Exploring the role of E. faecalis enterococcal polysaccharide antigen (EPA) and lipoproteins in evasion of phagocytosis.

Enterococcus faecalis is an opportunistic pathogen frequently causing nosocomial infections. The virulence of this organism is underpinned by its capacity to evade phagocytosis, allowing dissemination in the host. Immune evasion requires a surface polysaccharide produced by all enterococci, known as the enterococcal polysaccharide antigen (EPA). EPA consists of a cell wall-anchored rhamnose backbone substituted by strain-specific polysaccharides called 'decorations', essential for the biological activity of this polymer. However, the structural determinants required for innate immune evasion remain unknown, partly due to a lack of suitable validated assays. Here, we describe a quantitative, in vitro assay to investigate how EPA decorations alter phagocytosis. Using the E. faecalis model strain OG1RF, we demonstrate that a mutant with a deletion of the locus encoding EPA decorations can be used as a platform strain to express heterologous decorations, thereby providing an experimental system to investigate the inhibition of phagocytosis by strain-specific decorations. We show that the aggregation of cells lacking decorations is increasing phagocytosis and that this process does not involve the recognition of lipoproteins by macrophages. Collectively, our work provides novel insights into innate immune evasion by enterococci and paves the way for further studies to explore the structure/function relationship of EPA decorations.

The experience of surgical cancer patients during the COVID-19 pandemic at a large cancer centre in London.

BACKGROUND: The COVID-19 pandemic has had an enormous impact on the experiences of patients across all health disciplines, especially those of cancer patients. The study aimed to understand the experiences of cancer patients who underwent surgery during the first two waves of the pandemic at Guy's Cancer Centre, which is a large tertiary cancer centre in London. METHODS: A mixed-methods approach was adopted for this study. Firstly, a survey was co-designed by the research team and a patient study group. Patients who underwent surgery during the COVID-19 pandemic were invited to take part in this survey. Results were analysed descriptively. Three discussion groups were then conducted to focus on the main themes from the survey findings: communication, COVID-19 risk management and overall experience. These discussion groups were transcribed verbatim and underwent a thematic analysis using the NVivo software package. RESULTS: Out of 1657 patients invited, a total of 250 (15%) participants took part in the survey with a mean age of 66 (SD 12.8) and 52% females. The sample was representative of a wide range of tumour sites and was reflective of those invited to take part. Overall, the experience of the cancer patients was positive. They felt that the safety protocols implemented at the hospital were effective. Communication was considered key, and patients were receptive to a change in the mode of communication from in-person to virtual. CONCLUSIONS: Despite the immense challenges faced by our Cancer Centre, patients undergoing surgery during the first two waves of the COVID-19 pandemic had a generally positive experience with minimal disruptions to their planned surgery and ongoing care. Together with the COVID-19 safety precautions, effective communication between the clinical teams and the patients helped the overall patient experience during their surgical treatment.

Assessing the quality of patient-reported outcome measurements for gynecological cancers: a systematic review.

Aim: To provide perspective on patient-reported outcome measurement (PROM) instruments to adopt in patients diagnosed with gynecological cancers. Methods: A systematic search was conducted to identify PROMs developed for or applied in gynecological cancer populations. PROMs identified in more than one study subsequently underwent assessment according to the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) criteria. Results: Overall, 55 PROMs were identified within the gynecological cancer setting, and 20 were assessed according to COSMIN guidelines. Most PROMs had limited information reported, but a best fit approach was adopted to recommend a number of instruments for use in patients with gynecological cancer. Conclusion: Further study to assess the methodological quality of each PROM utilized in gynecological cancers is warranted to endorse the recommendations of this review.

Gynecological cancers are cancers which occur in the reproductive system of women. The cervical cancer screening program and development of new treatments mean that women with gynecological cancers are now living longer than before. However, these new treatments may have side effects that can affect the quality of life of women with cancer. Many care providers now agree that looking at women's quality of life during their gynecological cancer journey is an important part of their treatment. Patient-reported outcome measurements (PROMs) are questionnaires that the patient completes to measure their symptoms and quality of life. There are a lot of PROMs available to choose from, and it can be difficult to select one that is relevant and understandable for all women with gynecological cancer. This article searched the literature to find all PROMs that can be completed by women with gynecological cancer and then measured each of the PROM's quality. PROM quality was measured by looking at validity (whether the questionnaire measures what it is supposed to measure), reliability (that the questionnaire is not subject to different errors in measuring), and sensitivity (that the questionnaire can measure changes in questionnaire scores over time). Overall, this study found that there were a few PROMs that were of good enough quality to be completed by women with gynecological cancers. These questionnaires are called the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Cervical Cancer Module (EORTC QLQ-CX24), the Functional Assessment of Cancer Therapy - General (FACT-G), European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Endometrial Cancer (EORTC QLQ-EN24), Functional Assessment of Cancer Therapy Gynecologic Oncology Group ­ Neurotoxicity (FACT-GOG/Ntx), Functional Assessment of Cancer Therapy ­ Ovarian (FACT-O) and Female Sexual Function Index (FSFI). Each questionnaire can be filled out by women with different types of gynecological cancer, and the FSFI measures sexual problems that women may experience after cancer treatment.

Reducing post-caesarean infection in the Kimberley region of Western Australia: An audit-based observational study.

BACKGROUND: The higher burden of post-caesarean infection in the remote Kimberley region of Australia is intimately associated with poorer social determinants of health. This results in a confluence of environmental factors such as overcrowding and limited access to clean water and host factors such as diabetes mellitus and obesity which result in heightened susceptibility and vulnerability to infection. AIM: To ascertain infection rates following caesarean section in Broome Hospital, before and after the implementation of evidence-based strategies intended to reduce bacterial load and mitigate the impact of poor underlying social determinants of health. MATERIALS AND METHODS: This is a retrospective observational longitudinal audit study including women who underwent caesarean section in Broome Hospital between the time of 1 January 2019 and 1 May 2019 or 1 January 2021 and 1 May 2021. Files and theatre records were audited to determine demographic, surgical and post-partum infection in women who underwent caesarean section at Broome Hospital. The main outcome measure was infection within six weeks post-caesarean section. RESULTS: This study found a statistically significant improvement in post-operative infection rates in women who underwent caesarean section at Broome Hospital (41.7% vs 11.6%, P = 0.002). The two groups were statistically similar in background. CONCLUSION: The combination of various infection prevention initiatives targeted at reducing infection burden can result in clinical and statistically significant reductions in post-caesarean infections in high-risk populations with poor underlying social determinants of health.

Radical cancer treatment is safe during COVID-19: the real-world experience of a large London-based Comprehensive Cancer Centre during the first wave.

BACKGROUND: During the COVID pandemic, there was a paucity of data to support clinical decision-making for anticancer treatments. We evaluated the safety of radical treatments which were delivered whilst mitigating the risks of concurrent COVID-19 infection. METHODS: Using descriptive statistics, we report on the characteristics and short-term clinical outcomes of patients undergoing radical cancer treatment during the first COVID-19 wave compared to a similar pre-pandemic period. RESULTS: Compared to 2019, the number of patients undergoing radical treatment in 2020 reduced by: 28% for surgery; 18% for SACT; and 10% for RT. Within SACT, 36% received combination therapy, 35% systemic chemotherapy, 23% targeted treatments, 5% immunotherapy and 2% biological therapy. A similar proportion of RT was delivered in 2019 and 2020 (53% vs. 52%). Oncological outcomes were also similar to pre-COVID-19. The COVID-19 infection rates were low: 12 patients were positive pre surgery (1%), 7 post surgery (<1%), 17 SACT patients (2%) and 3 RT patients (<1%). No COVID-19-related deaths were reported. CONCLUSIONS: Whilst there were fewer patients receiving radical anticancer treatments, those who did receive treatment were treated in a safe environment. Overall, cancer patients should have the confidence to attend hospitals and be reassured of the safety measures implemented.

The impact of hospital attendance on COVID-19 infection in cancer patients: an assessment of data from Guy's Cancer.

Objective: The authors monitored positivity rates of asymptomatic SARS-CoV-2 tests during the second wave of COVID-19 at Guy's Cancer Centre. Methods: Logistic regression was used to investigate factors associated with asymptomatic COVID-19 positivity rates between 1 December 2020 and 28 February 2021 (n = 1346). Results: Living 20-40 km and 40-60 km from the alpha variant was associated with a reduced chance of a positive SARS-CoV-2 test compared with 0-20 km (odds ratio [OR]: 0.20; CI: 0.07-0.53 and OR: 0.38; CI: 0.15-0.98, respectively). An increased number of tests was associated with an increased chance of a positive SARS-CoV-2 test (OR: 1.10; CI: 1.04-1.16). Conclusion: The COVID-19 positivity rate of asymptomatic cancer patients is partly due to increased testing, with some contribution from the proximity of the patient population to the epicenter of the alpha variant.

The UK's second wave of COVID-19 was partly driven by the emergence of the alpha variant in the southeast of England in November 2020, spreading farther to become the predominant variant across England in December 2020. The alpha variant is associated with a greater transmissibility rate, posing an increased risk to the vulnerable population. This raised concerns about the welfare of cancer patients, as the disease and its treatment can lower one's ability to fight infection. This resulted in some cancer treatments being interrupted or stopped on the grounds of clinical safety and some follow-up care being disrupted. In order to investigate the factors associated with asymptomatic COVID-19 positivity rates between 1 December 2020 and 28 February 2021, the authors gathered information on the number of tests taken per cancer patient at Guy's and extracted data from Guy's approved research database, which houses all routinely collected clinical data on cancer patients. This included demographic data, such as post code and age, as well as number of visits to the hospital. From their analysis, the authors concluded that living closer to the epicenter of the alpha variant was associated with a high positivity rate; also, the more tests taken, the more likely the patients are to test positive. Therefore, the authors can conclude that attending the hospital does not increase the risk of transmission.

Cancer staff in an NHS cancer center: infections, vaccination, stress and well-being support during the COVID-19 pandemic.

Aim: To evaluate the impact of the pandemic on the well-being of cancer staff and determine the uptake of opt-in mitigation strategies. Materials & methods: Staff at Guy's Cancer Centre (London, UK) participated in an anonymized survey between May and August 2021. Results: Of 1182 staff, 257 (21.7%) participated. Ethnicity (p = 0.020) and comorbidity burden (p = 0.022) were associated with SARS-CoV-2 infection status. Of 199 respondents, seven (3.6%) were vaccine-hesitant, which was associated with low flu vaccine uptake (p < 0.001). Greater stress was associated with younger age (p = 0.030) and redeployment (p = 0.012). Lack of time and skepticism were barriers to using mental well-being resources. Conclusion: Albeit cautious, numerous trends the authors observed echo those in the published literature. Improved accessibility, awareness and utility of mental well-being resources are required.

COVID-19 is caused by the SARS-CoV-2 virus. The pandemic has applied immense pressure to healthcare workers, putting their physical and mental well-being at risk. However, the impact for cancer staff, specifically, is less known. In a survey of 257 cancer staff at Guy's Cancer Centre (London, UK; May­August 2021), the authors found that staff of particular ethnic groups, or with pre-existing illnesses, appeared more likely to become infected with SARS-CoV-2. Few staff were hesitant about SARS-CoV-2 vaccination, appearing more common among those not receiving the flu vaccine. For many, stress increased over time. However, barriers prevent staff from using mental well-being resources. With findings from larger studies, this work will be useful for strategies protecting cancer staff well-being.

Long-term effects of COVID-19 on cancer patients: the experience from Guy's Cancer Centre.

Background: Few studies have investigated the long-term effects of COVID-19 on cancer patients. Materials & methods: The authors conducted a telephone survey on the long-term symptoms of cancer patients from Guy's Cancer Centre. They compared patients whose symptoms occurred/got worse over 4 weeks after COVID-19 diagnosis (classified as long COVID) with patients who did not develop symptoms or whose symptoms occurred/got worse in the first 4 weeks after diagnosis. Results: The authors analyzed responses from 80 patients with a previous COVID-19 diagnosis; 51.3% (n = 41) developed long COVID. The most common symptoms were fatigue, breathlessness and cognitive impairment. Conclusion: Findings suggest that over half of the cancer population will experience long-term effects after their initial COVID-19 diagnosis. Further studies are required to validate the findings of this study.

Safe provision of systemic anti-cancer treatment for urological cancer patients during COVID-19: a tertiary centre experience in the first wave of COVID-19.

BACKGROUND: Safe provision of systemic anti-cancer treatment (SACT) during the COVID-19 pandemic remains an ongoing concern amongst clinicians. METHODS: Retrospective analysis on uro-oncology patients who continued or started SACT between 1st March and 31st May 2020 during the pandemic (with 2019 as a comparator). RESULTS: 441 patients received SACT in 2020 (292 prostate, 101 renal, 38 urothelial, 10 testicular) compared to 518 patients in 2019 (340 prostate, 121 renal, 42 urothelial, 15 testicular). In 2020, there were 75.00% fewer patients with stage 3 cancers receiving SACT (p < 0.0001) and 94.44% fewer patients receiving radical treatment (p = 0.00194). The number of patients started on a new line of SACT was similar between both years (118 in 2019 vs 102 in 2020; p = 0.898) but with 53.45% fewer patients started on chemotherapy in 2020 (p < 0.001). Overall, 5 patients tested positive for COVID-19 (one asymptomatic, one mild, two moderate, one severe resulting in death). Compared to 2019, 30-day mortality was similar (1.69% in 2019 vs 0.98% in 2020; p = 0.649) whereas 6-month mortality was lower (9.32% in 2019 vs 1.96% in 2020; p = 0.0209) in 2020. CONCLUSION: This study suggests that delivery of SACT to uro-oncology patients during COVID-19 pandemic may be safe in high-incidence areas with appropriate risk-reduction strategies.

Prevalence and impact of COVID-19 sequelae on treatment and survival of patients with cancer who recovered from SARS-CoV-2 infection: evidence from the OnCovid retrospective, multicentre registry study.

BACKGROUND: The medium-term and long-term impact of COVID-19 in patients with cancer is not yet known. In this study, we aimed to describe the prevalence of COVID-19 sequelae and their impact on the survival of patients with cancer. We also aimed to describe patterns of resumption and modifications of systemic anti-cancer therapy following recovery from SARS-CoV-2 infection. METHODS: OnCovid is an active European registry study enrolling consecutive patients aged 18 years or older with a history of solid or haematological malignancy and who had a diagnosis of RT-PCR confirmed SARS-CoV-2 infection. For this retrospective study, patients were enrolled from 35 institutions across Belgium, France, Germany, Italy, Spain, and the UK. Patients who were diagnosed with SARS-CoV-2 infection between Feb 27, 2020, and Feb 14, 2021, and entered into the registry at the point of data lock (March 1, 2021), were eligible for analysis. The present analysis was focused on COVID-19 survivors who underwent clinical reassessment at each participating institution. We documented prevalence of COVID-19 sequelae and described factors associated with their development and their association with post-COVID-19 survival, which was defined as the interval from post-COVID-19 reassessment to the patients' death or last follow-up. We also evaluated resumption of systemic anti-cancer therapy in patients treated within 4 weeks of COVID-19 diagnosis. The OnCovid study is registered in ClinicalTrials.gov, NCT04393974. FINDINGS: 2795 patients diagnosed with SARS-CoV-2 infection between Feb 27, 2020, and Feb 14, 2021, were entered into the study by the time of the data lock on March 1, 2021. After the exclusion of ineligible patients, the final study population consisted of 2634 patients. 1557 COVID-19 survivors underwent a formal clinical reassessment after a median of 22·1 months (IQR 8·4-57·8) from cancer diagnosis and 44 days (28-329) from COVID-19 diagnosis. 234 (15·0%) patients reported COVID-19 sequelae, including respiratory symptoms (116 [49·6%]) and residual fatigue (96 [41·0%]). Sequelae were more common in men (vs women; p=0·041), patients aged 65 years or older (vs other age groups; p=0·048), patients with two or more comorbidities (vs one or none; p=0·0006), and patients with a history of smoking (vs no smoking history; p=0·0004). Sequelae were associated with hospitalisation for COVID-19 (p<0·0001), complicated COVID-19 (p<0·0001), and COVID-19 therapy (p=0·0002). With a median post-COVID-19 follow-up of 128 days (95% CI 113-148), COVID-19 sequelae were associated with an increased risk of death (hazard ratio [HR] 1·80 [95% CI 1·18-2·75]) after adjusting for time to post-COVID-19 reassessment, sex, age, comorbidity burden, tumour characteristics, anticancer therapy, and COVID-19 severity. Among 466 patients on systemic anti-cancer therapy, 70 (15·0%) permanently discontinued therapy, and 178 (38·2%) resumed treatment with a dose or regimen adjustment. Permanent treatment discontinuations were independently associated with an increased risk of death (HR 3·53 [95% CI 1·45-8·59]), but dose or regimen adjustments were not (0·84 [0·35-2·02]). INTERPRETATION: Sequelae post-COVID-19 affect up to 15% of patients with cancer and adversely affect survival and oncological outcomes after recovery. Adjustments to systemic anti-cancer therapy can be safely pursued in treatment-eligible patients. FUNDING: National Institute for Health Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust.

The effectiveness of the Guy's Rapid Diagnostic Clinic (RDC) in detecting cancer and serious conditions in vague symptom patients.

BACKGROUND: Rapid Diagnostic Clinics (RDC) are being expanded nationally by NHS England. Guy's RDC established a pathway for GPs and internal referrals for patients with symptoms concerning for malignancy not suitable for a site-specific 2WW referral. However, little data assessing the effectiveness of RDC models are available in an English population. METHODS: We evaluated all patients referred to Guy's RDC between December 2016 and June 2019 (n = 1341) to assess the rate of cancer diagnoses, frequency of benign conditions and effectiveness of the service. RESULTS: There were 96 new cancer diagnoses (7.2%): lung (16%), haematological (13%) and colorectal (12%)-with stage IV being most frequent (40%). Median time to definitive cancer diagnosis was 28 days (IQR 15-47) and treatment 56 days (IQR 32-84). In all, 75% were suitable for treatment: surgery (26%), systemic (24%) and radiotherapy (14%). Over 180 serious non-neoplastic conditions were diagnosed (35.8%) of patients with no significant findings in two-third of patients (57.0%). CONCLUSIONS: RDCs provide GPs with a streamlined pathway for patients with complex non-site-specific symptoms that can be challenging for primary care. The 7% rate of cancer diagnosis exceeds many 2WW pathways and a third of patients presented with significant non-cancer diagnoses, which justifies the need for rapid diagnostics. Rapid Diagnostic Centres (RDCs) are being rolled out nationally by NHS England and NHS Improvement as part of the NHS long-term plan. The aim is for a primary care referral pathway that streamlines diagnostics, patient journey, clinical outcomes and patient experience. This pilot study of 1341 patients provides an in-depth analysis of the largest single RDC in England. Cancer was diagnosed in 7% of patients and serious non-cancer conditions in 36%-justifying the RDC approach in vague symptom patients.

Risk of COVID-19 death in cancer patients: an analysis from Guy's Cancer Centre and King's College Hospital in London.

BACKGROUND: Using an updated dataset with more patients and extended follow-up, we further established cancer patient characteristics associated with COVID-19 death. METHODS: Data on all cancer patients with a positive reverse transcription-polymerase chain reaction swab for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) at Guy's Cancer Centre and King's College Hospital between 29 February and 31 July 2020 was used. Cox proportional hazards regression was performed to identify which factors were associated with COVID-19 mortality. RESULTS: Three hundred and six SARS-CoV-2-positive cancer patients were included. Seventy-one had mild/moderate and 29% had severe COVID-19. Seventy-two patients died of COVID-19 (24%), of whom 35 died <7 days. Male sex [hazard ratio (HR): 1.97 (95% confidence interval (CI): 1.15-3.38)], Asian ethnicity [3.42 (1. 59-7.35)], haematological cancer [2.03 (1.16-3.56)] and a cancer diagnosis for >2-5 years [2.81 (1.41-5.59)] or ≥5 years were associated with an increased mortality. Age >60 years and raised C-reactive protein (CRP) were also associated with COVID-19 death. Haematological cancer, a longer-established cancer diagnosis, dyspnoea at diagnosis and raised CRP were indicative of early COVID-19-related death in cancer patients (<7 days from diagnosis). CONCLUSIONS: Findings further substantiate evidence for increased risk of COVID-19 mortality for male and Asian cancer patients, and those with haematological malignancies or a cancer diagnosis >2 years. These factors should be accounted for when making clinical decisions for cancer patients.

The importance of patient and public involvement in cancer research: time to create a new job profile.

Tweetable abstract Need to add #PPI coordinator to required job profiles in #research: improve research quality, enthuse research team and ensure #patients and their families are the center of our research activities.

Cohort profile: King's Health Partners bladder cancer biobank.

BACKGROUND: Bladder cancer (BC) is the 9th most common cancer worldwide, but little progress has been made in improving patient outcomes over the last 25 years. The King's Health Partners (KHP) BC biobank was established to study unanswered, clinically relevant BC research questions. Donors are recruited from the Urology or Oncology departments of Guy's Hospital (UK) and can be approached for consent at any point during their treatment pathway. At present, patients with bladder cancer are approached to provide their consent to provide blood, urine and bladder tissue. They also give access to medical records and linkage of relevant clinical and pathological data across the course of their disease. Between June 2017 and June 2019, 531 out of 997 BC patients (53.3%) gave consent to donate samples and data to the Biobank. During this period, the Biobank collected fresh frozen tumour samples from 90/178 surgical procedures (of which 73 were biopsies) and had access to fixed, paraffin embedded samples from all patients who gave consent. Blood and urine samples have been collected from 38 patients, all of which were processed into component derivatives within 1 to 2 h of collection. This equates to 193 peripheral blood mononuclear cell vials; 238 plasma vials, 224 serum vials, 414 urine supernatant vials and 104 urine cell pellets. This biobank population is demographically and clinically representative of the KHP catchment area. CONCLUSION: The King's Health Partners BC Biobank has assembled a rich data and tissue repository which is clinically and demographically representative of the local South East London BC population, making it a valuable resource for future BC research.

One Piece of the Jigsaw for the Cancer Recovery Strategy: Prevalence of COVID-19 in Patients With Cancer.

COVID-19 has forced governments to make drastic changes to healthcare systems. To start making informed decisions about cancer care, we need to understand the scale of COVID-19 infection. Therefore, we introduced swab testing for patients visiting Guy's Cancer Centre. Our Centre is one of the largest UK Cancer Centers at the epicenter of the UK COVID-19 epidemic. The first COVID-19 positive cancer patient was reported on 29 February 2020. We analyzed data from 7-15 May 2020 for COVID-19 tests in our cancer patients. 2,647 patients attended for outpatient, chemotherapy, or radiotherapy appointments. 654 were swabbed for COVID-19 (25%). Of those tested, 9 were positive for COVID-19 (1.38%) of which 7 were asymptomatic. Cancer service providers will need to understand their local cancer population prevalence. The absolute priority is that cancer patients have the confidence to attend hospitals and be reassured that they will be treated in a COVID-19 managed environment.

Frequency of pathogenic germline variants in BRCA1, BRCA2, PALB2, CHEK2 and TP53 in ductal carcinoma in situ diagnosed in women under the age of 50 years.

INTRODUCTION: Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal breast cancer, and approximately 20% of screen-detected tumours are pure DCIS. Most risk factors for breast cancer have similar associations with DCIS and IDC; however, there is limited data on the prevalence of the known high and moderate penetrance breast cancer predisposition genes in DCIS and which women with DCIS should be referred for genetic screening. The aim of this study was to assess the frequency of germline variants in BRCA2, BRCA1, CHEK2, PALB2 and TP53 in DCIS in women aged less than 50 years of age. METHODS: After DNA extraction from the peripheral blood, Access Array technology (Fluidigm) was used to amplify all exons of these five known breast cancer predisposition genes using a custom made targeted sequencing panel in 655 cases of pure DCIS presenting in women under the age of 50 years together with 1611 controls. RESULTS: Case-control analysis revealed an excess of pathogenic variants in BRCA2 (OR = 27.96, 95%CI 6.56-119.26, P = 2.0 × 10-10) and CHEK2 (OR = 8.04, 95%CI 2.93-22.05, P = 9.0 × 10-6), with weaker associations with PALB2 (P = 0.003), BRCA1 (P = 0.007) and TP53 (P = 0.02). For oestrogen receptor (ER)-positive DCIS the frequency of pathogenic variants was 9% under the age of 50 (14% with a family history of breast cancer) and 29% under the age of 40 (42% with a family history of breast cancer). For ER-negative DCIS, the frequency was 9% (16% with a family history of breast cancer) and 8% (11% with a family history of breast cancer) under the ages of 50 and 40, respectively. CONCLUSIONS: This study has shown that breast tumourigenesis in women with pathogenic variants in BRCA2, CHEK2, PALB2, BRCA1 and TP53 can involve a DCIS precursor stage and that the focus of genetic testing in DCIS should be on women under the age of 40 with ER-positive DCIS.

Correlates of high-impact physical activity measured objectively in older British adults.

Background: Exposure to higher magnitude vertical impacts is thought to benefit bone health. The correlates of this high-impact physical activity (PA) in later life are unknown. Methods: Participants were from the Cohort for Skeletal Health in Bristol and Avon, Hertfordshire Cohort Study and MRC National Survey of Health and Development. Associations of demographic, behavioural, physiological and psychological factors with vertical acceleration peaks ≥1.5 g (i.e. high-impact PA) from 7-day hip-worn accelerometer recordings were examined using linear regression. Results: A total of 1187 participants (mean age = 72.7 years, 66.6% females) were included. Age, sex, education, active transport, self-reported higher impact PA, walking speed and self-rated health were independently associated with high-impact PA whereas BMI and sleep quality showed borderline independent associations. For example, differences in log-high-impact counts were 0.50 (P < 0.001) for men versus women and -0.56 (P < 0.001) for worst versus best self-rated health. Our final model explained 23% of between-participant variance in high impacts. Other correlates were not associated with high-impact activity after adjustment. Conclusions: Besides age and sex, several factors were associated with higher impact PA in later life. Our findings help identify characteristics of older people that might benefit from interventions designed to promote osteogenic PA.

English translation and validation of the SarQoL®, a quality of life questionnaire specific for sarcopenia.

Background: the first quality of life questionnaire specific to sarcopenia, the SarQoL®, has recently been developed and validated in French. To extend the availability and utilisation of this questionnaire, its translation and validation in other languages is necessary. Objective: the purpose of this study was therefore to translate the SarQoL® into English and validate the psychometric properties of this new version. Design: cross-sectional. Setting: Hertfordshire, UK. Subjects: in total, 404 participants of the Hertfordshire Cohort Study, UK. Methods: the translation part was articulated in five stages: (i) two initial translations from French to English; (ii) synthesis of the two translations; (iii) backward translations; (iv) expert committee to compare the backward translations with the original questionnaire and (v) pre-test. To validate the English SarQoL®, we assessed its validity (discriminative power, construct validity), reliability (internal consistency, test-retest reliability) and floor/ceiling effects. Results: the SarQoL® questionnaire was translated without any major difficulties. Results indicated a good discriminative power (lower score of quality of life for sarcopenic subjects, P = 0.01), high internal consistency (Cronbach's alpha of 0.88), consistent construct validity (high correlations found with domains related to mobility, usual activities, vitality, physical function and low correlations with domains related to anxiety, self-care, mental health and social problems) and excellent test-retest reliability (intraclass coefficient correlation of 0.95, 95%CI 0.92-0.97). Moreover, no floor/ceiling has been found. Conclusions: a valid SarQoL® English questionnaire is now available and can be used with confidence to better assess the disease burden associated with sarcopenia. It could also be used as a treatment outcome indicator in research.

The acetaminophen metabolite N-acetyl-p-benzoquinone imine (NAPQI) inhibits glutathione synthetase in vitro; a clue to the mechanism of 5-oxoprolinuric acidosis?

1. Metabolic acidosis due to accumulation of l-5-oxoproline is a rare, poorly understood, disorder associated with acetaminophen treatment in malnourished patients with chronic morbidity. l-5-Oxoprolinuria signals abnormal functioning of the γ-glutamyl cycle, which recycles and synthesises glutathione. Inhibition of glutathione synthetase (GS) by N-acetyl-p-benzoquinone imine (NAPQI) could contribute to 5-oxoprolinuric acidosis in such patients. We investigated the interaction of NAPQI with GS in vitro. 2. Peptide mapping of co-incubated NAPQI and GS using mass spectrometry demonstrated binding of NAPQI with cysteine-422 of GS, which is known to be essential for GS activity. Computational docking shows that NAPQI is properly positioned for covalent bonding with cysteine-422 via Michael addition and hence supports adduct formation. 3. Co-incubation of 0.77 µM of GS with NAPQI (25-400 µM) decreased enzyme activity by 16-89%. Inhibition correlated strongly with the concentration of NAPQI and was irreversible. 4. NAPQI binds covalently to GS causing irreversible enzyme inhibition in vitro. This is an important novel biochemical observation. It is the first indication that NAPQI may inhibit glutathione synthesis, which is pivotal in NAPQI detoxification. Further studies are required to investigate its biological significance and its role in 5-oxoprolinuric acidosis.