Manchester Centre Research Articles

Cascade screening in HBOC and Lynch syndrome: guidelines and procedures in a UK centre

In the 33 years since the first diagnostic cancer predisposition gene (CPG) tests in the Manchester Centre for Genomic Medicine, there has been substantial changes in the identification of index cases and cascade testing for at-risk family members. National guidelines in England and Wales are usually determined from the National Institute of healthcare Evidence and these have impacted on the thresholds for testing BRCA1/2 in Hereditary Breast Ovarian Cancer (HBOC) and in determining that all cases of colorectal and endometrial cancer should undergo screening for Lynch syndrome. Gaps for testing other CPGs relevant to HBOC have been filled by the UK Cancer Genetics Group and CanGene-CanVar project (web ref. https://www.cangene-canvaruk.org/). We present time trends (1990–2020) of identification of index cases with germline CPG variants and numbers of subsequent cascade tests, for BRCA1, BRCA2, and the Lynch genes (MLH1, MSH2, MSH6 and PMS2). For BRCA1/2 there was a definite increase in the proportion of index cases with ovarian cancer only and pre-symptomatic index tests both doubling from 16 to 32% and 3.2 to > 8% respectively. A mean of 1.73–1.74 additional family tests were generated for each BRCA1/2 index case within 2 years. Overall close to one positive cascade test was generated per index case resulting in > 1000 risk reducing surgery operations. In Lynch syndrome slightly more cascade tests were performed in the first two years potentially reflecting the increased actionability in males with 42.2% of pre-symptomatic tests in males compared to 25.8% in BRCA1/2 (p < 0.0001).

High spatial resolution assessment of air quality in urban centres using lichen carbon, nitrogen and sulfur contents and stable-isotope-ratio signatures

Air pollution and poor air quality is impacting human health globally and is a major cause of respiratory and cardiovascular disease and damage to human organ systems. Automated air quality monitoring stations continuously record airborne pollutant concentrations, but are restricted in number, costly to maintain and cannot document all spatial variability of airborne pollutants. Biomonitors, such as lichens, are commonly used as an inexpensive alternative to assess the degree of pollution and monitor air quality. However, only a few studies combined lichen carbon, nitrogen and sulfur contents, with their stable-isotope-ratio signatures (δ13C, δ15N and δ34S values) to assess spatial variability of air quality and to ‘fingerprint’ potential pollution sources. In this study, a high-spatial resolution lichen biomonitoring approach (using Xanthoria parietina and Physcia spp.) was applied to the City of Manchester (UK), the centre of the urban conurbation Greater Manchester, including considerations of its urban characteristics (e.g., building heights and traffic statistics), to investigate finer spatial detail urban air quality. Lichen wt% N and δ15N signatures, combined with lichen nitrate (NO3−) and ammonium (NH4+) concentrations, suggest a complex mixture of airborne NOx and NHx compounds across Manchester. In contrast, lichen S wt%, combined with δ34S strongly suggest anthropogenic sulfur sources, whereas C wt% and δ13C signatures were not considered reliable indicators of atmospheric carbon emissions. Manchester’s urban attributes were found to influence lichen pollutant loadings, suggesting deteriorated air quality in proximity to highly trafficked roads and densely built-up areas. Lichen elemental contents and stable-isotope-ratio signatures can be used to identify areas of poor air quality, particularly at locations not covered by automated air quality measurement stations. Therefore, lichen biomonitoring approaches provide a beneficial method to supplement automated monitoring stations and also to assess finer spatial variability of urban air quality.Graphical abstract

Patient and public involvement in hearing research: opportunities, impact and reflections with case studies from the Manchester Centre for Audiology and Deafness

Objective Patient and public involvement (PPI) in research improves relevance to end users and improves processes including recruitment participants. PPI in our research has gone from being non-existent to ubiquitous over a few years. We provide critical reflections on the benefits and challenges of PPI. Design Case studies are reported according to a modified GRIP2 framework; the aims, methodology, impact of PPI and critical reflections on each case and our experiences with PPI in general. Study sample We report five UK projects that included PPI from teenagers, families, people living with dementia, autistic people, and people from South Asian and d/Deaf communities. Results Our experience has progressed from understanding the rationale to grappling methodologies and integrating PPI in our research. PPI took place at all stages of research, although commonly involved input to design including recruitment and development of study materials. Methodologies varied between projects, including PPI co-investigators, advisory panels and online surveys. Conclusion On-going challenges include addressing social exclusion from research for people that lack digital access following increasing on-line PPI and involvement from underserved communities. PPI was initially motivated by funders; however the benefits have driven widespread PPI, ensuring our research is relevant to people living with hearing loss.

BANN shines a light on innovative practice

The British Association of Neuroscience Nurses (BANN) is driven in supporting the development of roles within Neuroscience Nursing. The second article in this series highlights the fantastic career of Louise Dulhanty, a Neurovascular Consultant Nurse at the Manchester Centre for Clinical Neurosciences.

The Everyday Economy: Introduction

AbstractThis introduction to the everyday economy collection provides a brief summary of the concept as advanced by Julie Froud, Karel Williams and their collaborators at Manchester's Centre for Research on Socio‐Cultural Change, followed by an overview of articles by Anna Coote, Tess Lanning and Rachel Laurence, Sarah Longlands, Alex Colás and Jason Edwards, David Edgerton, Christine Berry, Luke Raikes and Anna Killick.

078 Myotonic dystrophy service redesign: report on a patient engagement event

IntroductionInternational consensus-based care recommendations for Myotonic Dystrophy Type 1 (DM1) have been published recently. Audit of the DM1 service at the Manchester Centre for Clinical Neurosciences (MCCN) against these was presented at the 2019 ABN. Significant scope for improve- ment was identified.MethodsAs part of DM1 service redesign at MCCN an engagement event was organised. Opinions of patients, carers and relatives on service provision and areas for improvement were explored. With reference to published care recommendations, attendees participated in structured small group discus- sions. Responses were recorded by a facilitator and thematic analysis performed.ResultsIn total, 69 service-users attended. Themes emerging included a perceived lack of support between consultant appointments, inadequate access to specialist therapy services, a lack of awareness of available support services, and an inadequate understanding of DM1 by healthcare professionals. Suggestions for improvement included setting up joint appointments and patient forums for group discus- sion, increased use of telephone/online appointments, and setup of a more responsive service facilitated by a specialist nurse.ConclusionThese findings have been incorporated in to the DM1 service redesign programme at MCCN, which has included the recent appointment of a neuromuscular specialist nurse. Re-audit of the service is planned.james.dent@doctors.org.uk

Digital Gothic: An Interview with Xavier Aldana Reyes

&#x0D; Xavier Aldana Reyes is Reader/Associate Professor in English Literature and Film at Manchester Metropolitan University and a founder member of the Manchester Centre for Gothic Studies. He is author of Gothic Cinema (2020), Spanish Gothic (2017), Horror Film and Affect (2016) and Body Gothic (2014), and editor of Twenty-First-Century Gothic: An Edinburgh Companion (with Maisha Wester, 2019), Horror: A Literary History (2016) and Digital Horror (with Linnie Blake, 2015). Xavier is chief editor of the Horror Studies book series at the University of Wales Press, and has edited anthologies of Gothic and horror fiction for the British Library. One of Xavier's research interests is the optical dynamics of found footage horror films. On this topic, he has published an article on narrative framing for Gothic Studies, and chapters on affective immersion in the film [REC] (2007) and viewer involvement and guilt in The Last Horror Movie (2003). More recently, he wrote a chapter on 'Online Gothic' that considers social media found footage horror for the collection The Edinburgh Companion to Globalgothic (2022).&#x0D;

Hard roads to travel: Lessons learnt from practising community archaeology

ABSTRACT Manchester Centre for Public History and Heritage has developed community archaeology projects with marginalized communities, and within areas where archaeology is often disregarded, socially, economically, and politically. These projects use approaches based on the co-production of historical and archaeological knowledge, and have ethical implications for academics and participants; projects actively engaging the public in archaeology often do so by linking modern day communities to historical communities, and in this process uncover uncomfortable truths and painful pasts. To explore the issues raised by this work, this paper self and collaboratively reflects on experiences from two contrasting community archaeology projects in the UK and Nigeria. This discusses lessons learnt from these ‘socially engaged’ community archaeology projects, including contentious and unanticipated aspects that arose in the field, and such issues as dealing with conflicting values, ensuring long-term sustainability, supporting duty of care, and understanding psychological and emotional risk.

Electronic self-reporting of adverse events for patients undergoing cancer treatment: the eRAPID research programme including two RCTs

Electronic self-reporting of adverse events for patients undergoing cancer treatment: the eRAPID research programme including two RCTs

30 year experience of index case identification and outcomes of cascade testing in high-risk breast and colorectal cancer predisposition genes

It is 30 years since the first diagnostic cancer predisposition gene (CPG) test in the Manchester Centre for Genomic Medicine (MCGM), providing opportunities for cancer prevention, early detection and targeted treatments in index cases and at-risk family members. Here, we present time trends (1990–2020) of identification of index cases with a germline CPG variant and numbers of subsequent cascade tests, for 15 high-risk breast and gastro-intestinal tract cancer-associated CPGs: BRCA1, BRCA2, PALB2, PTEN, TP53, APC, BMPR1a, CDH1, MLH1, MSH2, MSH6, PMS2, SMAD4, STK11 and MUTYH. We recorded 2082 positive index case diagnostic screening tests, generating 3216 positive and 3140 negative family cascade (non-index) tests. This is equivalent to an average of 3.05 subsequent cascade tests per positive diagnostic index test, with 1.54 positive and 1.51 negative non-index tests per family. The CPGs with the highest numbers of non-index positive cases identified on cascade testing were BRCA1/2 (n = 1999) and the mismatch repair CPGs associated with Lynch Syndrome (n = 731). These data are important for service provision and health economic assessment of CPG diagnostic testing, in terms of cancer prevention and early detection strategies, and identifying those likely to benefit from targeted treatment strategies.

Surgical management of Encapsulating Peritoneal Sclerosis (EPS) in children: international case series and literature review

BackgroundEncapsulating Peritoneal Sclerosis (EPS) is a rare phenomenon in paediatric patients with kidney failure treated with peritoneal dialysis (PD). This study highlights clinical challenges in the management of EPS, with particular emphasis on peri-operative considerations and surgical technique.MethodsRetrospective analysis of all paediatric patients with EPS treated at the Manchester Centre for Transplantation.ResultsFour patients were included with a median duration of 78 months on PD. All patients had recurrent peritonitis (> 3 episodes), and all had symptoms within three months of a change of dialysis modality from PD to haemodialysis or transplant. In Manchester, care was delivered by a multi-disciplinary team, including surgeons delivering the adult EPS surgical service with a particular focus on nutritional optimisation, sepsis control, and wound management. The surgery involved laparotomy, lavage, and enterolysis of the small bowel + / − stoma formation, depending on intra-abdominal contamination. Two patients had a formal stoma, which were reversed at three and six months, respectively. Two patients underwent primary closure of the abdomen, whereas two patients had re-look procedures at 48 h with secondary closure. One patient had a post-operative wound infection, which was managed medically. One patient’s stoma became detached, leading to an intra-abdominal collection requiring re-laparotomy. The median length of stay was 25 days, and patients were discharged once enteral feeding was established. All patients remained free of recurrence with normal gut function and currently two out of four have functioning transplants.ConclusionsThis series demonstrates 100% survival and parenteral feed independence following EPS surgery. Post-operative morbidity was common; however, with individualised experience-based decision-making and relevant additional interventions, patients made full recoveries. Health and development post-surgery continued, allowing the potential for transplantation.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Establishment of CORONET: COVID-19 Risk in Oncology Evaluation Tool to Identify Cancer Patients at Low Versus High Risk of Severe Complications of COVID-19 Infection Upon Presentation to Hospital

Establishment of CORONET: COVID-19 Risk in Oncology Evaluation Tool to Identify Cancer Patients at Low Versus High Risk of Severe Complications of COVID-19 Infection Upon Presentation to Hospital

115 An Audit on Dexamethasone Prescribing Practice on Surgically Managed Metastatic Spinal Cord Compression Patients in the Manchester Centre for Clinical Neurosciences: Lessons Learned in Closing the Loop

Abstract Metastatic Spinal Cord Compression is a surgical emergency owing to its propensity to cause significant morbidity and mortality. Dexamethasone is prescribed to reduce oedema and promote vascular membrane stabilization. The is done so until a more definitive management has been performed. This is a retrospective study evaluating the steroid-prescribing practice for MSCC patients in 2018 at a tertiary spinal unit in Greater Manchester. Thirty-three patients who underwent stabilisation were evaluated in terms of both steroid prescribing and weaning practices. Standards used against for both were the NICE guidelines and the Edinburgh/Christie’s guidelines. Of the 33 patients evaluated, only 1 patient received the correct loading dose of 16mg, whilst 27 went straight to being given 8mg BD. 5 did not receive dexamethasone at all. In terms of discontinuation/weaning, 26 were weaned accordingly and 2 were not weaned to continue as adjuvant treatment. Dexamethasone prescribing practises has since improved over the past two years. 93% of the patients have been correctly weaned as compared to 38% in the past. In terms of prescription, much needs to be done as almost all the patients evaluated did not get the correct loading dose despite receiving the appropriate maintenance.

116 Patient Long Stay in the Manchester Centre for Clinical Neurosciences Complex Spines Department: Numbers, Reasons, and Recommendations

Abstract Patient long-stay is one of the main causes of inefficient resource management in the National Health Service. Similarly, delays in treatment and access to social care contributes to the trust’s economic burden but also causes a significant delay in care for society's most vulnerable. A single-centre evaluation of patient long stay was performed in a tertiary spinal unit in Greater Manchester. The top 50 patients who stayed the longest in an acute spinal bed between 2018 and 2019 were selected for analysis. Demographics, indication for transfer from another trust, overall length of stay, and the main reasons for such were evaluated. Of the 50 assessed, there was an average length of stay of 46.9 days and the majority were comprised of patients with metastatic spinal cord compression. 74% had delays to surgery due to poor medical optimisation pre-transfer. 41% remained as an inpatient longer than necessary due to non-medical concerns. The main reasons included awaiting placement in a rehabilitation facility, social care issues and delays in repatriation back to their referring trust for ongoing care. Delays in treatment and length of stay were found to be increased in patients who were poorly optimised pre-operatively and who required complex social and medical care post-operatively.

Advances in genetic technologies result in improved diagnosis of mismatch repair deficiency in colorectal and endometrial cancers

BackgroundTesting cancers for mismatch repair deficiency (dMMR) by immunohistochemistry (IHC) is a quick and inexpensive means of triaging individuals for germline Lynch syndrome testing. The aim of this study was...

Clinical and Genetic Findings in CTNNA1-Associated Macular Pattern Dystrophy

Clinical and Genetic Findings in CTNNA1-Associated Macular Pattern Dystrophy

Assessment of mismatch repair deficiency in ovarian cancer

BackgroundHereditary causes of ovarian cancer include Lynch syndrome, which is due to inherited pathogenic variants affecting one of the four mismatch repair genes involved in DNA repair. The aim of...

A role for human leucocyte antigens in the susceptibility to SARS-Cov-2 infection observed in transplant patients.

We analysed data from 80 patients who tested positive for SARS‐CoV‐2 RNA who had previously been HLA typed to support transplantation. Data were combined from two adjacent centres in Manchester and Leeds to achieve a sufficient number for early analysis. HLA frequencies observed were compared against two control populations: first, against published frequencies in a UK deceased donor population (n = 10,000) representing the target population of the virus, and second, using a cohort of individuals from the combined transplant waiting lists of both centres (n = 308), representing a comparator group of unaffected individuals of the same demographic. We report a significant HLA association with HLA‐ DQB1*06 (53% vs. 36%; p < .012; OR 1.96; 95% CI 1.94–3.22) and infection. A bias towards an increased representation of HLA‐A*26, HLA‐DRB1*15, HLA‐DRB1*10 and DRB1*11 was also noted but these were either only significant using the UK donor controls, or did not remain significant after correction for multiple tests. Likewise, HLA‐A*02, HLA‐B*44 and HLA‐C*05 may exert a protective effect, but these associations did not remain significant after correction for multiple tests. This is relevant information for the clinical management of patients in the setting of the current SARS‐CoV‐2 pandemic and potentially in risk‐assessing staff interactions with infected patients.

INTERVIEW WITH XAVIER ALDANA REYES

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Sporadic vestibular schwannoma: a molecular testing summary

ObjectivesCases of sporadic vestibular schwannoma (sVS) have a low rate of association with germline pathogenic variants. However, some individuals with sVS can represent undetected cases of neurofibromatosis type 2 (NF2)...