinical and patient treatment response to DDA, but not to non-DDA or DDRi therapies, such as WEE1 inhibitor or olaparib in breast cancer. SLFN11-low/absent cancers were identified across different tumour types tested. Combinations of DDA with DDRi targeting the replication-stress response (ATR, CHK1 and WEE1) could re-sensitise SLFN11-absent/low cancer models to the DDA treatment and were effective in upper gastrointestinal and genitourinary malignancies. CONCLUSION: SLFN11 informs on the standard of care chemotherapy based on DDA and the effect of selected combinations with ATR, WEE1 or CHK1 inhibitor in a wide range of cancer types and models.

The effect of Council decision making on the ability of Cambridgeshire communities to develop initiatives that lessen the need for formal health and social care services

Meeting Abstracts of the BACR conference: response and resistance in cancer therapy Abstracts

Telehealth and Remote Interventions for Children With Cerebral Palsy: Scoping Review.

BACKGROUND: Remote treatment, or telehealth, has shown promise for children with cerebral palsy (CP) prior to 2020; however, the beginning of the global COVID-19 pandemic limiting access to hospitals for face-to-face treatments has driven the need for telehealth and led to a surge in its development. Due to the recent developments, there has been limited synthesis of the available evidence of telehealth for children with CP. OBJECTIVE: This study aimed to analyze and summarize the existing evidence for telehealth interventions for the treatment of children with CP and identify any areas requiring further research. METHODS: A scoping review was performed. A systematic search of available literature in MEDLINE and PubMed was performed during July 2021. Inclusion criteria for articles were primary research and systematic reviews that investigated telehealth, included children with CP, were published between 2010-2021, and were written in English. Exclusion criteria were secondary research other than systematic reviews; interventions that did not meet the World Health Organization definition of telehealth; or studies where all participants were aged >18 years, children's results were not reported separately, or there were no results reported for children with CP. A scoping review was chosen due to the expected heterogeneity of the participants, as well as the expected small sample sizes and inconsistency of measured outcomes; therefore, a narrative reporting of the results was considered appropriate. RESULTS: In all, 5 papers were identified, which included the results of 11 studies-2 of the included articles were systematic reviews, which included the results of 3 studies each. These 6 studies, together with 5 primary research articles, were included in this scoping review. The existing evidence is of low methodological quality, primarily consisting of case series. There is some evidence that the requirements of telehealth differ depending on the children's developmental stage and functional level. Telehealth is reported to reduce caregiver burden. There is mixed evidence on children's compliance with telehealth. Overall, the results of telehealth interventions for the treatment of children with CP were positive, indicating either comparable or improved results compared with children receiving usual face-to-face care. CONCLUSIONS: The evidence base is lacking in breadth and methodological quality to provide robust clinical recommendations. Most studies investigated hand function only, indicating the limited scope of existing research. However, this review shows that telehealth has demonstrated potential to improve function for children with CP while making health care services more accessible and reducing caregiver burden. Areas requiring further research include telehealth interventions for the lower limb, postural management, and pain control and the barriers to implementing telehealth.

Threat of imposter participants in health research.

Construction and validation of sham insoles used in clinical trials: A systematic review.

BACKGROUND: Insoles are commonly prescribed to treat pathologies in a variety of patient groups; however, there is limited evidence to guide clinical decision-making. A well-validated sham insole is critical to conducting a double-blind placebo-controlled trial. OBJECTIVES: The aims were to establish: (1) How are sham insoles constructed? (2) What measures are undertaken to ensure adequate blinding? (3) What methods are used to validate the biomechanical effects? STUDY DESIGN: A systematic search of the methodology of level I-II therapeutic evidence. METHODS: Searches were conducted in MEDLINE, Embase, Cumulative Index of Nursing and Allied Health Literature, and Cochrane Central Register of Controlled Trials. Inclusion criteria were placebo-controlled clinical trials, sham insoles used, treatment insoles alter biomechanics, treatment insoles meet the ISO definition of foot orthotics, sham and treatment insoles tested in normal walking, and article available in English. RESULTS: The search generated 270 results. Twenty-four trials were included. 19% of sham insoles were described sufficiently to be replicated. The most common sham construction characteristics were full length, ethylene-vinyl acetate material, and flat insoles. 58% of studies were double-blinded; however, many did not describe any blinding methods. There is evidence that blinding the intervention details and a similar insole appearance is effective to blind participants. 13% of studies included a shoe-only condition to allow assessment of the biomechanical effects of sham insoles. CONCLUSIONS: There is inconsistent construction, blinding, and biomechanical validation of sham insoles. This casts a substantial doubt on the quality and reliability of the evidence base to support the prescription of insoles.

Post-stroke ankle-foot orthoses: Examining referral trends in the Scottish multi-disciplinary team.

PURPOSE: As per the Best Practice Statement: Use of Ankle-Foot Orthoses Following Stroke (BPS), members of the stroke multidisciplinary team should refer stroke patients with mobility problems to orthotics. Therefore, the objectives of this study were to (1) assess awareness of the BPS; (2) assess referral patterns and trends; and (3) identify barriers to referral to the Orthotic Service in Scotland. METHODS: An online survey of the stroke MDT, working in Scotland, whose current role involves work with stroke patients. A survey was distributed via the Scottish Stroke Allied Health Professionals Forum, Scottish Stroke Nurses Forum, British Association of Stroke Physicians, and Scottish Stroke Managed Clinical Networks. RESULTS: Statistically significant association was found between: Awareness of BPS and NHS Board Area; Profession and whether clinicians have referred to orthotics; Confidence in assessment criteria and profession; Referral to departments other than Orthotics and profession. CONCLUSION: Physiotherapists are relied upon by members of the Stroke MDT to identify mobility problems and refer to Orthotics. The BPS should be re-disseminated, particularly to the East of Scotland and GPs, to improve awareness of referral criteria. Reduced waiting list times and joint physiotherapist-orthotist clinics may reduce referral barriers to the Orthotic Service.

Allied health professionals' views on important outcomes of children's elective lower limb orthopaedic surgery: a qualitative interview study to inform a core outcome set.

PURPOSE: A common methodological limitation of research that guides surgical procedure selection for children's elective lower limb orthopaedic surgeries is inconsistent outcome selection. Improving outcome consistency can be achieved through the development of a core outcome set (COS). The aim of this study is to identify which outcomes are considered important for children's elective lower limb orthopaedic surgeries by allied health professionals (AHPs) and explore why they select these outcomes, to inform a COS development project. METHODS: Online semi-structured interviews were conducted with relevant AHPs. Participants were selected using maximum variation purposive sampling; selection was based on profession and inpatient/outpatient role. The data set was analysed using an inductive and deductive approach to thematic analysis. RESULTS: Four physiotherapists, three orthotists, three prosthetists, and two occupational therapists were interviewed. Most identified outcomes of importance related to "activities and participation". From the data, we conceptualised that AHPs with effective multidisciplinary communication focused on child-centred outcomes, while clinicians with limited multidisciplinary teamwork focused on role-based outcomes. CONCLUSIONS: There is concurrence between outcomes identified as important in this study, and other qualitative studies in similar populations. These important outcomes were seldom measured in previous studies or in routine clinical practice.Implications for rehabilitationAllied health professionals (AHPs) prioritise activity and participation outcomes after children's elective lower limb orthopaedic surgery.It is important to the rehabilitation of children after elective lower limb orthopaedic surgery that all involved AHPs collaborate with the wider multidisciplinary team.Multidisciplinary team communication encourages collaborative outcome identification, and discourages role defined outcome focus.

Walk a mile in these AFOs: A response to Zaino et al.

In Reply: Letter to the Editor Regarding Health-related Quality of Life in Idiopathic Toe Walkers: A Multicenter Prospective Cross-sectional Study.

Health-related Quality of Life in Idiopathic Toe Walkers: A Multicenter Prospective Cross-sectional Study.

OBJECTIVE: Despite idiopathic toe walking (ITW) being a significant source of stress and anxiety for children and parents alike, little is known about the effect on health-related quality of life (HRQoL). The primary research question for this study was "Is ITW associated with impaired HRQoL, and is the degree of equinus contracture related to the degree of impairment?" METHODS: Twelve pediatric orthopaedic centers across the United Kingdom participated in this prospective, cross-sectional observational study of children younger than 18 years with ITW. Data were collected between May 2022 and July 2022. Using a standardized, piloted proforma, data collected included: demographics, toe-walking duration, passive ankle range of motion (Silfverskiold test), associated autism spectrum disorder or attention deficit hyperactivity disorder, previous and planned treatments, and Oxford Ankle Foot Questionnaire for Children scores. Domain scores were compared with a healthy control group and correlation was made to plantarflexion contracture using standard nonparametric statistical methods. RESULTS: Data were collected from 157 children. Significant reductions in physical, school and play, and emotional domain scores were noted compared with healthy controls. A significant moderate correlation was noted between passive ankle dorsiflexion and physical domain scores. There were no significant differences in Oxford Ankle Foot Questionnaire for Children scores among patient groups by treatment. CONCLUSIONS: ITW in children is associated with an impairment in HRQoL, not only across the physical domain but also the school and play and emotional domains. The more severe the equinus contracture, the worse the physical domain scores. LEVEL OF EVIDENCE: Level II-prospective cross-sectional observational study.

Survey on the Use of Surgical Navigation for Endoscopic Sinus Surgery in the UK

Somatic Loss of BCLAF-1 in an Encephalocele Secondary to Idiopathic Intracranial Hypertension

Spectral Imaging for Microbubble Characterization.

Microbubbles stabilized by an outer lipid shell have been studied extensively for both diagnostic and therapeutic applications. The shell composition can significantly influence microbubble behavior, but performing quantitative measurements of shell properties is challenging. The aim of this study is to investigate the use of spectral imaging to characterize the surface properties of a range of microbubble formulations representing both commercial and research agents. A lipophilic dye, C-laurdan, whose fluorescence emission varies according to the properties of the local environment, was used to compare the degree and uniformity of the lipid order in the microbubble shell, and these measurements were compared with the acoustic response and stability of the different formulations. Spectral imaging was found to be suitable for performing rapid and hence relatively high throughput measurements of microbubble surface properties. Interestingly, despite significant differences in lipid molecule size and charge, all of the different formulations exhibited highly ordered lipid shells. Measurements of liposomes with the same composition and the debris generated by destroying lipid microbubbles with ultrasound (US) showed that these exhibited a lower and more varied lipid order than intact microbubbles. This suggests that the high lipid order of microbubbles is due primarily to compression of the shell as a result of surface tension and is only minimally affected by composition. This also explains the similarity in acoustic response observed between the formulations, because microbubble dynamics are determined by the diameter and shell viscoelastic properties that are themselves a function of the lipid order. Within each population, there was considerable variability in the lipid order and response between individual microbubbles, suggesting the need for improved manufacturing techniques. In addition, the difference in the lipid order between the shell and lipid debris may be important for therapeutic applications in which shedding of the shell material is exploited, for example, drug delivery.