A disease-associated gene desert directs macrophage inflammation through ETS2.

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.

Fit for Duty: Lessons Learned from Outpatient and Homebound Hematopoietic Cell Transplantation to Prepare Family Caregivers for Home-Based Care.

In the past decade, the demand for home-based care has been amplified by the Coronavirus disease 2019 pandemic. Home-based care has significant benefits for patients, their families, and healthcare systems, but it relies on the often-invisible workforce of family and friend caregivers who shoulder essential health care responsibilities, frequently with inadequate training and support. Hematopoietic cell transplantation (HCT), a potentially curative but intensive treatment for many patients with blood disorders, is being increasingly offered in home-based care settings and necessitates the involvement of family caregivers for significant patient care responsibilities. However, guidelines for supporting and preparing HCT caregivers to effectively care for their loved ones at home have not yet been established. Here, informed by the literature and our collective experience as clinicians and researchers who care for diverse patients with hematologic malignancies undergoing HCT, we provide considerations and recommendations to better support and prepare family caregivers in home-based HCT and, by extension, family caregivers supporting patients with other serious illnesses at home. We suggest tangible ways to screen family caregivers for distress and care delivery challenges, educate and train them to prepare for their caregiving role, and create an infrastructure of support for family caregivers within this emerging care delivery model.

Development and evaluation of a novel pre-operative surgery school and behavioural change intervention for patients undergoing elective major surgery: Fit-4-Surgery School.

Group pre-operative education has usually been limited to conditioning expectations and providing education. Prehabilitation has highlighted modifiable lifestyle factors that are amenable to change and may improve clinical outcomes. We instituted a pre-operative 'Fit-4-Surgery School' for patients scheduled for major surgery, to educate and promote healthy behaviour. We evaluated patients' views having attended the school, and after surgery we asked how it had changed their behaviour with a lifestyle questionnaire. The school was launched in May 2016 and was attended by 586/1017 (58%) of invited patients. Patients who did not attend: lived further away, median (IQR [range]) 8 (4-19 [0-123]) miles vs. 5 (3-14 [0-172]) miles, p < 0.001; and were more deprived, Index of Multiple Deprivation Rank decile median (IQR [range]), 6 (4-8 [1-10]) vs. 7 (4-9 [1-10]), p = 0.04. Of the 492/586 (84%) participants who completed an evaluation questionnaire, 462 (94%) would recommend the school to a friend having surgery and 296 (60%) planned lifestyle changes. After surgery, 232/586 (40%) completed a behavioural change questionnaire, 106 (46%) of whom reported changing at least one lifestyle factor, most commonly by increasing exercise. The pre-operative school was acceptable to patients.

Pre-Transplant Marital Status and Hematopoietic Cell Transplantation Outcomes

Background: Evidence about the impact of marital status before hematopoietic cell transplantation (hct) on outcomes after hct is conflicting. Methods: We identified patients 40 years of age and older within the Center for International Blood and Marrow Transplant Research registry who underwent hct between January 2008 and December 2015. Marital status before hct was declared as one of: married or living with a partner, single (never married), separated or divorced, and widowed. We performed a multivariable analysis to determine the association of marital status with outcomes after hct. Results: We identified 10,226 allogeneic and 5714 autologous hct cases with, respectively, a median follow-up of 37 months (range: 1-102 months) and 40 months (range: 1-106 months). No association between marital status and overall survival was observed in either the allogeneic (p = 0.58) or autologous (p = 0.17) setting. However, marital status was associated with grades 2-4 acute graft-versus-host disease (gvhd), p < 0.001, and chronic gvhd, p = 0.04. The risk of grades 2-4 acute gvhd was increased in separated compared with married patients [hazard ratio (hr): 1.13; 95% confidence interval (ci): 1.03 to 1.24], and single patients had a reduced risk of grades 2-4 acute gvhd (hr: 0.87; 95% ci: 0.77 to 0.98). The risk of chronic gvhd was lower in widowed compared with married patients (hr: 0.82; 95% ci: 0.67 to 0.99). Conclusions: Overall survival after hct is not influenced by marital status, but associations were evident between marital status and grades 2-4 acute and chronic gvhd. To better appreciate the effects of marital status and social support, future research should consider using validated scales to measure social support and patient and caregiver reports of caregiver commitment, and to assess health-related quality of life together with health care utilization.

Core surgical field camps: a new deanery-based model for enhancing advanced skills in core surgical trainees through simulation.

Hands-on wet lab simulation training is a vital part of modern surgical training. Since 2010, surgical 'boot camps' have been run by many UK deaneries to teach core surgical trainees basic entry level skills. Training in advanced skills often requires attendance at national fee-paying courses. In the Wessex Deanery, multiple, free of charge, core surgical 'field camps' were developed to provide more advanced level teaching in the particular specialty preference of each core surgical trainee. After the COVID-19 pandemic, national hands-on courses will be challenging to provide and deanery-based advanced skills training may be the way forward for craft-based specialties. The experiences over 2 years of delivering the Wessex core surgical field camps are shared, giving a guide and advice for other trainers on how to run a field camp.

A cohort study investigating the relationship between patient reported outcome measures and pre-operative frailty in patients with operable, non-palliative colorectal cancer.

BACKGROUND: Frailty refers to the reduction in homeostatic reserve resulting from an accumulation of physiological deficits over a lifetime. Frailty is common in older patients undergoing surgery and is an independent risk factor for post-operative mortality, morbidity and increased length of hospital stay. In frail individuals, stressors, such as surgery, can precipitate an acute deterioration in health, manifesting as delirium, falls, reduction in mobility or continence, rendering these individuals at an increased risk of adverse perioperative outcomes. However, little is known about how frailty affects the patient experience, functional ability and quality of life (QoL) after surgery. In addition, the distribution of frailty in this population is unknown. METHODS: We will conduct a multi-centre observational trial to investigate the relationship between patient reported outcome measures and preoperative frailty. We aim to recruit approximately two-hundred patients with operable, potentially curative colorectal cancer. Eligible patients will be identified at three hospital sites. QoL and functional ability (measured using EORTC QLQ-C30 and WHO-DAS 2.0 respectively) will be recorded at the pre-operative assessment clinic, and at 6 and 12 weeks postoperatively. Frailty scores including the Edmonton Frail Scale (EFS) and Rockwood clinical frailty scale (CFS) will be calculated both preoperatively, and at 12 weeks post-operatively. Secondary outcome measures including post-operative morbidity and mortality will be measured using Clavien Dindo classification and 90-day mortality. DISCUSSION: This observational feasibility study seeks to define the prevalence of frailty in older (> 65 years) colorectal cancer patients and understand how frailty impacts on patient reported outcome measures. This information will help to inform larger studies relating to treatment decision algorithms and promote shared decision making in this population.

Advances in image enhancement for sarcoma surgery.

The recurrence rate of soft tissue and bone sarcomas strongly correlates to the status of the surgical margin after excision, yet excessive removal of tissue may lead to distinct, otherwise avoidable morbidity. Therefore, adequate margination of sarcomas both pre- and intra-operatively is a clinical necessity that has not yet fully been met. Current guidance for soft-tissue sarcomas recommends an ultrasound scan followed by magnetic resonance imaging (MRI). For bone sarcomas, two plane radiographs are required, followed similarly by an MRI scan. The introduction of more precise imaging modalities may reduce the morbidity associated with sarcoma surgery; the PET-CT and PET-MRI approaches in particular demonstrating high clinical efficacy. Despite advancements in the accuracy in pre-operative imaging, translation of an image to surgical margins is difficult, regularly resulting in wider resection margins than required. For soft tissue sarcomas there is currently no standard technique for image guided resections, while for bone sarcomas fluoroscopy may be used, however margins are not easily discernible during the surgical procedure. Near infra-red (NIR) fluorescence guided surgery offers an intra-operative modality through which complete tumour resection with adequate tumour-free margins may be achieved, while simultaneously minimising surgical morbidity. NIR imaging presents a potentially valuable adjunct to sarcoma surgery. Early reports indicate that it may be able to provide the surgeon with helpful information on anatomy, perfusion, lymphatic drainage, tumour margins and metastases. The use of NIR fluorochromes have also been demonstrated to be well tolerated by patients. However, prior to widespread implementation, studies related to cost-effectiveness and the development of protocols are essential. Nevertheless, NIR imaging may become ubiquitous in the future, carrying the potential to transform the surgical management of sarcoma.

Levosimendan in patients with reduced left ventricular function undergoing isolated coronary or valve surgery.

OBJECTIVE: In the Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) trial, no differences in clinical outcomes were observed between levosimendan and placebo in a broad population of patients undergoing cardiac surgery. In previous studies, the benefits of levosimendan were most clearly evident in patients undergoing isolated coronary artery bypass grafting (CABG) surgery. In a prespecified analysis of LEVO-CTS, we compared treatment-related outcomes and costs across types of cardiac surgical procedures. METHODS: Overall, 563 (66.4%) patients underwent isolated CABG, 97 (11.4%) isolated valve, and 188 (22.2%) combined CABG/valve surgery. Outcomes included the co-primary 4-component composite (30-day mortality, 30-day renal replacement, 5-day myocardial infarction, or 5-day mechanical circulatory support), the 2-component composite (30-day mortality or 5-day mechanical circulatory support), 90-day mortality, low cardiac output syndrome (LCOS), and 30-day medical costs. RESULTS: The 4- and 2-component outcomes were not significantly different with levosimendan and placebo in patients undergoing CABG (15.2% vs 19.3% and 7.8% vs 10.4%), valve (49.0% vs 33.3% and 22.4% vs 2.1%), or combined procedures (39.6% vs 35.9% and 24.0% vs 19.6%). Ninety-day mortality was lower with levosimendan in isolated CABG (2.1% vs 7.9%; hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.11-0.64), but not significantly different in valve (8.3% vs 2.0%; HR, 4.10; 95% CI, 0.46-36.72) or combined procedures (10.4% vs 7.6%; HR, 1.39; 95% CI, 0.53-3.64; interaction P = .011). LCOS (12.0% vs 22.1%; odds ratio, 0.48; 95% CI, 0.30-0.76; interaction P = .118) was significantly lower in levosimendan-treated patients undergoing isolated CABG. Excluding study drug costs, median and mean 30-day costs were $53,707 and $65,852 for levosimendan and $54,636 and $67,122 for placebo, with a 30-day mean difference (levosimendan - placebo) of -$1270 (bootstrap 95% CI, -$8722 to $6165). CONCLUSIONS: Levosimendan was associated with lower 90-day mortality and LCOS in patients undergoing isolated CABG, but not in those undergoing isolated valve or combined CABG/valve procedures.

Airway mycosis in allergic airway disease.

The allergic airway diseases, including chronic rhinosinusitis (CRS), asthma, allergic bronchopulmonary mycosis (ABPM) and many others, comprise a heterogeneous collection of inflammatory disorders affecting the upper and lower airways and lung parenchyma that represent the most common chronic diseases of humanity. In addition to their shared tissue tropism, the allergic airway diseases are characterized by a distinct pattern of inflammation involving the accumulation of eosinophils, type 2 macrophages, innate lymphoid cells type 2 (ILC2), IgE-secreting B cells, and T helper type 2 (Th2) cells in airway tissues, and the prominent production of type 2 cytokines including interleukin (IL-) 33, IL-4, IL-5, IL-13, and many others. These factors and related inflammatory molecules induce characteristic remodeling and other changes of the airways that include goblet cell metaplasia, enhanced mucus secretion, smooth muscle hypertrophy, tissue swelling and polyp formation that account for the major clinical manifestations of nasal obstruction, headache, hyposmia, cough, shortness of breath, chest pain, wheezing, and, in the most severe cases of lower airway disease, death due to respiratory failure or disseminated, systemic disease. The syndromic nature of the allergic airway diseases that now include many physiological variants or endotypes suggests that distinct endogenous or environmental factors underlie their expression. However, findings from different perspectives now collectively link these disorders to a single infectious source, the fungi, and a molecular pathogenesis that involves the local production of airway proteinases by these organisms. In this review, we discuss the evidence linking fungi and their proteinases to the surprisingly wide variety of chronic airway and systemic disorders and the immune pathogenesis of these conditions as they relate to environmental fungi. We further discuss the important implications these new findings have for the diagnosis and future therapy of these common conditions.

Rotating night shift work and menopausal age.

STUDY QUESTION: How are rotating night shift schedules associated with age at menopause among a large, national cohort of shift working nurses? SUMMARY ANSWER: Our findings suggest that working rotating night shifts with sufficient frequency may modestly accelerate reproductive senescence among women who may already be predisposed to earlier menopause. WHAT IS KNOWN ALREADY: Younger age at menopause has been associated with increased risk of adverse health outcomes, particularly those linked to reproduction. Night work has been associated with reproductive dysfunction, including disruption of menstrual cycle patterns. STUDY DESIGN, SIZE, DURATION: This cohort study was conducted among 80 840 women of the Nurses' Health Study 2 (NHS2), with prospective follow-up from 1991 through 2013. Loss-to-follow-up of the NHS2 is estimated to be <10%. PARTICIPANTS/MATERIALS, SETTING, METHODS: We assessed the association between cumulative and current rotating night shift work and age at natural menopause over 22 years of follow-up (1991-2013). Cox proportional hazards models were used to estimate hazard ratios (HR) for menopause, adjusted for age, smoking status, body mass index, physical activity, alcohol consumption, reproductive factors and exogenous hormone use. MAIN RESULTS AND THE ROLE OF CHANCE: Over follow-up, 27 456 women (34%) reached natural menopause. Women who worked 20 or more months of rotating night shifts in the prior 2-year had an increased risk of earlier menopause (multivariable-adjusted (MV)-HR = 1.09, 95% CI: 1.02-1.16) compared to women without rotating night shift work. This risk was stronger among women undergoing menopause or otherwise censored under age 45 years (MV-HR = 1.25, 95% CI: 1.08-1.46), than it was for those continuing in the study when >45 years old (MV-HR = 1.05, 95% CI: 0.99-1.13). Working 10 or more years of cumulative rotating night work was also associated with higher risk of menopause among women reaching menopause under age 45 (MV-HR10-19 years = 1.22, 95% CI: 1.03-1.44; MV-HR≥20 years = 1.73, 95% CI: 0.90-3.35), though not over the age of 45 years (MV-HR10-19 years = 1.04, 95% CI: 0.99-1.10; MV-HR≥20 years = 1.01, 95% CI: 0.89-1.15). LIMITATIONS, REASONS FOR CAUTION: The degree to which observed effects of rotating night shifts on age at natural menopause are due to circadian disruption, rather than fatigue and stress associated with working more demanding schedules, is uncertain due to potential residual confounding by these factors. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to assess the effects of night work on menopausal timing among a larger national cohort of shift working women. Women already prone to earlier menopause may further truncate their reproductive lifetime by working schedules comprising day as well as night shifts. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by Center for Disease Control and Prevention/The National Institute for Occupational Safety and Health Grant 5R01OH009803 (PI: Schernhammer E), as well as UM1 CA176726 from the National Institute of Health. The funding sources had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the article; and decision to submit the article for publication. The authors have no conflicts of interest.

Sequential facial skin rejuvenation with intense pulsed light and non-ablative fractionated laser resurfacing in fitzpatrick skin type II-IV patients: A prospective multicenter analysis.

BACKGROUND: While skin aging is triggered by multiple factors and typically presents with multiple manifestations, conventional treatment regimens deploy a single treatment modality. Typical approaches exploit ablative techniques, which involve considerable patient discomfort and downtime and can induce adverse events. Non-ablative fractionated laser (NAFL) resurfacing promotes neocollagenesis, with significantly fewer complications and discomfort. At the same time, intense pulsed light (IPL) therapies have a marked impact on skin tone, with an effect on collagen deposition. This study evaluated the combined effect of same-day, sequential IPL-NAFL treatment on photoaging of the face. DESIGN: In this prospective study, 30 patients presenting Fitzpatrick skin types II-IV, elastosis scores 3-6 and mild to moderate pigmentation, underwent three sessions, of full-face IPL therapy, followed immediately by NAFL treatment, conducted at 4-6 weeks intervals. Wrinkle/elastosis and skin qualities were scored at 1, 3, and 6 months after the last treatment session. Immediate responses were evaluated up to 30 min following treatment and adverse events were monitored throughout the study period. RESULTS: Wrinkle/elastosis scores gradually improved over the treatment period, with 59% of patients presenting a ≥1-point improvement in FES scores by the 1-month follow-up session, which persisted also at the 6 months follow-up visit. Good to excellent pigmentation responses were recorded for ≥63% and improvements in texture, brightness, and tightness were recorded for ≥80% of patients throughout the follow-up period. Over 90% of the treated patients exhibited improved or much improved overall appearance. Patient scorings and satisfaction level reflected physician assessments. Treatments were well tolerated and the social downtime observed was of 1.5 ± 0.25 days. CONCLUSION: The same-day combined IPL-NAFL regimen proved safe and elicited a significant skin rejuvenating effect, in a similar manner to that shown in other same-day combined therapies, without prolonging downtime of each individual modality. Lasers Surg. Med. 51:141-149, 2019. © 2018 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

Calcium signalling links MYC to NUAK1.

NUAK1 is a member of the AMPK-related family of kinases. Recent evidence suggests that NUAK1 is an important regulator of cell adhesion and migration, cellular and organismal metabolism, and regulation of TAU stability. As such, NUAK1 may play key roles in multiple diseases ranging from neurodegeneration to diabetes and metastatic cancer. Previous work revealed a crucial role for NUAK1 in supporting viability of tumour cells specifically when MYC is overexpressed. This role is surprising, given that NUAK1 is activated by the tumour suppressor LKB1. Here we show that, in tumour cells lacking LKB1, NUAK1 activity is maintained by an alternative pathway involving calcium-dependent activation of PKCα. Calcium/PKCα-dependent activation of NUAK1 supports engagement of the AMPK-TORC1 metabolic checkpoint, thereby protecting tumour cells from MYC-driven cell death, and indeed, MYC selects for this pathway in part via transcriptional regulation of PKCα and ITPR. Our data point to a novel role for calcium in supporting tumour cell viability and clarify the synthetic lethal interaction between NUAK1 and MYC.

Unique transcriptome signatures and GM-CSF expression in lymphocytes from patients with spondyloarthritis.

Spondyloarthritis encompasses a group of common inflammatory diseases thought to be driven by IL-17A-secreting type-17 lymphocytes. Here we show increased numbers of GM-CSF-producing CD4 and CD8 lymphocytes in the blood and joints of patients with spondyloarthritis, and increased numbers of IL-17A+GM-CSF+ double-producing CD4, CD8, γδ and NK cells. GM-CSF production in CD4 T cells occurs both independently and in combination with classical Th1 and Th17 cytokines. Type 3 innate lymphoid cells producing predominantly GM-CSF are expanded in synovial tissues from patients with spondyloarthritis. GM-CSF+CD4+ cells, isolated using a triple cytokine capture approach, have a specific transcriptional signature. Both GM-CSF+ and IL-17A+GM-CSF+ double-producing CD4 T cells express increased levels of GPR65, a proton-sensing receptor associated with spondyloarthritis in genome-wide association studies and pathogenicity in murine inflammatory disease models. Silencing GPR65 in primary CD4 T cells reduces GM-CSF production. GM-CSF and GPR65 may thus serve as targets for therapeutic intervention of spondyloarthritis.

Analysis of 11 years of clinical negligence claims in esophagogastric cancer in England.

In the National Health Service (NHS), clinical negligence claims and associated compensations are constantly rising. The aim of this study is to identify the size, trends, and causes of litigations claims in relation to esophagogastric (EG) cancer in the NHS. Data requests were submitted to the NHS Litigation Authority (NHSLA) for the period of January 2003 to December 2013. Data were reviewed, categorized clinically, and analyzed in terms of causes and costs behind claims. In this time period, there were 163 claims identified from the NHSLA database. Ninety-five (58.3%) claims were successful with a pay out of £6.25 million. An increasing overall claim frequency and success rate were found over the last few years. Majority of the claims were from gastric cancer 84 (88.4%). The commonest cause of complaint in successful claims was delay or failure in diagnosis (21.1%) and treatment (17.9%). There were only 10.5% successful intraoperative claims, of which 50% were due to unnecessary or additional procedures. The frequency and success rates of malpractice claims in EG cancer are rising. The failure or delay in diagnosing and treatment in EG malignancy are the common cause for successful litigation claims. The findings further reinforce the need to improve early diagnosis.

miR-10b-5p is a novel Th17 regulator present in Th17 cells from ankylosing spondylitis.

OBJECTIVE: To determine the microRNA (miR) signature in ankylosing spondylitis (AS) T helper (Th)17 cells. METHODS: Interleukin (IL)-17A-producing CD4+ T cells from patients with AS and healthy controls were FACS-sorted for miR sequencing and qPCR validation. miR-10b function was determined by miR mimic expression followed by cytokine measurement, transcriptome analysis, qPCR and luciferase assays. RESULTS: AS Th17 cells exhibited a miR signature characterised by upregulation of miR-155-5p, miR-210-3p and miR-10b. miR-10b has not been described previously in Th17 cells and was selected for further characterisation. miR-10b is transiently induced in in vitro differentiated Th17 cells. Transcriptome, qPCR and luciferase assays suggest that MAP3K7 is targeted by miR-10b. Both miR-10b overexpression and MAP3K7 silencing inhibited production of IL-17A by both total CD4 and differentiating Th17 cells. CONCLUSIONS: AS Th17 cells have a specific miR signature and upregulate miR-10b in vitro. Our data suggest that miR-10b is upregulated by proinflammatory cytokines and may act as a feedback loop to suppress IL-17A by targeting MAP3K7. miR-10b is a potential therapeutic candidate to suppress pathogenic Th17 cell function in patients with AS.

A protocol for management of blood loss in surgical treatment of peritoneal malignancy by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND AND AIMS: The treatment of peritoneal malignancies with cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to be associated with massive surgical blood loss. Maintaining high fibrinogen levels throughout surgery may reduce blood loss in these patients. The primary aim of the study was to see if Tranexamic Acid (TXA) and cryoprecipitate reduced surgical blood loss and hence red cell transfusions. A comparison was made with a cohort of patients treated with fresh frozen plasma (FFP) alone. The secondary aim was to measure the effect of both protocols on coagulation parameters and the incidence of arterial or venous thrombosis. METHOD: We used prospectively collected data from 201 patients who had complete CRS with HIPEC for peritoneal malignancy using different protocols during two discrete 12-month time periods. RESULTS: The new transfusion protocol led to a higher average fibrinogen level intra-operatively and post-operatively, with a significant reduction in average RBC, FFP and platelet transfusion intra-operatively per patient from 4·2 to 1·8 units, 6·2 to 0·2 units and 0·1 to 0 units, respectively. No significant difference in PT or APTT was seen between patients treated with the standard and new protocols. Venous thrombosis occurred in seven patients treated with the standard protocol and five with the new protocol. A single case of arterial thrombosis was seen in both groups. CONCLUSION: Patients treated with upfront TXA and cryoprecipitate during CRS required less RBC transfusion than those treated with the standard protocol of early FFP.

A multidisciplinary team approach minimises prophylactic mastectomy rates.

BACKGROUND: Prophylactic mastectomy (PM) has become increasingly common but is not without complications especially if accompanied by reconstructive surgery. In patients with sporadic unilateral breast cancer, contralateral PM offers no survival advantage. Multidisciplinary team (MDT) communication and interaction may facilitate shared decision-making and curtail PM rates. The aim of this study was investigate the effect of a regional MDT meeting on PM decision-making. METHODS: We conducted an observational study involving retrospective review of prospectively recorded MDT meeting records for a 151 patient requests for PM from 2011 to 2014. Final MDT decisions were recorded as PM 'accepted', 'declined' or 'pending'. For MDT sanctioned requests, the factors justifying PM were recorded. Where PM was declined, justification for MDT refusal was sought and recorded. RESULTS: Approximately half of all requests for PM have been upheld (53.0%) and 1/3 of requests have been declined (32.5%). Of those declined, low risk of contralateral breast cancer versus relatively high risk of systemic relapse were commonly cited as justification for PM refusal (45.7%). A proportion of patients who initiated PM discussion subsequently changed their minds (19.6%), or failed to attend clinic appointments (6.5%). Some patients were deemed medically unfit for complex reconstructive surgery (13%), or were declined on the basis of an apparent cosmetic drive for surgery (6.5%), concerns regarding depression or anxiety (2.2%) and/or if family history could not be substantiated (6.5%). DISCUSSION: MDT meetings facilitate cross-specialty interrogation of requests for PM, minimise unnecessary surgery and restrict PM to those likely to derive maximum benefit.

Development of an enzymatic pretargeting strategy for dual-modality imaging.

A pretargeted imaging strategy based on the HaloTag dehalogenase enzyme is described. Here, a HaloTag-Trastuzumab conjugate has been used as the primary agent targeting HER2 expression, and three new radiolabelled HaloTag ligands have been used as secondary agents, two of which offer dual-modality (SPECT/optical) imaging capability.

Nimbolide targets BCL2 and induces apoptosis in preclinical models of Waldenströms macroglobulinemia.

Neem leaf extract (NLE) has medicinal properties, which have been attributed to its limonoid content. We identified the NLE tetranorterpenoid, nimbolide, as being the key limonoid responsible for the cytotoxicity of NLE in various preclinical models of human B-lymphocyte cancer. Of the models tested, Waldenströms macroglobulinemia (WM) cells were most sensitive to nimbolide, undergoing significant mitochondrial mediated apoptosis. Notably, nimbolide toxicity was also observed in drug-resistant (bortezomib or ibrutinib) WM cells. To identify putative targets of nimbolide, relevant in WM, we used chemoinformatics-based approaches comprised of virtual in silico screening, molecular modeling and target-ligand reverse docking. In silico analysis revealed the antiapoptotic protein BCL2 was the preferential binding partner of nimbolide. The significance of this finding was further tested in vitro in RS4;11 (BCL2-dependent) tumor cells, in which nimbolide induced significantly more apoptosis compared with BCL2 mutated (Jurkat BCL2(Ser70-Ala)) cells. Lastly, intraperitoneal administration of nimbolide in WM tumor xenografted mice, significantly reduced tumor growth and IgM secretion in vivo, while modulating the expression of several proteins as seen on immunohistochemistry. Overall, our data demonstrate that nimbolide is highly active in WM cells, as well as other B-cell cancers, and engages BCL2 to exert its cytotoxic activity.

Quality-of-life outcomes with coronary artery bypass graft surgery in ischemic left ventricular dysfunction: a randomized trial.

BACKGROUND: The STICH (Surgical Treatment for Ischemic Heart Failure) trial compared a strategy of routine coronary artery bypass grafting (CABG) with guideline-based medical therapy for patients with ischemic left ventricular dysfunction. OBJECTIVE: To describe treatment-related quality-of-life (QOL) outcomes, a major prespecified secondary end point in the STICH trial. DESIGN: Randomized trial. (ClinicalTrials.gov: NCT00023595). SETTING: 99 clinical sites in 22 countries. PATIENTS: 1212 patients with a left ventricular ejection fraction of 0.35 or less and coronary artery disease. INTERVENTION: Random assignment to medical therapy alone (602 patients) or medical therapy plus CABG (610 patients). MEASUREMENTS: A battery of QOL instruments at baseline (98.9% complete) and 4, 12, 24, and 36 months after randomization (collection rates were 80% to 89% of those eligible). The principal prespecified QOL measure was the Kansas City Cardiomyopathy Questionnaire, which assesses the effect of heart failure on patients' symptoms, physical function, social limitations, and QOL. RESULTS: The Kansas City Cardiomyopathy Questionnaire overall summary score was consistently higher (more favorable) in the CABG group than in the medical therapy group by 4.4 points (95% CI, 1.8 to 7.0 points) at 4 months, 5.8 points (CI, 3.1 to 8.6 points) at 12 months, 4.1 points (CI, 1.2 to 7.1 points) at 24 months, and 3.2 points (CI, 0.2 to 6.3 points) at 36 months. Sensitivity analyses to account for the effect of mortality on follow-up QOL measurement were consistent with the primary findings. LIMITATION: Therapy was not masked. CONCLUSION: In this cohort of symptomatic high-risk patients with ischemic left ventricular dysfunction and multivessel coronary artery disease, CABG plus medical therapy produced clinically important improvements in quality of life compared with medical therapy alone over 36 months. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.