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Peer reviewed: True, OBJECTIVE: To describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories. DESIGN: Laboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years' missing data. RESULTS: Individual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed. CONCLUSION: The NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry.

Introduction: Breast cancer is the most common cancer in women. Women with personal history of breast cancer are at increased risk of second primary cancers including ovarian cancer. Bilateral salpingo-oophorectomy (BSO) is a well-established option for ovarian cancer risk reduction. However, the benefit of ovarian cancer risk reduction should be balanced against the health sequelae caused by the premature estrogen loss. We examined the associations between BSO after breast cancer diagnosis and long-term health outcomes, using large-scale linked electronic health records. Methods: We selected women diagnosed with invasive breast cancer before the age of 75 between 1995 and 2019 using data from the National Cancer Registration Dataset (NCRD), which describes all cancers registered in England. These women were linked to the Hospital Episode Statistics (HES) Admitted Patient Care (APC) dataset to identify the delivery of BSO, while the use of hormonal replacement therapy (HRT) was identified from the community dispensed prescriptions dataset. Long-term outcomes (e.g., ischemic heart disease) were selected from HES, and the NCRD provided data on second cancer diagnosis and all-cause mortality. Multiple imputation was used to impute missing data on stage, grade, hormonal receptor status and ethnicity. Women were followed from the date of breast cancer diagnosis to development of an outcome of interest or censoring or end of data collection. Multivariable Cox regression was used to examine the associations, with BSO modeled as a time-dependent covariate. The analysis was stratified by patient age at BSO ( Results: The study included 566,731 women, with median follow up time 8.40 (IQR: 4.4-14.5) years. Of those, 23,881 women had BSO after their breast cancer diagnosis. BSO before the age of 55 was not associated with all-cause mortality (hazard ratio (HR):1.03, 95%CI:0.98-1.08), while BSO after the age of 55 was associated with a small reduction in the risk of all-cause mortality (HR:0.93, 95%CI:0.89-0.99). BSO before and after the age of 55 was associated with increased risk of ischemic heart disease with HRs of 1.23(95%CI:1.07-1.41) and 1.13(95%CI:1.02-1.25), respectively. There was no association between BSO and cerebrovascular events (HR:0.97, 95%CI:0.82-1.15, for BSO under age 55, HR:0.96, 95%CI:0.87-1.07, for BSO after age 55). Ongoing analyses are investigating the associations stratified by the severity of cardiovascular outcome (fatal/non-fatal) and the use of HRT, and the associations with second cancers and neuropsychiatric outcomes. Conclusion: BSO after 55 does not appear to be associated with detrimental health effects in women diagnosed with breast cancer. Further examination of the associations between BSO and other long-term health outcomes and the influence of HRT in younger women is needed. Citation Format: Hend Hassan, Tameera Rahman, Andrew Bacon, Craig Knott, Isaac Allen, Catherine Huntley, Lucy Loong, Yvonne Walburga, Katrina Lavelle, Eva Morris, Steven Hardy, Bethany Torr, Diana M Eccles, Clare Turnbull, Marc Tischkowitz, Paul Pharoah, Antonis C. Antoniou. Long-term health outcomes of bilateral salpingo-oophorectomy in women with personal history of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 988.

Background: Second primary cancer (SPC) incidence is rising among breast cancer (BC) survivors, but these risks remain unclear. We estimated SPC risks for male and female BC survivors using large-scale electronic health record data from a linkage of National Cancer Registration and Analysis Service data and Hospital Episode Statistics surgical records in England. Material and Methods: We used a retrospective cohort study design comprising 763,578 female and 4,795 male BC survivors first diagnosed with BC between 1995-2018. We calculated overall and site-specific SPC standardized incidence ratios (SIRs) by comparing observed and expected SPC counts for 19 cancer sites. Study participants were followed from one year after the first BC diagnosis until either a SPC diagnosis (excluding ipsilateral breast and non-melanoma skin cancers), death, migration, relevant surgical procedures, or the end of 2019. Expected SPC counts were calculated using year-, age- and sex-specific cancer incidence rates in the general English population. We stratified the SIRs by age group, sex, and cancer site. We estimated Kaplan-Meier absolute risks of site-specific SPCs and assessed the influence of age at first BC diagnosis using Cox proportional hazards models. Results: There were 68,550 and 720 incident SPCs among female and male BC survivors, respectively. There was a significant increased risk of all SPCs combined for female BC survivors (SIR: 1.19, 95%CI: 1.18-1.20). There were significant increased risks for SPC at all sites combined, all non-breast sites combined, and at 12 further specific sites for females and at 2 specific sites for males. Among females, the increase was greatest for contralateral breast (SIR: 1.82, 95%CI: 1.79-1.85) and uterine cancers (SIR: 1.80, 95%CI: 1.76-1.85). The risk at all sites combined was higher for women first diagnosed with BC before age 50 (SIR: 1.89, 95%CI: 1.85-1.92) compared to women diagnosed with BC at age 50 or over (SIR: 1.11, 95%CI: 1.10-1.12). The largest associations were observed for contralateral breast (SIR: 3.19, 95%CI: 3.11-3.29) and uterine (SIR: 1.77, 95%CI: 1.73-1.82) SPCs in the younger and older age groups, respectively. Increasing age at first female BC diagnosis was associated with decreasing CBC absolute risks, but significantly increased absolute risks of all other SPCs. Male BC survivors were at increased risk of contralateral breast (SIR: 42.39, 95%CI: 28.39-60.89) and prostate (SIR: 1.29, 95%CI: 1.13-1.46) SPCs. Conclusions: This is the largest study to date to assess SPC risks following BC in either men or women. SPC risks were significantly increased, both in combination and at specific sites. These findings could help guide clinical management, such as screening recommendations, for BC survivors. Further analysis is underway to investigate the effects of chemotherapy, radiotherapy, hormonal therapy, comorbidities, or germline BC susceptibility. Citation Format: Isaac Allen, Tameera Rahman, Andrew Bacon, Craig Knott, Sophie Jose, Sally Vernon, Hend Hassan, Catherine Huntley, Lucy Loong, Yvonne Walburga, Katrina Lavelle, Eva Morris, Steven Hardy, Beth Torr, Diana Eccles, Clare Turnbull, Marc Tischkowitz, Paul Pharoah, Antonis C. Antoniou. Second primary cancer risks for female and male breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3057.

Point‐of‐care tests (POCTs) offer considerable potential for improving clinical and public health management of COVID‐19 by providing timely information to guide decision‐making, but data on real‐world performance are in short supply. Besides SARS‐CoV‐2‐specific tests, there is growing interest in the role of surrogate (non‐specific) tests such as FebriDx, a biochemical POCT which can be used to distinguish viral from bacterial infection in patients with influenza‐like illnesses. This short report assesses what is currently known about FebriDx performance across settings and populations by comparison with some of the more intensively evaluated SARS‐CoV‐2‐specific POCTs. While FebriDx shows some potential in supporting triage for early‐stage infection in acute care settings, this is dependent on SARS‐CoV‐2 being the most likely cause for influenza‐like illnesses, with reduction in discriminatory power when COVID‐19 case numbers are low, and when co‐circulating viral respiratory infections become more prevalent during the autumn and winter. Too little is currently known about its performance in primary care and the community to support use in these contexts, and further evaluation is needed. Reliable SARS CoV2‐specific POCTs—when they become available—are likely to rapidly overtake surrogates as the preferred option given the greater specificity they provide.

Funder: National Institute for Health Research; funder-id: http://dx.doi.org/10.13039/501100000272, Background: Understanding the T cell response to SARS-CoV-2 is critical to vaccine development, epidemiological surveillance and disease control strategies. This systematic review critically evaluates and synthesises the relevant peer-reviewed and pre-print literature published from 01/01/2020-26/06/2020. Methods: For this systematic review, keyword-structured literature searches were carried out in MEDLINE, Embase and COVID-19 Primer. Papers were independently screened by two researchers, with arbitration of disagreements by a third researcher. Data were independently extracted into a pre-designed Excel template and studies critically appraised using a modified version of the MetaQAT tool, with resolution of disagreements by consensus. Findings were narratively synthesised. Results: 61 articles were included. 55 (90%) studies used observational designs, 50 (82%) involved hospitalised patients with higher acuity illness, and the majority had important limitations. Symptomatic adult COVID-19 cases consistently show peripheral T cell lymphopenia, which positively correlates with increased disease severity, duration of RNA positivity, and non-survival; while asymptomatic and paediatric cases display preserved counts. People with severe or critical disease generally develop more robust, virus-specific T cell responses. T cell memory and effector function has been demonstrated against multiple viral epitopes, and, cross-reactive T cell responses have been demonstrated in unexposed and uninfected adults, but the significance for protection and susceptibility, respectively, remains unclear. Conclusion: A complex pattern of T cell response to SARS-CoV-2 infection has been demonstrated, but inferences regarding population level immunity are hampered by significant methodological limitations and heterogeneity between studies, as well as a striking lack of research in asymptomatic or pauci-symptomatic individuals. In contrast to antibody responses, population-level surveillance of the T cell response is unlikely to be feasible in the near term. Focused evaluation in specific sub-groups, including vaccine recipients, should be prioritised.

BackgroundProgress in characterising the humoral immune response to Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) has been rapid but areas of uncertainty persist. Assessment of the full range of evidence generated to date to understand the characteristics of the antibody response, its dynamics over time, its determinants and the immunity it confers will have a range of clinical and policy implications for this novel pathogen. This review comprehensively evaluated evidence describing the antibody response to SARS-CoV-2 published from 01/01/2020-26/06/2020.MethodsSystematic review. Keyword-structured searches were carried out in MEDLINE, Embase and COVID-19 Primer. Articles were independently screened on title, abstract and full text by two researchers, with arbitration of disagreements. Data were double-extracted into a pre-designed template, and studies critically appraised using a modified version of the Public Health Ontario Meta-tool for Quality Appraisal of Public Health Evidence (MetaQAT) tool, with resolution of disagreements by consensus. Findings were narratively synthesised.Results150 papers were included. Most studies (113 or 75%) were observational in design, were based wholly or primarily on data from hospitalised patients (108, 72%) and had important methodological limitations. Few considered mild or asymptomatic infection. Antibody dynamics were well described in the acute phase, up to around three months from disease onset, but the picture regarding correlates of the antibody response was inconsistent. IgM was consistently detected before IgG in included studies, peaking at weeks two to five and declining over a further three to five weeks post-symptom onset depending on the patient group; IgG peaked around weeks three to seven post-symptom onset then plateaued, generally persisting for at least eight weeks. Neutralising antibodies were detectable within seven to 15 days following disease onset, with levels increasing until days 14–22 before levelling and then decreasing, but titres were lower in those with asymptomatic or clinically mild disease. Specific and potent neutralising antibodies have been isolated from convalescent plasma. Cross-reactivity but limited cross-neutralisation with other human coronaviridae was reported. Evidence for protective immunity in vivo was limited to small, short-term animal studies, showing promising initial results in the immediate recovery phase.ConclusionsLiterature on antibody responses to SARS-CoV-2 is of variable quality with considerable heterogeneity of methods, study participants, outcomes measured and assays used. Although acute phase antibody dynamics are well described, longer-term patterns are much less well evidenced. Comprehensive assessment of the role of demographic characteristics and disease severity on antibody responses is needed. Initial findings of low neutralising antibody titres and possible waning of titres over time may have implications for sero-surveillance and disease control policy, although further evidence is needed. The detection of potent neutralising antibodies in convalescent plasma is important in the context of development of therapeutics and vaccines. Due to limitations with the existing evidence base, large, cross-national cohort studies using appropriate statistical analysis and standardised serological assays and clinical classifications should be prioritised.

IntroductionUnderstanding the cellular immune response to SARS-CoV-2 is critical to vaccine development, epidemiological surveillance and control strategies. This systematic review critically evaluates and synthesises the relevant peer-reviewed and pre-print literature published in recent months.MethodsFor this systematic review, independent keyword-structured literature searches were carried out in MEDLINE, Embase and COVID-19 Primer for studies published from 01/01/2020-26/06/2020. Papers were independently screened by two researchers, with arbitration of disagreements by a third researcher. Data were independently extracted into a pre-designed Excel template and studies critically appraised using a modified version of the MetaQAT tool, with resolution of disagreements by consensus. Findings were narratively synthesised.Results61 articles were included. Almost all studies used observational designs, were hospital-based, and the majority had important limitations. Symptomatic adult COVID-19 cases consistently show peripheral T cell lymphopenia, which positively correlates with increased disease severity, duration of RNA positivity, and non-survival; while asymptomatic and paediatric cases display preserved counts. People with severe or critical disease generally develop more robust, virus-specific T cell responses. T cell memory and effector function has been demonstrated against multiple viral epitopes, and, cross-reactive T cell responses have been demonstrated in unexposed and uninfected adults, but the significance for protection and susceptibility, respectively, remains unclear.InterpretationA complex pattern of T cell response to SARS-CoV-2 infection has been demonstrated, but inferences regarding population level immunity are hampered by significant methodological limitations and heterogeneity between studies. In contrast to antibody responses, population-level surveillance of the cellular response is unlikely to be feasible in the near term. Focused evaluation in specific sub-groups, including vaccine recipients, should be prioritised.

Background The prevalence of self-harm among children and young people in the UK is increasing, with few accessing formal support. Drivers of self-harm remain poorly understood, and evidence-based opportunities to intervene are scarce. We aimed to identify factors associated with self-harm in young people to inform local action. Methods In this retrospective, observational study, we identified 196 residents of the south London Borough of Lambeth, aged 12–26 years, presenting to two emergency departments for injuries related to self-harm in the 2015–16 financial year (April 1, 2015, to March 31, 2016). A pragmatic sample size of 100 was selected via computer randomisation for further analysis. Electronic mental health records were retrospectively analysed using a data collection protocol that was validated with researchers before data collection. Demographics and psychiatric history were obtained from pre-coded databases linking electronic mental health records and Hospital Episode Statistics data on emergency department attendance for self-harm. Presentation details and social risk factors were derived from assessment of case notes pertaining to the 2 weeks after first presentation; we noted any risk factors that had been positively recorded. Data relating to the individual's first presentation within the study period were used; subsequent attendances were not included in the sample. We analysed the data using descriptive statistics. Ethical approval for data access and linkage was granted by the Oxford Research Ethics Committee C (18/SC/0372), Clinical Records Interactive Search system Oversight Committee (project numbers 14–026 and 19–004), and the National Health Service (NHS) Health Research Authority Confidentiality Advisory Group (reference ECC 3–04(f)/2011). This study received approval as an audit project through Southwark Operational Directorate in the South London and Maudsley Foundation NHS Trust. Findings 48 (48%) of the 100 selected participants had documented experience of psychological trauma, including exposure to violence. 18 (18%) lived in unstable accommodation, and 20 (20%) were known to social services. Difficulties at home (16 [16%]) and stress relating to housing, school, or financial pressures (13 [13%]) were common documented triggers for the self-harm episode at presentation. Peer influence was rarely noted, although 27 (27%) had recorded experience of bullying. Interpretation Adverse life experiences were prevalent and align with wider population prevalence estimates. Common triggers for self-harm relate to home and school environment and wider socioeconomic stressors, supporting the link between wider determinants of health and self-harm, and contributing to the case for public health action. Risk factors and triggers identified provide potential areas for additional targeted support to prevent development or escalation of self-harm behaviours. Funding UK National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust, and King's College London.

Henri de Toulouse-Lautrec, a 19th century artist celebrated for his depictions of the Moulin Rouge and Parisian nightlife, suffered from an unknown disorder. His symptoms were not only rare, but also difficult to determine. Both during his lifetime and following his death potential diagnoses have proved controversial, including the most popularly supported suggestion of pycnodysostosis. Addressing the ongoing debate of Toulouse-Lautrec's diagnosis, this article reconsiders the evidence. It summarises multiple perspectives and draws on more recent medical research, while acknowledging that the available sources are often unreliable. Ultimately, while there may be no definitive solution to the mystery of Toulouse-Lautrec's diagnosis, it is possible to draw one conclusion. Observing its impact on his life and work, it is clear that the condition formed the foundation of Toulouse-Lautrec's artistic career, shaping the way he perceived the world and defining the artworks that are now so widely admired.

Joseph Merrick, the Elephant Man, presented to the Royal London Hospital in 1884 with an obscure condition that puzzled his contemporaries, and fascinates clinicians to this day. Throughout the 1900s, a number of theories were advanced to explain the numerous growths that covered his body: neurofibromatosis, Proteus syndrome, and a combination of childhood injury, fibrous dysplasia, and pyarthrosis. The debate continued throughout the 20th century without resolution. Today, new consensus on the genetic and clinical diagnosis of neurofibromatosis and Proteus syndrome has allowed advancements in the Elephant Man's diagnosis. Using recent clinical diagnostic criteria it is now possible to conclude that Joseph Merrick was in all likelihood suffering from Proteus syndrome. Nevertheless, details of his genotype remain unknown. Obtaining intact DNA from the Elephant Man's skeleton is challenging, yet it is possible that sequencing Merrick's genome could provide genetic confirmation of his clinical diagnosis, and shed light on the process of tumourigenesis.