Clinical, electrophysiologic and serologic evidence of cancer associated retinopathy preceding a diagnosis of breast cancer.

We report the case of a woman in her 50s who presented headaches, blurred vision, diplopia and loss of peripheral vision. She was treated for normal tension glaucoma based on optic nerve cupping prior to the development of diplopia. Records demonstrated visual field constriction over 4 months despite well-controlled intraocular pressures. Examination revealed decreased visual acuity and visual field constriction. The multifocal electroretinogram was abnormal. After a thorough review of her medical and family history, a concern for cancer-associated retinopathy developed. Blood samples were positive for antiretinal antibodies against 23 kDA and 46 kDA proteins. Cancer screening was recommended as the aetiology for retinopathy was unknown and revealed a left breast lump. Following lumpectomy with adjuvant chemoradiation, her visual acuity normalised and visual field defects completely resolved. This case serves to provide an example that distant systemic symptoms may be a manifestation of the underlying malignancy and the importance of clinical suspicion with prompt evaluation.

Defining predictors of responsiveness to advanced therapies in Crohn's disease and ulcerative colitis: protocol for the IBD-RESPONSE and nested CD-metaRESPONSE prospective, multicentre, observational cohort study in precision medicine.

INTRODUCTION: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments. METHODS AND ANALYSIS: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk. TRIAL REGISTRATION NUMBER: ISRCTN96296121.

Surgical outcomes in only eye cataract surgery.

INTRODUCTION: Performing cataract surgery in the setting of only one seeing-eye has significant benefits but also potential negative consequences for both patient and surgeon. This study investigates the surgical outcomes in patients undergoing cataract surgery on their only seeing-eye. METHODS: A retrospective analysis was conducted in a single tertiary centre of all adult patients who had undergone cataract surgery on their only eye, where the fellow eye had a vision of 1.0 LogMAR or worse. Complication rates and visual outcomes were compared against data from the National Ophthalmology Database (NOD) Audit. RESULTS: 918 patients underwent cataract surgery on their only seeing-eye and had their postoperative visual acuity recorded. The overall unadjusted complication rate was 4.0% (versus 2.5% from NOD data) with the rate of posterior capsule rupture (PCR) being 1.9% (versus 1.14% from NOD data). 72.5% (versus 91.5% from NOD data) of patients attained a post-operative visual acuity of 0.3 LogMAR or better. The grade of surgeon performing the surgery did not have a statistically significant effect on the risk of complications. DISCUSSION: In this cohort of only-eye patients undergoing cataract surgery, there was a small increased risk of operative complications including an increased, unadjusted risk of PCR, and fewer eyes achieved 0.3 LogMAR vision post-operatively compared to the NOD audit data. Grade of surgeon did not have an impact on the complication rate, indicating that with appropriate supervision, trainee surgeons may gain experience in only-eye surgery without additional risk to the patient. Further multicentre studies are recommended to assess reproducibility across units.

Constructing Health State Descriptions for Low-Risk Thyroid Cancer: Stakeholder Engagement and Formative Qualitative Research.

OVERVIEW: This paper describes stakeholder involvement and formative qualitative research in the creation of health state descriptions (HSDs) or vignettes for low-risk thyroid cancer. The aim of this project was to engage stakeholders in the contribution of a novel set of HSDs, an important first step in the process of assessing value in thyroid cancer health states. METHODS: We draw upon formative, descriptive qualitative methods, following a multi-stage framework of data collection. We conducted individual semi-structured interviews, cognitive interviews, and focus groups with thyroid cancer patients, community providers, academic subspecialists, and participants with no thyroid cancer diagnosis (N = 31). The HSDs went through several iterations over the course of a year, in collaboration with a highly engaged community advisory board, laying the groundwork for HSDs that are comprehensible, comparable, and appropriate for stated-preference research. FINDINGS: Thyroid cancer survivors compared their experiences with those described in the HSDs. Feedback included concern for the emotional well-being of study participants who would be reading them. Providers were attuned to the need for clinical accuracy and made suggestions to reflect their clinical experience, including for patients with complications or disease progression. The pilot participants with no thyroid cancer were particularly valuable in promoting the need to simplify language and maximize readability. DISCUSSION: Stakeholder engagement was critical to being responsive to feedback as the iterations were refined and presented. Continuous engagement and consultation with multiple sources strengthened the HSDs. A secondary outcome from this project is that stakeholders expressed interest in adapting the HSDs into decision aids for people newly diagnosed with low-risk thyroid cancer.

The Quality of Operative Performance Narrative Feedback: A Retrospective Data Comparison Between End of Rotation Evaluations and Workplace-based Assessments.

OBJECTIVE: To describe the quality of operative performance feedback using evaluation tools commonly used by general surgery residency training programs. SUMMARY OF BACKGROUND DATA: The majority of surgical training programs administer an evaluation through which faculty members may rate and comment on trainee operative performance at the end of the rotation (EOR). Many programs have also implemented the system for improving and measuring procedural learning (SIMPL), a workplace-based assessment tool with which faculty can rate and comment on a trainee's operative performance immediately after a case. It is unknown how the quality of narrative operative performance feedback delivered with these tools compares. METHODS: The authors collected EOR evaluations and SIMPL narrative comments on trainees' operative performance from 3 university-based surgery training programs during the 2016-2017 academic year. Two surgeon raters categorized comments relating to operative skills as being specific or general and as encouraging and/or corrective. Comments were then classified as effective, mediocre, ineffective, or irrelevant. The frequencies with which comments were rated as effective were compared using Chi-square analysis. RESULTS: The authors analyzed a total of 600 comments. 10.7% of EOR and 58.3% of SIMPL operative performance evaluation comments were deemed effective (P < 0.0001). CONCLUSIONS: Evaluators give significantly higher quality operative performance feedback when using workplace-based assessment tools rather than EOR evaluations.

A quality of life survey in patients with long-term silicone oil or phthisis bulbi.

AIM: The aim of this study is to determine whether there is any difference in the quality of life of patients with a blind eye with long-term silicone oil compared to without. METHOD: Patients with either long-term silicone oil in situ (N = 17), defined as a period greater than 6 months duration with no plan for future removal, or those with a phthisical, non oil-filled eye were identified (N = 13). Two validated questionnaires (NEI VFQ-25 and the FACE-Q) that cover indicators for visual function, pain and cosmesis were sent to all patients in the two cohorts. RESULTS: There was no significant difference found in quality of life outcomes between the two groups in terms of visual function, pain or cosmesis. CONCLUSION: The results of this study support a holistic approach to the consent process before vitreoretinal surgery. Patients that may need to undergo multiple vitreoretinal procedures, where the endstage result is a long-term silicone oil fill, should be informed that their functional outcome may be similar to having no surgical intervention.

Second chances.

An 81-year-old woman presented with light perception vision in her left eye and had pallid swelling of the left optic disk. Temporal artery biopsy was normal. Magnetic resonance imaging revealed enlargement and enhancement of the left orbital optic nerve. There were vitreous cells, but a vitrectomy specimen showed only a benign lymphocytic population. Her vision deteriorated to no light perception in the left eye, and an optic nerve biopsy revealed a diffuse astrocytoma of World Health Organization grade II.

Building a global surgery initiative through evaluation, collaboration, and training: the Massachusetts General Hospital experience.

OBJECTIVE: The Massachusetts General Hospital (MGH) Department of Surgery established the Global Surgery Initiative (GSI) in 2013 to transform volunteer and mission-based global surgery efforts into an educational experience in surgical systems strengthening. The objective of this newly conceived mission is not only to perform advanced surgery but also to train surgeons beyond MGH through international partnerships across disciplines. At its inception, a clear pathway to achieve this was not established, and we sought to identify steps that were critical to realizing our mission statement. SETTING: Massachusetts General Hospital, Boston, MA, USA and Mbarara Regional Referral Hospital, Mbarara, Uganda PARTICIPANTS: Members of the MGH and MRRH Departments of Surgery including faculty, fellows, and residents RESULTS: The MGH GSI steering committee identified 4 steps for sustaining a robust global surgery program: (1) administer a survey to the MGH departmental faculty, fellows, and residents to gauge levels of experience and interest, (2) catalog all ongoing global surgical efforts and projects involving MGH surgical faculty, fellows, and residents to identify areas of overlap and opportunities for collaboration, (3) establish a longitudinal partnership with an academic surgical department in a limited-resource setting (Mbarara University of Science and Technology (MUST) at Mbarara Regional Referral Hospital (MRRH)), and (4) design a formal curriculum in global surgery to provide interested surgical residents with structured opportunities for research, education, and clinical work. CONCLUSIONS: By organizing the collective experiences of colleagues, synchronizing efforts of new and former efforts, and leveraging the funding resources available at the local institution, the MGH GSI hopes to provide academic benefit to our foreign partners as well as our trainees through longitudinal collaboration. Providing additional financial and organizational support might encourage more surgeons to become involved in global surgery efforts. Creating a partnership with a hospital in a limited-resource setting and establishing a formal global surgery curriculum for our residents allows for education and longitudinal collaboration. We believe this is a replicable model for building other academic global surgery endeavors that aim to strengthen health and surgical systems beyond their own institutions.

Increased intracranial pressure in spontaneous CSF leak patients is not associated with papilledema.

OBJECTIVE: Spontaneous cerebrospinal fluid (CSF) leaks typically present in patients with undiagnosed idiopathic intracranial hypertension (IIH) secondary to pressure erosion of the skull base. Despite elevated intracranial pressure (ICP) on lumbar puncture or ventriculostomy, patients with spontaneous CSF leaks rarely complain of visual disturbances. The objective of this study is to correlate the presence of preoperative papilledema with opening ICP in patients undergoing endoscopic repair of spontaneous CSF leaks. STUDY DESIGN: Prospective study. SETTING: Tertiary hospital. METHODS: Prospective evaluation of patients with spontaneous CSF leaks was performed over a 1-year period (December 2012 to December 2013). Fundoscopic examination for papilledema was completed preoperatively and CSF pressure measured by lumbar puncture or ventriculostomy intraoperatively. Data regarding demographics, nature of presentation, and body mass index (BMI) were also recorded and compared to a control cohort of IIH patients with papilledema. RESULTS: Sixteen patients (average age 52) were evaluated. Obesity was present in 94% of individuals (average BMI = 43, range, 27-65). Papilledema was absent preoperatively in all subjects. Opening pressures via lumbar puncture/ventriculostomy were 27.4 ± 7.7 cmH20. Following 6 hours of clamping, measurements significantly increased to 36 ± 9.6 cmH20 (P < .001). IIH controls (average age 33, average BMI = 36, range, 21-52) exhibited average ICP (36.2 ± 11.7) identical to postclamp measurements in the spontaneous CSF leak cohort. CONCLUSIONS: Subjects with spontaneous CSF leaks had postclamping average ICP identical to controls with IIH and papilledema. Such evidence suggests that a CSF leak in this patient population provides sufficient pressure diversion to avoid the development of papilledema.

Outcomes after ileal pouch anal anastomosis in patients with primary sclerosing cholangitis.

BACKGROUND AND AIMS: Outcomes after ileal pouch anal anastomosis (IPAA) are not well established in patients with primary sclerosing cholangitis (PSC). We conducted a comprehensive outcomes assessment in these patients. METHODS: A retrospective case note review of complications in all PSC-IPAA (n=21) and matched ulcerative colitis patients with IPAA (UC-IPAA; n=79) after surgery in Oxford (1983-2012) was conducted, and functional outcomes (Öresland score) were evaluated (2012). Quality of life [Cleveland Global Quality of Life Questionnaire, Short Form-36 (SF-36)], and sexual function were also assessed (2012) including patients with PSC-associated UC without IPAA (PSC-UC; n=19). Sub-group analysis of patients with large duct (ld) PSC-IPAA (n=17) was also performed. RESULTS: The 1-, 5-, 10- and 20-year risk of acute pouchitis for PSC-IPAA was 10%, 19%, 31% and 65% respectively, compared to 3%, 10%, 14% and 28% in UC-IPAA (p=0.03). More PSC-IPAA (36%) had poor nocturnal pouch function (vs 2% in UC-IPAA; p=0.0016). There were no differences in surgical complications, quality of life or sexual function between the 3 main groups. LdPSC-IPAA had poorer pouch function (Öresland score: 7.7 vs 5.4 in UC-IPAA; p=0.02), and worse quality of life [SF-36 Physical: 42 vs 50.5 in UC-IPAA; 47.7 in PSC-UC; p=0.03 and Mental Health summary scores: 41.6 vs 51.2 in UC-IPAA; 42.3 in PSC-UC; p=0.04]. CONCLUSIONS: PSC-IPAA suffer more acute pouchitis and have worse functional outcomes than UC-IPAA. LdPSC-IPAA also have poorer quality of life.

Implementing an induction scheduling procedure and consent form to improve quality of care.

Inappropriate elective inductions of labor put patients at increased risk of cesarean, neonatal morbidity, and elevated cost. A scheduling procedure and consent form were implemented to eliminate elective induction at less than 39 weeks gestation and align indications for induction with American College of Obstetricians and Gynecologists guidelines. In 25 of the 28 months following implementation of the new process, we achieved the goal of eliminating elective induction of labor at less than 39 weeks gestation.

Identification of a mechanism underlying regulation of the anti-angiogenic forkhead transcription factor FoxO1 in cultured endothelial cells and ischemic muscle.

Chronic limb ischemia, a complication commonly observed in conjunction with cardiovascular disease, is characterized by insufficient neovascularization despite the up-regulation of pro-angiogenic mediators. One hypothesis is that ischemia induces inhibitory signals that circumvent the normal capillary growth response. FoxO transcription factors exert anti-proliferative and pro-apoptotic effects on many cell types. We studied the regulation of FoxO1 protein in ischemic rat skeletal muscle following iliac artery ligation and in cultured endothelial cells. We found that FoxO1 expression was increased in capillaries within ischemic muscles compared with those from rats that underwent a sham operation. This finding correlated with increased expression of p27(Kip1) and reduced expression of Cyclin D1. Phosphorylated Akt was reduced concurrently with the increase in FoxO1 protein. In skeletal muscle endothelial cells, nutrient stress as well as lack of shear stress stabilized FoxO1 protein, whereas shear stress induced FoxO1 degradation. Endogenous FoxO1 co-precipitated with the E3 ubiquitin ligase murine double minute-2 (Mdm2) in endothelial cells, and this interaction varied in direct relation to the extent of Akt and Mdm2 phosphorylation. Moreover, ischemic muscles had a decreased level of Mdm2 phosphorylation and a reduced interaction between Mdm2 and FoxO1. Our results provide novel evidence that the Akt-Mdm2 pathway acts to regulate endothelial cell FoxO1 expression and illustrate a potential mechanism underlying the pathophysiological up-regulation of FoxO1 under ischemic conditions.

A performance improvement process to tackle tachysystole.

Inappropriate use of oxytocin is an important patient safety issue. In this article, the authors describe success in "tackling tachysystole" using an evidence-based algorithm for oxytocin administration. Monthly audits (N = 1160) reached 100% compliance. An algorithm posted at the bedside, multidisciplinary follow-up, education, and widely disseminated results helped counter resistance and normalization of deviance. Clinicians need standardized definitions and guidelines with measures of progress to manage safety concerns such as tachysystole.

MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases.

The melanoma antigen (MAGE) family consists of more than 60 genes, many of which are cancer-testis antigens that are highly expressed in cancer and play a critical role in tumorigenesis. However, the biochemical and cellular functions of this enigmatic family of proteins have remained elusive. Here, we identify really interesting new gene (RING) domain proteins as binding partners for MAGE family proteins. Multiple MAGE family proteins bind E3 RING ubiquitin ligases with specificity. The crystal structure of one of these MAGE-RING complexes, MAGE-G1-NSE1, reveals structural insights into MAGE family proteins and their interaction with E3 RING ubiquitin ligases. Biochemical and cellular assays demonstrate that MAGE proteins enhance the ubiquitin ligase activity of RING domain proteins. For example, MAGE-C2-TRIM28 is shown to target p53 for degradation in a proteasome-dependent manner, consistent with its tumorigenic functions. These findings define a biochemical and cellular function for the MAGE protein family.

Patient-centered communication and prognosis discussions with cancer patients.

OBJECTIVE: To examine physician communication associated with prognosis discussion with cancer patients. METHODS: We conducted a study of physician-patient communication using trained actors. Thirty-nine physicians, including 19 oncologists and 20 family physicians participated in the study. Actors carried two hidden digital recorders to unannounced visits. We coded recordings for eliciting and validating patient concerns, attentive voice tone, and prognosis talk. RESULTS: Actor adherence to role averaged 92% and the suspected detection rate was 14%. In a multiple regression, eliciting and validating patient concerns (beta=.40, C.I.=0.11-0.68) attentiveness (beta=.32, C.I.=0.06-0.58) and being an oncologist vs. a family physician (beta=.33, C.I.=0.33-1.36) accounted for 46% of the variance in prognosis communication. CONCLUSION: Eliciting and validating patient concerns and attentiveness voice tone is associated with increased discussion of cancer patient prognosis as is physician specialty. PRACTICE IMPLICATIONS: Eliciting and validating patient concerns and attentive voice tone may be markers of physician willingness to discuss emotionally difficult topics. Educating physicians about mindful practice may increase their ability to collect important information and to attend to patient concerns.

Differential role of beta-catenin in VEGF and histamine-induced MMP-2 production in microvascular endothelial cells.

Increases in endothelial cell permeability and production of matrix-degrading enzymes are two early steps in the angiogenic process. Factors such as vascular endothelial growth factor (VEGF) and histamine induce the angiogenic process through alterations in both permeability and proteolysis. We hypothesized that beta-catenin acts as a positive regulator of MMP-2 and MT1-MMP transcription following VEGF or histamine stimulation. Rat microvascular endothelial cells were exposed to VEGF or histamine overnight and MMP-2 protein production was assessed by gelatin zymography. Latent MMP-2 protein levels were increased following VEGF and histamine treatment as were MMP-2 mRNA transcript levels. Endothelial cells exposed to VEGF and histamine had an increased level of nuclear beta-catenin, which was sensitive to inhibition of the PI3-kinase signaling pathway. Promoter assays indicated increased transcriptional activity of both MMP-2 and MT1-MMP in endothelial cells co-transfected with luciferase reporter constructs and beta-catenin. Inhibition of beta-catenin signaling with inhibitor of catenin and T cell factor (ICAT) revealed that the VEGF-induced increase in MMP-2 mRNA is beta-catenin dependent. Interestingly, while MMP-2 mRNA levels increased in response to histamine H1 or H2 receptor activation, significantly larger increases were observed in cells co-treated with ICAT and histamine or the histamine receptor agonists, HTMT and dimaprit. While both VEGF and histamine increase nuclear beta-catenin and MMP-2 production, the role of beta-catenin in MMP-2 regulation differs between the two stimuli.

Teleconferencing surgery enhances effective communication and enriches medical education.

Medical student surgical training has traditionally occurred in the operating room (OR). Present technology allows real time communication between the OR and a remote classroom. We seek to evaluate the value of the teleconferencing (TC) environment compared with the traditional OR environment. Students enrolled in the third-year core clerkship in surgery participated in both TC and OR teaching sessions. A total of 23 sessions were conducted and observed (TC=8; OR=15). In TC sessions, students asked over 4 times as many questions (17.4+/-8.5 vs. 3.4+/-3.0; P<0.01) and faculty asked 4 times as many questions of the students (13.1+/-6.8 vs. 3.1+/-2.7; P<0.01). In TC sessions, students felt more able to ask questions (P<0.01), left with fewer unanswered questions (P<0.01), and more felt it was a good use of their time (P=0.04). These findings demonstrate that TC is a valuable modality for medical student education.