Surrey and Sussex Healthcare NHS Trust

Introduction: Intravenous(IV) immunoglobulin(Ig) treatment is known to alleviate behavioral deficits in the experimentally induced model of sepsis. To delineate the mechanisms by which IVIg treatment prevents neuronal dysfunction, an array of immunological and apoptosis markers was investigated. Methods: Sepsis was induced by cecal ligation perforation(CLP) in rats. The animals were divided into five groups; sham, control, CLP + saline, CLP + immunoglobulin G IgG(250 mg/kg,iv), and CLP + immunoglobulins enriched with immunoglobulin M-IgGAM(250 mg/kg,iv). Blood and brain samples were taken in two sets of experiments after CLP to see the early(24 hrs) and late(10 days) effects of treatment. Total complement activity, complement 3(C3) and soluble complement C5b-9 levels were measured in sera of rats using ELISA-based methods. Cerebral complement content was analyzed by Western Blot. Immune cell infiltration and gliosis were examined by immunohistochemistry using cluster of differentiation 3, CD4, CD8, CD11b, CD19 and glial fibrillary acidic protein antibodies. Apoptotic neuronal death was investigated by TUNEL staining and Western Blot-based semi-quantitative evaluation of brain homogenates by bax and bcl-2 antibodies. Results: IV IgG and IgGAM administration significantly reduced systemic complement activity but increased serum C3 and soluble C5b-9 levels. Likewise, Western Blot data showed slightly increased C5b-9 expression and significantly reduced C1q expression in brain samples of IgGAM-treated but not IgG-treated septic rats especially in the first day of administration. No cerebral cellular infiltrates were observed in treated and non-treated septic rats. By contrast, IV IgG and IgGAM treatment induced considerable amelioration in glial cell proliferation which was increased in non-treated rats. IgG and IgGAM treated rats exhibited significantly reduced numbers of apoptotic neurons and cerebral expression levels of bax and bcl-2 as compared to nontreated rats. Conclusions: We suggest that IV IgG and IgGAM administration ameliorates neuronal dysfunction and behavioral deficits by reducing apoptotic cell death and glial cell proliferation. IgGAM treatment might be suppressing classical complement pathway by reducing C1q expression.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

OBJECTIVE: To develop a novel prognostic indicator for use in patients with advanced cancer that is significantly better than clinicians' estimates of survival. DESIGN: Prospective multicentre observational cohort study. SETTING: 18 palliative care services in the UK (including hospices, hospital support teams, and community teams). PARTICIPANTS: 1018 patients with locally advanced or metastatic cancer, no longer being treated for cancer, and recently referred to palliative care services. MAIN OUTCOME MEASURES: Performance of a composite model to predict whether patients were likely to survive for "days" (0-13 days), "weeks" (14-55 days), or "months+" (>55 days), compared with actual survival and clinicians' predictions. RESULTS: On multivariate analysis, 11 core variables (pulse rate, general health status, mental test score, performance status, presence of anorexia, presence of any site of metastatic disease, presence of liver metastases, C reactive protein, white blood count, platelet count, and urea) independently predicted both two week and two month survival. Four variables had prognostic significance only for two week survival (dyspnoea, dysphagia, bone metastases, and alanine transaminase), and eight variables had prognostic significance only for two month survival (primary breast cancer, male genital cancer, tiredness, loss of weight, lymphocyte count, neutrophil count, alkaline phosphatase, and albumin). Separate prognostic models were created for patients without (PiPS-A) or with (PiPS-B) blood results. The area under the curve for all models varied between 0.79 and 0.86. Absolute agreement between actual survival and PiPS predictions was 57.3% (after correction for over-optimism). The median survival across the PiPS-A categories was 5, 33, and 92 days and survival across PiPS-B categories was 7, 32, and 100.5 days. All models performed as well as, or better than, clinicians' estimates of survival. CONCLUSIONS: In patients with advanced cancer no longer being treated, a combination of clinical and laboratory variables can reliably predict two week and two month survival.

BACKGROUND: Artesunate is an antimalarial agent with broad anti-cancer activity in in vitro and animal experiments and case reports. Artesunate has not been studied in rigorous clinical trials for anticancer effects. AIM: To determine the anticancer effect and tolerability of oral artesunate in colorectal cancer (CRC). METHODS: This was a single centre, randomised, double-blind, placebo-controlled trial. Patients planned for curative resection of biopsy confirmed single primary site CRC were randomised (n = 23) by computer-generated code supplied in opaque envelopes to receive preoperatively either 14 daily doses of oral artesunate (200 mg; n = 12) or placebo (n = 11). The primary outcome measure was the proportion of tumour cells undergoing apoptosis (significant if > 7% showed Tunel staining). Secondary immunohistochemical outcomes assessed these tumour markers: VEGF, EGFR, c-MYC, CD31, Ki67 and p53, and clinical responses. FINDINGS: 20 patients (artesunate = 9, placebo = 11) completed the trial per protocol. Randomization groups were comparable clinically and for tumour characteristics. Apoptosis in > 7% of cells was seen in 67% and 55% of patients in artesunate and placebo groups, respectively. Using Bayesian analysis, the probabilities of an artesunate treatment effect reducing Ki67 and increasing CD31 expression were 0.89 and 0.79, respectively. During a median follow up of 42 months 1 patient in the artesunate and 6 patients in the placebo group developed recurrent CRC. INTERPRETATION: Artesunate has anti-proliferative properties in CRC and is generally well tolerated.

Over the past 70 years, the global population and age structure have been changing rapidly. Analyses from the 2017 Global Burden of Diseases, Injuries, and Risk Factors Study forecasted a continuation of global ageing throughout the remainder of the 21st century, creating major challenges for health-care systems to ensure healthy longevity for ageing societies. Oral health is an intrinsic constituent of general health and wellbeing; however, oral health is largely overlooked on the global health agenda. Oral conditions are mostly preventable or treatable, yet older people often do not receive the necessary routine care to maintain a good standard of oral health. The neglect of oral health constitutes a failure of global health policy and a failure to deliver the basic human rights of older people. The aim of this Personal View is to encourage a refreshed vision of oral health, enabling policy makers to recognise the implications of poor oral health in older adults. We call for urgent action to manage the projected challenges throughout the coming decades, to ensure that additional years of life are spent in a state of good health and to help mark global ageing, not as a burden, but as a major anthropological achievement.

Over the last decade there has been increasing interest and enthusiasm in point-of-care ultrasound (POCUS) as an aide to traditional examination techniques in assessing acutely unwell adult patients. However, it currently remains the domain of a relatively small handful of physicians within the UK. There are numerous reasons for this, notably a lack of training pathways and supervisors but also a lack of understanding of the evidence base behind this imaging modality. This review article aims to explore some of the evidence base behind POCUS for a number of medical pathologies, and where possible compare it to evidenced traditional examination techniques. We discuss the issues around training in bedside ultrasound and recommend a push to integrate POCUS training into internal medicine curricula and support trainers to comprehensively deliver this.

BACKGROUND: Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data. RESULTS: A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P = 0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P = 0.08). The incidence of adverse events did not differ significantly between the groups. CONCLUSIONS: Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439.).

Laparoscopic approaches have increasingly assumed a central role in the management of benign and malignant surgical diseases. While laparoscopy is less morbid than open surgery, it still requires several incisions, each > or =1-2 cm long. Each incision risks morbidity from bleeding, hernia and/or internal organ damage, and incrementally decreases cosmesis. An alternative to conventional laparoscopy is single-incision laparoscopic surgery (SILS), in which articulating or bent instrumentation with specialized multi-lumen ports is used. These technical innovations obviate the need to externally space trocars for triangulation, thus allowing the creation of a small, solitary portal of entry into the abdomen. Laboratory and early clinical series showed the feasibility as well as safe and successful completion of SILS. Natural-orifice transluminal endoscopic surgery (NOTES) is another exciting development in minimally invasive urology, but existing flexible endoscopes and instruments are limited in providing a platform for this form of advanced surgery, resulting in the slow adoption of NOTES. Future work is needed to improve existing instrumentation, increase clinical experience, assess the benefits of both surgical approaches, and explore other potential applications for these novel techniques.

BACKGROUND: In-patients in crisis report poor experiences of mental healthcare not conducive to recovery. Concerns include coercion by staff, fear of assault from other patients, lack of therapeutic opportunities and limited support. There is little high-quality evidence on what is important to patients to inform recovery-focused care.AimsTo conduct a systematic review of published literature, identifying key themes for improving experiences of in-patient mental healthcare. METHOD: A systematic search of online databases (MEDLINE, PsycINFO and CINAHL) for primary research published between January 2000 and January 2016. All study designs from all countries were eligible. A qualitative analysis was undertaken and study quality was appraised. A patient and public reference group contributed to the review. RESULTS: Studies (72) from 16 countries found four dimensions were consistently related to significantly influencing in-patients' experiences of crisis and recovery-focused care: the importance of high-quality relationships; averting negative experiences of coercion; a healthy, safe and enabling physical and social environment; and authentic experiences of patient-centred care. Critical elements for patients were trust, respect, safe wards, information and explanation about clinical decisions, therapeutic activities, and family inclusion in care. CONCLUSIONS: A number of experiences hinder recovery-focused care and must be addressed with the involvement of staff to provide high-quality in-patient services. Future evaluations of service quality and development of practice guidance should embed these four dimensions.Declaration of interestK.B. is editor of British Journal of Psychiatry and leads a national programme (Synergi Collaborative Centre) on patient experiences driving change in services and inequalities.

Potential health benefits of blueberries may be due to vascular effects of anthocyanins that predominantly circulate in blood as phenolic acid metabolites. We investigated which role blueberry anthocyanins and circulating metabolites play in mediating improvements in vascular function and explore potential mechanisms using metabolomics and nutrigenomics. Purified anthocyanins exerted a dose-dependent improvement of endothelial function in healthy humans, as measured by flow-mediated dilation. The effects were similar to those of wild blueberries containing similar amounts of anthocyanins, whereas control drinks containing fiber, minerals, or vitamins had no significant effect. Daily 1-month wild blueberry consumption increased flow-mediated dilation and lowered 24-hour ambulatory systolic blood pressure. Of the 63 anthocyanin plasma metabolites quantified, 14 and 21 correlated with acute and chronic flow-mediated dilation improvements, respectively. Injection of these metabolites improved flow-mediated dilation in mice. Daily wild blueberry consumption led to differential expression (>1.2-fold) of 608 genes and 3 microRNAs, with Mir-181c showing a 13-fold increase in peripheral blood mononuclear cells. Patterns of 13 metabolites were independent predictors of gene expression changes and pathway enrichment analysis revealed significantly modulated biological processes involved in cell adhesion, migration, immune response, and cell differentiation. Our results identify anthocyanin metabolites as major mediators of vascular bioactivities of blueberries and changes of cellular gene programs. Trial registration: NCT025208.

INTRODUCTION: Rapid Sequence Induction of anaesthesia (RSI) is the recommended method to facilitate emergency tracheal intubation in trauma patients. In emergency situations, a simple and standardised RSI protocol may improve the safety and effectiveness of the procedure. A crucial component of developing a standardised protocol is the selection of induction agents. The aim of this study is to compare the safety and effectiveness of a traditional RSI protocol using etomidate and suxamethonium with a modified RSI protocol using fentanyl, ketamine and rocuronium. METHODS: We performed a comparative cohort study of major trauma patients undergoing pre-hospital RSI by a physician-led Helicopter Emergency Medical Service. Group 1 underwent RSI using etomidate and suxamethonium and Group 2 underwent RSI using fentanyl, ketamine and rocuronium. Apart from the induction agents, the RSI protocol was identical in both groups. Outcomes measured included laryngoscopy view, intubation success, haemodynamic response to laryngoscopy and tracheal intubation, and mortality. RESULTS: Compared to Group 1 (n = 116), Group 2 RSI (n = 145) produced significantly better laryngoscopy views (p = 0.013) and resulted in significantly higher first-pass intubation success (95% versus 100%; p = 0.007). A hypertensive response to laryngoscopy and tracheal intubation was less frequent following Group 2 RSI (79% versus 37%; p < 0.0001). A hypotensive response was uncommon in both groups (1% versus 6%; p = 0.05). Only one patient in each group developed true hypotension (SBP < 90 mmHg) on induction. CONCLUSIONS: In a comparative, cohort study, pre-hospital RSI using fentanyl, ketamine and rocuronium produced superior intubating conditions and a more favourable haemodynamic response to laryngoscopy and tracheal intubation. An RSI protocol using fixed ratios of these agents delivers effective pre-hospital trauma anaesthesia.

Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02.

Bariatric surgery can facilitate weight loss and improvement in medical comorbidities. It has a profound impact on nutrition, and patients need access to follow-up and aftercare. NICE CG189 Obesity emphasized the importance of a minimum of 2 years follow-up in the bariatric surgical service and recommended that following discharge from the surgical service, there should be annual monitoring as part of a shared care model of chronic disease management. NHS England Obesity Clinical Reference Group commissioned a multi-professional subgroup, which included patient representatives, to develop bariatric surgery follow-up guidelines. Terms of reference and scope were agreed upon. The group members took responsibility for different sections of the guidelines depending on their areas of expertise and experience. The quality of the evidence was rated and strength graded. Four different shared care models were proposed, taking into account the variation in access to bariatric surgical services and specialist teams across the country. The common features include annual review, ability for a GP to refer back to specialist centre, submission of follow-up data to the national data base to NBSR. Clinical commissioning groups need to ensure that a shared care model is implemented as patient safety and long-term follow-up are important.

AIMS: Endothelial function is essential for cardiovascular health, and flow-mediated dilation (FMD) is an established technique to measure it. This paper aims to assess FMD values in apparently healthy individuals and provides reference values to facilitate wider clinical use. METHODS AND RESULTS: In 1,579 apparently healthy individuals (aged 18-76), fasted FMD values (data from 44 studies, 6 institutions, 22 operators) were normally distributed and inversely univariately correlated with age, body mass index, glucose, cholesterol, blood pressure, and brachial artery (BA) diameter. Significant multivariate predictors of FMD were age (-0.4%/decade), BMI (0.04%/kg/m2), smoking (-0.7%), and BA diameter (-0.44%/mm) that together explained 19% of the variability independent of operator, institution or ultrasound machine. Individuals in the high FMD tertile (>6.8%) were younger, had smaller BA diameter, lower blood pressure and cholesterol. In individuals with low- and intermediate fatal cardiovascular risk (SCORE), 26% and 53% of individuals, respectively, had FMD values in the low tertile (<5.4%). After adding data from 385 patients with stable coronary artery disease (CAD), ROC analysis (c = 0.841, P < 0.001) showed that FMD of >6.5% excluded CAD (95% sensitivity; 60% specificity) and FMD <3.1% excluded 95% healthy individuals (95% specificity, 31% sensitivity). A meta-analysis and meta-regression of 82 clinical trials (11 countries, n = 3,509) using similar FMD methodology showed that despite considerable heterogeneity (I2 = 0.97) FMD in healthy individuals was on average 6.4% (95%CI: 6.2%, 6.7%) with no significant differences between countries but a significant age-dependent decline (-0.3%/decade, R2 = 0.13). CONCLUSIONS: We provide an age-adapted frame of FMD reference intervals in apparently healthy individuals for use as a biomarker of cardiovascular health. As the degree of vascular endothelial function integrates environmental and genetic factors with classical CV risk factors, FMD may more comprehensively classify individuals with and without standard modifiable cardiovascular risk factors and serve as a target for cardiovascular prevention.

BACKGROUND: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. METHODS: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated 'standard' or 'COVID-altered', in the preoperative, operative and post-operative setting. FINDINGS: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had 'COVID-altered' management. 'Bridging' endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2-9%) using 'NHS Predict'. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. CONCLUSIONS: The majority of 'COVID-altered' management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown.

BACKGROUND: Despite numerous studies on prehospital airway management, results are difficult to compare due to inconsistent or heterogeneous data. The objective of this study was to assess advanced airway management from international physician-staffed helicopter emergency medical services. METHODS: We collected airway data from 21 helicopter emergency medical services in Australia, England, Finland, Hungary, Norway and Switzerland over a 12-month period. A uniform Utstein-style airway template was used for collecting data. RESULTS: The participating services attended 14,703 patients on primary missions during the study period, and 2,327 (16 %) required advanced prehospital airway interventions. Of these, tracheal intubation was attempted in 92 % of the cases. The rest were managed with supraglottic airway devices (5 %), bag-valve-mask ventilation (2 %) or continuous positive airway pressure (0.2 %). Intubation failure rates were 14.5 % (first-attempt) and 1.2 % (overall). Cardiac arrest patients showed significantly higher first-attempt intubation failure rates (odds ratio: 2.0; 95 % CI: 1.5-2.6; p < 0.001) compared to non-cardiac arrest patients. Complications were recorded in 13 %, with recognised oesophageal intubation being the most frequent (25 % of all patients with complications). For non-cardiac arrest patients, important risk predictors for first-attempt failure were patient age (a non-linear association) and administration of sedatives (reduced failure risk). The patient's sex, provider's intubation experience, trauma type (patient category), indication for airway intervention and use of neuromuscular blocking agents were not risk factors for first-attempt intubation failure. CONCLUSIONS: Advanced airway management in physician-staffed prehospital services was performed frequently, with high intubation success rates and low complication rates overall. However, cardiac arrest patients showed significantly higher first-attempt failure rates compared to non-cardiac arrest patients. All failed intubations were handled successfully with a rescue device or surgical airway. STUDY REGISTRATION: www.clinicaltrials.gov NCT01502111 . Registered 22 December 2011.

Scabies is an important public health problem in residential care homes. Delayed diagnosis contributes to outbreaks, which may be prolonged and difficult to control. We investigated factors influencing outbreak recognition, diagnosis and treatment, and staff experiences of outbreak control, identifying areas for intervention. We carried out a semi-structured survey of managers, affected residents and staff of seven care homes reporting suspected scabies outbreaks in southern England over a 6-month period. Attack rates ranged from 2% to 50%, and most cases had dementia (37/39, 95%). Cases were diagnosed clinically by GPs (59%) or home staff (41%), none by dermatologists. Most outbreaks were attributable to avoidably late diagnosis of the index case. Participants reported considerable challenges in managing scabies outbreaks, including late diagnosis and recognition of outbreaks; logistically difficult mass treatment; distressing treatment processes and high costs. This study demonstrates the need for improved support for care homes in detecting and managing these outbreaks.

// Ping Wang 1 , Peiguo Wang 1 , Becky Liu 2 , Jing Zhao 1 , Qingsong Pang 1 , Samir G. Agrawal 3 , Li Jia 4 , Feng-Ting Liu 1 1 Department of Radiobiology, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Centre of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China 2 East Surrey Hospital, Surrey and Sussex Healthcare NHS Trust, Redhill, Surrey, United Kingdom 3 Pathology Group, Blizard Institute, Queen Mary University of London, London, United Kingdom 4 Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom Correspondence to: Ping Wang, e-mail: wangping@tjmuch.com Feng-Ting Liu, e-mail: liufengting@tjmuch.com Keywords: Bax, DRP1, mitochondrial fragmentation, apoptosis, UV irradiation Received: March 09, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: May 21, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: June 04, 2015 ABSTRACT Translocation of the pro-apoptotic protein Bax from the cytosol to the mitochondria is a crucial step in DNA damage-mediated apoptosis, and is also found to be involved in mitochondrial fragmentation. Irradiation-induced cytochrome c release and apoptosis was associated with Bax activation, but not mitochondrial fragmentation. Both Bax and Drp1 translocated from the cytosol to the mitochondria in response to irradiation. However, Drp1 mitochondrial translocation and oligomerization did not require Bax, and failed to induce apoptosis in Bax deficient diffuse large B-cell lymphoma (DLBCL) cells. Using fluorescent microscopy and the intensity correlation analysis, we demonstrated that Bax and Drp1 were colocalized and the levels of colocalization were increased by UV irradiation. Using co-immuno-precipitation, we confirmed that Bax and Drp1 were binding partners. Irradiation induced a time-associated increase in the interaction between active Bax and Drp1. Knocking down Drp1 using siRNA blocked UV irradiation-mediated Bax mitochondrial translocation. In conclusion, our findings demonstrate for the first time, that Drp1 is required for Bax mitochondrial translocation, but Drp1-induced mitochondrial fragmentation alone is not sufficient to induce apoptosis in DLBCL cells.

Anti tumour necrosis factor (anti-TNF) drugs increase the risk of serious respiratory infection and impair protective immunity following pneumococcal and influenza vaccination. Here we report SARS-CoV-2 vaccine-induced immune responses and breakthrough infections in patients with inflammatory bowel disease, who are treated either with the anti-TNF antibody, infliximab, or with vedolizumab targeting a gut-specific anti-integrin that does not impair systemic immunity. Geometric mean [SD] anti-S RBD antibody concentrations are lower and half-lives shorter in patients treated with infliximab than vedolizumab, following two doses of BNT162b2 (566.7 U/mL [6.2] vs 4555.3 U/mL [5.4], p <0.0001; 26.8 days [95% CI 26.2 - 27.5] vs 47.6 days [45.5 - 49.8], p <0.0001); similar results are also observed with ChAdOx1 nCoV-19 vaccination (184.7 U/mL [5.0] vs 784.0 U/mL [3.5], p <0.0001; 35.9 days [34.9 - 36.8] vs 58.0 days [55.0 - 61.3], p value < 0.0001). One fifth of patients fail to mount a T cell response in both treatment groups. Breakthrough SARS-CoV-2 infections are more frequent (5.8% (201/3441) vs 3.9% (66/1682), p = 0.0039) in patients treated with infliximab than vedolizumab, and the risk of breakthrough SARS-CoV-2 infection is predicted by peak anti-S RBD antibody concentration after two vaccine doses. Irrespective of the treatments, higher, more sustained antibody levels are observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Our results thus suggest that adapted vaccination schedules may be required to induce immunity in at-risk, anti-TNF-treated patients.

Male breast cancer (MBC) is rare. We assembled 446 MBCs on tissue microarrays and assessed clinicopathological information, together with data from 15 published studies, totalling 1984 cases. By immunohistochemistry we investigated 14 biomarkers (ERα, ERβ1, ERβ2, ERβ5, PR, AR, Bcl-2, HER2, p53, E-cadherin, Ki67, survivin, prolactin, FOXA1) for survival impact. The main histological subtype in our cohort and combined analyses was ductal (81%, 83%), grade 2; (40%, 44%), respectively. Cases were predominantly ERα (84%, 82%) and PR positive (74%, 71%), respectively, with HER2 expression being infrequent (2%, 10%), respectively. In our cohort, advanced age (>67) was the strongest predictor of overall (OS) and disease free survival (DFS) (p = 0.00001; p = 0.01, respectively). Node positivity negatively impacted DFS (p = 0.04). FOXA1 p = 0.005) and AR p = 0.009) were both positively prognostic for DFS, remaining upon multivariate analysis. Network analysis showed ERα, AR and FOXA1 significantly correlated. In summary, the principle phenotype of MBC was luminal A, ductal, grade 2. In ERα+ MBC, only AR had prognostic significance, suggesting AR blockade could be employed therapeutically.