The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade

Age-related macular degeneration (AMD) is a complex neurodegenerative eye disease with behavioral and genetic etiology and is the leading cause of irreversible vision loss among elderly Caucasians. Functionally significant genetic variants in the alternative pathway of complement have been strongly linked to disease. More recently, a rare variant in the terminal pathway of complement has been associated with increased risk, Complement component 9 (C9) P167S. To assess the functional consequence of this variant, C9 levels were measured in two independent cohorts of AMD patients. In both cohorts, it was demonstrated that the P167S variant was associated with low C9 plasma levels. Further analysis showed that patients with advanced AMD had elevated sC5b-9 compared to those with non-advanced AMD, although this was not associated with the P167S polymorphism. Electron microscopy of membrane attack complexes (MACs) generated using recombinantly produced wild type or P167S C9 demonstrated identical MAC ring structures. In functional assays, the P167S variant displayed a higher propensity to polymerize and a small increase in its ability to induce hemolysis of sheep erythrocytes when added to C9-depleted serum. The demonstration that this C9 P167S AMD risk polymorphism displays increased polymerization and functional activity provides a rationale for the gene therapy trials of sCD59 to inhibit the terminal pathway of complement in AMD that are underway

Early initiation of chemotherapy following complete resection of advanced ovarian cancer associated with improved survival: NRG Oncology/Gynecologic Oncology Group study.

BACKGROUND: To determine whether time from surgery to initiation of chemotherapy impacts survival in advanced ovarian carcinoma. PATIENTS AND METHODS: This is a post-trial ad hoc analysis of Gynecologic Oncology Group protocol 218, a phase III randomized, double-blind, placebo-controlled trial designed to study the antiangiogenesis agent, bevacizumab, in primary and maintenance therapy for patients with newly diagnosed advanced ovarian carcinoma. Maximum attempt at debulking was an eligibility criterion. Stage III patients, not stage IV, were required to have gross macroscopic or palpable residual disease following surgery. The survival impact of time from surgery to initiation of chemotherapy was studied using Cox regression models and stratified by treatment arm, residual disease and other clinical and pathologic factors. RESULTS: One thousand seven hundred eighteen assessable patients were randomized (stage III (n = 1237); stage IV (n = 477), including those with complete resection (stage IV only, n = 81), low-volume residual (≤1 cm, n = 701), and suboptimal (>1 cm, n = 932). On multivariate analysis, time to chemotherapy initiation was predictive of overall survival (P < 0.001), with the complete resection group (i.e. stage IV) encountering an increased risk of death when time to initiation of chemotherapy exceeded 25 days (95% confidence interval 16.6-49.9 days). CONCLUSION: Survival for women with advanced ovarian cancer may be adversely affected when initiation of chemotherapy occurs >25 days following surgery. Our analysis applies to stage IV only as women with stage III who underwent complete resection were not eligible for this trial. These results, however, are consistent with Gompertzian first-order kinetics where patients with microscopic residual are most vulnerable. CLINICAL TRIALS IDENTIFIER: NCT00262847

Locally advanced adenocarcinoma and adenosquamous carcinomas of the cervix compared to squamous cell carcinomas of the cervix in gynecologic oncology group trials of cisplatin-based chemoradiation

OBJECTIVE: Conflicting results have been reported for adeno- and adenosquamous carcinomas of the cervix with respect to their response to therapy and prognosis. The current study sought to evaluate impact of adeno- and adenosquamous histology in the randomized trials of primary cisplatin-based chemoradiation for locally advanced cervical cancer. METHODS: Patients with adeno- and adenosquamous cervical carcinomas were retrospectively studied and compared to squamous cell carcinomas in GOG trials of chemoradiation. RESULTS: Among 1671 enrolled in clinical trials of chemoradiation, 182 adeno- and adenosquamous carcinomas were identified (10.9%). A higher percentage of adeno- and adenosquamous carcinomas were stage IB2 (27.5% versus 20.0%) and fewer had stage IIIB (21.4% versus 28.6%). The mean tumor size was larger for squamous than adeno- and adenosquamous. Adeno- and adenosquamous carcinomas were more often poorly differentiated (46.2% versus 26.8%). When treated with radiation therapy alone, the 70 patients with adeno- and adenosquamous carcinoma of the cervix showed a statistically poorer overall survival (p=0.0499) compared to the 647 patients with squamous cell carcinoma of the cervix. However, when treated with radiation therapy with concurrent cisplatin-based chemotherapy, the 112 patients with adeno- and adenosquamous carcinomas had a similar overall survival (p=0.459) compared the 842 patients with squamous cell carcinoma. Adverse effects to treatment were similar across histologies. CONCLUSION: Adeno- and adenosquamous carcinomas of the cervix are associated with worse overall survival when treated with radiation alone but with similar progression-free and overall survival compared to squamous cell carcinomas of the cervix when treated with cisplatin based chemoradiation

Development and preliminary results of an Electronic Medical Record (EMR)-integrated smartphone telemedicine program to deliver asthma care remotely

Background: Technology-based interventions that can function within real-world practice and improve outcomes without increasing provider burden are needed, yet few successfully cross the research-to-practice divide. This paper describes the process of developing a clinically-integrated smartphone-telemedicine program for adults with asthma and results from proof-of-concept testing. Methods: To ensure integration with practice, we used a contextually-grounded intervention development approach and May\u27s implementation theory to design the intervention, with emphasis on systems capabilities and stakeholder needs. The intervention incorporated symptom monitoring by smart phone, smartphone telemedicine visits and self-management training with a nurse, and clinical decision support software, which provided automated calculations of asthma severity, control, and step-wise therapy. Seven adults (aged 18-40) engaged in a 3-month beta-test. Asthma outcomes (control, quality of life, FEV1) and healthcare utilization patterns were measured at baseline and end-of-study. Results: Each participant received an average of 4 telemedicine visits with 94% patient satisfaction. All participants had uncontrolled asthma at baseline; by end-of-study 5/7 classified as well controlled. Mean asthma control improved 1.55 points (CI=0.59-2.51); quality of life improved 1.91 points CI=0.50-3.31), and FEV1 percent predicted increased 14.86% (CI=-3.09-32.80) with effect sizes of d=1.16, 1.09, and 0.96, respectively. Preventive healthcare utilization increased significantly (1.86 visits/year vs. 0.28/year prior, CI 0.67-2.47) as did prescriptions for controller medications (9.29 refills/year vs. 1.57 refills/year, CI 4.85-10.58) Conclusion: Smartphone telemedicine may be an effective means to improve outcomes and deliver asthma care remotely. However, careful attention to systems capabilities and stakeholder acceptability is needed to ensure successful integration with practice

Disease Extent at Secondary Cytoreductive Surgery is Predictive of Progression-free and Overall Survival in Advanced Stage Ovarian Cancer: an NRG Oncology/Gynecologic Oncology Group study

Purpose GOG 152 was a randomized trial of secondary cytoreductive surgery (SCS) in patients with suboptimal residual disease (residual tumor nodule >1 cm in greatest diameter) following primary cytoreductive surgery for advanced stage ovarian cancer. The current analysis was undertaken to evaluate the impact of disease findings at SCS on progression-free survival (PFS) and overall survival (OS). Methods Among the 550 patients enrolled on GOG-152, two-hundred-sixteen patients were randomly assigned following 3 cycles of cisplatin and paclitaxel to receive SCS. In 15 patients (7%) surgery was declined or contraindicated. In the remaining 201 patients the operative and pathology reports were utilized to classify their disease status at the beginning of SCS as; no gross disease/microscopically negative N= 40 (19.9%), no gross disease/microscopically positive N= 8 (4.0%), and gross disease N=153 (76.1%). Results The median PFS for patients with no gross disease/microscopically negative was 16.1 months, no gross disease/microscopically positive was 13.5 months and for gross disease was 11.7 months, p=0.002. The median OS for patients with no gross disease/microscopically negative was 51.5 months, no gross disease/microscopically positive was 42.6 months and for gross disease was 34.9 months, p=0.018. Conclusion Although as previously reported SCS did not change PFS or OS, for those who underwent the procedure, their operative and pathologic findings were predictive of PFS and OS. Surgical/pathological residual disease is a biomarker of response to chemotherapy and predictive of PFS and OS

A mixed‐methods analysis of younger adults\u27 perceptions of asthma, self‐management, and preventive care: This isn\u27t helping me none

Background: Young adults (ages 18‐44) have increased emergency department use for asthma and poor adherence to medications. The objective of this mixed‐methods study was to understand experiences with and approaches to managing asthma, of which little is known in this age group. Methods: Surveys (Asthma Control Questionnaire, Asthma Quality of Life Questionnaire) and 1:1 semi‐structured interviews were used to explore experiences with asthma, symptoms, self‐management behaviors, and relationship to asthma control and quality of life. Qualitative data were analyzed using content analysis techniques. Descriptive statistics and bivariate correlations were used to examine distributive characteristics and associations between variables. Results: Forty urban adults participated (mean age 32.7 ± 6.2, 1σ). Coughing was reported nearly 46% more often than wheezing, with 42.5% (17/40) coughing until the point of vomiting most days. Most participants delayed using medication for symptoms due to misperceptions about inhalers. Higher symptom frequency and worse asthma control were associated with greater use of non‐pharmacologic symptom management strategies (r=0.645, p\u3c0.001; r=0.360, p=0.022, respectively). Five themes were identified regarding young adults experiences with asthma: (1) having asthma means being limited and missing out on life; (2) healthcare for asthma is burdensome and other things are more important; (3) there is not enough personal benefit in medical interactions to make preventive care worthwhile; (4) there is insufficient support and education about asthma for adults; and (5) people normalize chronic symptoms over time and find ways of coping that fit with their lifestyle. Conclusions & Clinical Relevance: Young adults may tolerate symptoms without using quick‐relief medication or seeking preventive care. Increasing engagement with preventive services will require decreasing perceived burdens and increasing the personal benefits of care. Evaluating for non‐pharmacologic approaches to managing symptoms and asthma‐related coughing may identify uncontrolled asthma. Enhanced training for clinicians in patient‐centric asthma care may be needed

Partisan Asymmetries in Online Political Activity

We examine partisan differences in the behavior, communication patterns and social interactions of more than 18,000 politically-active Twitter users to produce evidence that points to changing levels of partisan engagement with the American online political landscape. Analysis of a network defined by the communication activity of these users in proximity to the 2010 midterm congressional elections reveals a highly segregated, well clustered partisan community structure. Using cluster membership as a high-fidelity (87% accuracy) proxy for political affiliation, we characterize a wide range of differences in the behavior, communication and social connectivity of left- and right-leaning Twitter users. We find that in contrast to the online political dynamics of the 2008 campaign, right-leaning Twitter users exhibit greater levels of political activity, a more tightly interconnected social structure, and a communication network topology that facilitates the rapid and broad dissemination of political information.Comment: 17 pages, 10 figures, 6 table

Going Mobile with Primary Care: Smartphone-Telemedicine for Asthma Management in Young Urban Adults (TEAMS)

Background: The majority of adults with persistent asthma have chronically uncontrolled disease and interventions to improve outcomes are needed. We evaluated the efficacy, feasi- bility, and acceptability of a multi-component smartphone-telemedicine program (TEAMS) to deliver asthma care remotely, support provider adherence to asthma management guide- lines, and improve patient outcomes. Methods: TEAMS utilized: (1) remote symptom monitoring, (2) nurse-led smartphone-tele- medicine with self-management training for patients, and (3) Electronic medical record- based clinical decision support software. Adults aged 18-44 (N=33) and primary care providers (N=4) were recruited from a safety-net practice in Upstate New York. Asthma con- trol, quality of life, and FEV1 were measured at 0, 3 and 6 months. Acceptability was assessed via survey and end-of-study interviews. Paired t-test and mixed effects modeling were used to evaluate the effect of the intervention on asthma outcomes. Results: At baseline, 80% of participants had uncontrolled asthma. By 6-months, 80% classi- fied as well-controlled. Improvements in control and quality of life were large (d=1.955, d=1.579). FEV%pred increased 4.2% (d=1.687) with the greatest gain in males, smokers, and lower educational status. Provider adherence to national guidelines increased from 43.3% to 86.7% (CI = 22.11-64.55) and patient adherence to medication increased from 45.58% to 85.29% (CI = 14.79-64.62). Acceptability was 95.7%; In follow up interviews, 29/30 patients and all providers indicated TEAMS worked better than usual care, supported effective self- management, and reduced symptoms over time, which led to greater self-efficacy and motivation to manage asthma. Discussion: Based on these findings, we conclude that smartphone telemedicine could substantially improve clinical asthma management, adherence to guidelines, and patient outcomes