Health Innovation Manchester

Despite growing interest surrounding the integration of genetic risk tools such as polygenic risk scores (PRSs) into routine care for early disease identification and management, major questions remain about whether and how these tools are to be implemented at-scale. Many interventions have explored their use in encouraging the adoption of preventative health behaviours-yet existing evidence remains undetermined, limited by the focus on White European populations. The present study used structural equation modelling to explore genetic risk perceptions surrounding type 2 diabetes (T2D) in a sample of British Bangladeshi and British Pakistani volunteers-combining questionnaire data alongside genomic and clinical information to identify the characteristics of individuals who are likely to act on genetic risk information. We conducted this study with volunteers enrolled in Genes & Health-a large-scale (n > 60,000) study in the UK recruiting British Bangladeshi and British Pakistani volunteers from community and NHS settings. Eligible participants between the ages of 16 to 59 years were invited to complete a 15-minute questionnaire containing measures of genetic risk perceptions surrounding T2D, as well as intention to adopt health behaviours and that can prevent or delay T2D. Questionnaire responses were then integrated with participants' genomic and clinical data available at Genes & Health to construct a model-characterising their mediating relationships in informing participants' intention. A total of 626 participants responded to the questionnaire (response rate = 17%, 37.70% aged 46 to 59 years, 62.62% female). Being between the ages of 46 to 59 years (β = 0.52, 95% CI [0.26, 0.79], p < 0.05), having greater self-reported perceived control over health (β = 0.41, 95% CI [0.26, 0.56], p < 0.05) and interest in genetic testing (β = 0.62, 95% CI [0.46, 0.78], p < 0.05) all had direct positive effects on participants' intention. Household income showed an indirect effect on intention, mediated by interest in genetic testing, β = 0.24, 95% CI [0.12, 0.37]. Self-identified ethnicity also demonstrated indirect effects on intention via two mediating pathways-both involving participants' T2D PRSs and self-reported family history of T2D (β = 0.03, 95% CI [0.02, 0.05] and β = 0.002, 95% CI [0.001, 0.01]). Our results showed that older age, greater perceived control over health and interest in genetic testing are all predictive of participants' likelihood of adopting preventative heath behaviours in response to genetic risk information about T2D. We also found evidence pointing to the roles that wider socio-demographic, clinical and familial variables can play in informing and mediating genetic risk perceptions. These findings should raise awareness about potential challenges to the equitable delivery and management of genetic risk tools-and strengthen calls for wider family- and system-level approaches that can help address potential health inequalities, as efforts surrounding the large-scale implementation of genomics into existing health systems continue to grow.

The objective of the current study was to present the results of an international working group survey identifying perceived limitations of existing facial nerve grading scales to inform the development of a novel grading scale for assessing early postoperative facial paralysis that incorporates regional scoring and is anchored in recovery prognosis and risk of associated complications. Survey. A working group of 48 multidisciplinary clinicians with expertise in skull base, cerebellopontine angle, temporal bone, or parotid gland surgery. House-Brackmann grade is the most widely used system to assess facial nerve function among working group members (81%), although more than half (54%) agreed that the system they currently use does not adequately estimate the risk of associated complications, such as corneal injury, and confidence in interrater and intrarater reliability is generally low. Simplicity was ranked as the most important attribute of a novel postoperative facial nerve grading system to increase the likelihood of adoption, followed by reliability and accuracy. There was widespread consensus (91%) that the eye is the most critical facial region to focus on in the early postoperative setting. Members were invited to submit proposed grading systems in alignment with the objectives of the working group for subsequent validation. From these data, we plan to develop a simple, clinically anchored, and reproducible staging system with regional scoring for assessing early postoperative facial nerve function after surgery of the skull base, cerebellopontine angle, temporal bone, or parotid gland.

Histoplasma capsulatum exposure is rarely suspected in Indonesia. Pulmonary histoplasmosis can occur simultaneously with pulmonary tuberculosis (TB) or as an alternative diagnosis in clinically-diagnosed TB patients with no microbiological evidence of TB. This study aimed to determine the seroprevalence of anti-H. capsulatum IgG antibody among pulmonary TB patients. This was a sub-study of 306 participants from a prospective cohort pulmonary TB study conducted at seven TB referral hospitals in Indonesia. The study population was presumptive pulmonary TB adult patients who underwent microbiological TB examinations and were categorized as drug-sensitive (DS), drug-resistant (DR), and clinically-diagnosed TB. Anti-H. capsulatum IgG antibody levels at baseline were measured using MVista Histoplasma Ab enzyme immunoassays. Data were summarized using descriptive statistics. Bivariate and multivariate logistic regression analysis were performed to assess factors associated with anti-H. capsulatum IgG antibody positive result. 12.7% (39/306) of pulmonary TB patients were positive for anti-H. capsulatum IgG antibodies (DR-TB patients (15.9%, 18/114), DS-TB (13.0%, 15/115), and clinically-diagnosed TB (7.8%, 6/77)). The median unit value of anti-H. capsulatum IgG antibody for all positive samples was 15.7 (IQR 10.2-28.9) EU. This median unit value was higher in clinically-diagnosed TB patients compared to DS-TB or DR-TB patients (38.1 (IQR 25.6-46.6) EU, 19.7 (IQR 12.3-28.9) EU, and 10.9 (IQR 9.2-15.4), respectively). There were 10 patients (3.3%) with anti-H. capsulatum IgG antibody levels above 30 EU. Factors associated with the anti-H. capsulatum IgG antibody positive result were malignancies (OR 4.88, 95% CI 1.09-21.69, p = 0.037) and cavitary lesions (OR 2.27, 95% CI 1.09-4.70, p = 0.028). Our results provide evidence of exposure to H. capsulatum among pulmonary TB patients in Indonesia. Further studies are needed to provide a comprehensive picture of this fungal disease in other populations and regions to enhance awareness among clinicians and public health officials.

Terrorist incidents lead to a range of mental health outcomes for people affected, sometimes extending years after the event. Secondary stressors can exacerbate them, and social support can provide mitigation and aid recovery. There is a need to better understand distress and mitigating factors among survivors of the Manchester Arena attack in 2017. We explored three questions. First, what experiences of distress did participants report? Second, how might secondary stressors have influenced participants' psychosocial recoveries? Third, what part has social support played in the relationships between distress and participants' recovery trajectories? We conducted a cross-sectional online survey of a convenience sample of survivors of the Manchester Arena bombing (N = 84) in January 2021 (3 years 8 months post-incident), and a longitudinal study of the same participants' scores on mental health measures over 3 years from September 2017. Survivors' mental well-being scores in early 2021 were significantly lower than general population norms. Longitudinal follow-up provided evidence of enduring distress. Secondary stressors, specifically disruptions to close relationships, were associated with greater post-event distress and slower recovery. We found an indirect relationship between identifying with, and receiving support from, others present at the event and mental well-being >3 years later. The Arena attack has had an enduring impact on mental health, even in survivors who had a mild response to the event. The quality of close relationships is pivotal to long-term outcome. Constructive support from family and friends, and people with shared experiences, are key to social cure processes that facilitate coping and recovery.

Bazex-Dupré-Christol syndrome (BDCS; MIM301845) is a rare X-linked dominant genodermatosis characterized by follicular atrophoderma, congenital hypotrichosis and multiple basal cell carcinomas (BCCs). Previous studies have linked BDCS to an 11·4-Mb interval on chromosome Xq25-q27.1. However, the genetic mechanism of BDCS remains an open question. To investigate the genetic aetiology and molecular mechanisms underlying BDCS. We ascertained multiple individuals from eight unrelated families affected with BDCS (F1-F8). Whole-exome (F1 and F2) and genome sequencing (F3) were performed to identify putative disease-causing variants within the linkage region. Array comparative genomic hybridization and quantitative polymerase chain reaction (PCR) were used to explore copy number variations, followed by long-range gap PCR and Sanger sequencing to amplify the duplication junctions and to define the head-tail junctions. Hi-C was performed on dermal fibroblasts from two affected individuals with BDCS and one control. Public datasets and tools were used to identify regulatory elements and transcription factor binding sites within the minimal duplicated region. Immunofluorescence was performed in hair follicles, BCCs and trichoepitheliomas from patients with BDCS and sporadic BCCs. The ACTRT1 variant c.547dup (p.Met183Asnfs*17), previously proposed to cause BDCS, was evaluated with t allele frequency calculator. In eight families with BDCS, we identified overlapping 18-135-kb duplications (six inherited and two de novo) at Xq26.1, flanked by ARHGAP36 and IGSF1. Hi-C showed that the duplications did not affect the topologically associated domain, but may alter the interactions between flanking genes and putative enhancers located in the minimal duplicated region. We detected ARHGAP36 expression near the control hair follicular stem cell compartment, and found increased ARHGAP36 levels in hair follicles in telogen, in BCCs and in trichoepitheliomas from patients with BDCS. ARHGAP36 was also detected in sporadic BCCs from individuals without BDCS. Our modelling showed the predicted maximum tolerated minor allele frequency of ACTRT1 variants in control populations to be orders of magnitude higher than expected for a high-penetrant ultra-rare disorder, suggesting loss of function of ACTRT1 variants to be an unlikely cause for BDCS. Noncoding Xq26.1 duplications cause BDCS. The BDCS duplications most likely lead to dysregulation of ARHGAP36. ARHGAP36 is a potential therapeutic target for both inherited and sporadic BCCs. What is already known about this topic? Bazex-Dupré-Christol syndrome (BDCS) is a rare X-linked basal cell carcinoma susceptibility syndrome linked to an 11·4-Mb interval on chromosome Xq25-q27.1. Loss-of-function variants in ACTRT1 and its regulatory elements were suggested to cause BDCS. What does this study add? BDCS is caused by small tandem noncoding intergenic duplications at chromosome Xq26.1. The Xq26.1 BDCS duplications likely dysregulate ARHGAP36, the flanking centromeric gene. ACTRT1 loss-of-function variants are unlikely to cause BDCS. What is the translational message? This study provides the basis for accurate genetic testing for BDCS, which will aid precise diagnosis and appropriate surveillance and clinical management. ARHGAP36 may be a novel therapeutic target for all forms of sporadic basal cell carcinomas.

BackgroundThe response to the COVID-19 pandemic in the United Kingdom included large scale changes to healthcare delivery, without fully understanding the potential for unexpected effects caused by these changes.The aim was “to ascertain the characteristics of patients, uncertainty over diagnosis, or features of the emergency response to the pandemic that could be modified to mitigate against future excess deaths”.MethodsReview of the entire pathway of care of patients whose death was registered in Salford during the 8 week period of the first wave (primary care, secondary care, 111 and 999 calls) in order to create a single record of healthcare prior to death. An expert panel judged avoidability of death against the National Mortality Case Record Review Programme scale. The panel identified themes using a structured judgement review format.ResultsThere were 522 deaths including 197 in hospital, and 190 in care homes. 51% of patients were female, 81% Caucasian, age 79 ± 9 years. Dementia was present in 35%, COVID-19 was cause of death in 44%.Healthcare contact prior to death was most frequently with primary care (81% of patients). Forty-six patients (9%) had healthcare appointments cancelled (median 1 cancellation, range 1–9). Fewer than half of NHS 111 calls were answered during this period.18% of deaths contained themes consistent with some degree of avoidability. In people aged ≥75 years who lived at home this was 53%, in care home residents 29% and in patients with learning disability 44% (n = 9). Common themes were; delays in patients presenting to care providers (10%), delays in testing (17%), avoidable exposure to COVID-19 (26%), delays in provider response (5%), and sub-optimal care (11%). For avoidability scores of 2 or 3 (indicating more than 50% chance of avoidability), 44% of cases had > 2 themes.ConclusionsThe initial emergency response had unforeseen consequences resulting in late presentation, sub-optimal assessments, and delays in receiving care. Death in more vulnerable groups was more likely to display avoidability themes.

Public health teams need to understand how the public responds to vaccination messages in a pandemic or epidemic to inform successful campaigns encouraging the uptake of new vaccines as they become available. A rapid systematic review was performed by searching PsycINFO, MEDLINE, healthevidence.org, OSF Preprints and PsyArXiv Preprints in May 2020 for studies including at least one health message promoting vaccine uptake of airborne-, droplet- and fomite-spread viruses. Included studies were assessed for quality using the Mixed Methods Appraisal Tool (MMAT) or the Assessment of Multiple Systematic Reviews (AMSTAR), and for patient and public involvement (PPI) in the research. Thirty-five articles were included. Most reported messages for seasonal influenza (n = 11; 31%) or H1N1 (n = 11; 31%). Evidence from moderate to high quality studies for improving vaccine uptake included providing information about virus risks and vaccination safety, as well as addressing vaccine misunderstandings, offering vaccination reminders, including vaccination clinic details, and delivering mixed media campaigns across hospitals or communities. Behavioural influences (beliefs and intentions) were improved when: shorter, risk-reducing or relative risk framing messages were used; the benefits of vaccination to society were emphasised; and beliefs about capability and concerns among target populations (e.g., vaccine safety) were addressed. Clear, credible, messages in a language target groups can understand were associated with higher acceptability. Two studies (6%) described PPI in the research process. Future campaigns should consider the beliefs and information needs of target populations in their design, including ensuring that vaccine eligibility and availability is clear, and messages are accessible. More high quality research is needed to demonstrate the effects of messaging interventions on actual vaccine uptake.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 [95% confidence interval (CI) 4.84–5.29] for men of European ancestry to 3.74 [95% CI 3.36–4.17] for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher [95% CI 2.14–2.22], and men of East Asian ancestry 0.73-times lower [95% CI 0.71–0.76], than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.