Circular orbits and spin in black-hole initial data

The construction of initial data for black-hole binaries usually involves the choice of free parameters that define the spins of the black holes and essentially the eccentricity of the orbit. Such parameters must be chosen carefully to yield initial data with the desired physical properties. In this paper, we examine these choices in detail for the quasiequilibrium method coupled to apparent-horizon/quasiequilibrium boundary conditions. First, we compare two independent criteria for choosing the orbital frequency, the "Komar-mass condition" and the "effective-potential method," and find excellent agreement. Second, we implement quasi-local measures of the spin of the individual holes, calibrate these with corotating binaries, and revisit the construction of non-spinning black hole binaries. Higher-order effects, beyond those considered in earlier work, turn out to be important. Without those, supposedly non-spinning black holes have appreciable quasi-local spin; furthermore, the Komar-mass condition and effective potential method agree only when these higher-order effects are taken into account. We compute a new sequence of quasi-circular orbits for non-spinning black-hole binaries, and determine the innermost stable circular orbit of this sequence.Comment: 24 pages, 17 figures, accepted for publication in Physical Review D, revtex4; Fixed error in computing proper separation and updated figures and tables accordingly, added reference to Sec. IV.A, fixed minor error in Sec. IV.B, added new data to Tables IV and V, fixed 1 reference, fixed error in Eq. (A7b), included minor changes from PRD editin

Validation of the Saint George's Respiratory Questionnaire in Uganda.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) will soon be the third leading global cause of death and is increasing rapidly in low/middle-income countries. There is a need for local validation of the Saint George's Respiratory Questionnaire (SGRQ), which can be used to identify those experiencing lifestyle impairment due to their breathing. METHODS: The SGRQ was professionally translated into Luganda and reviewed by our field staff and a local pulmonologist. Participants included a COPD-confirmed clinic sample and COPD-positive and negative members of the community who were enrolled in the Lung Function in Nakaseke and Kampala (LiNK) Study. SGRQs were assembled from all participants, while demographic and spirometry data were additionally collected from LiNK participants. RESULTS: In total, 103 questionnaires were included in analysis: 49 with COPD from clinic, 34 community COPD-negative and 20 community COPD-positive. SGRQ score varied by group: 53.5 for clinic, 34.4 for community COPD-positive and 4.1 for community COPD-negative (p<0.001). The cross-validated c statistic for SGRQ total score predicting COPD was 0.87 (95% CI 0.75 to 1.00). SGRQ total score was associated with COPD severity (forced expiratory volume in 1 s per cent of predicted), with an r coefficient of -0.60 (-0.75, -0.39). SGRQ score was associated with dyspnoea (OR 1.05/point; 1.01, 1.09) and cough (1.07; 1.03, 1.11). CONCLUSION: Our Luganda language SGRQ accurately distinguishes between COPD-positive and negative community members in rural Uganda. Scores were correlated with COPD severity and were associated with odds of dyspnoea and cough. We find that it can be successfully used as a respiratory questionnaire for obstructed adults in Uganda

Integrating imaging and RNA-seq improves outcome prediction in cervical cancer

Approaches using a single type of data have been applied to classify human tumors. Here we integrate imaging features and transcriptomic data using a prospectively collected tumor bank. We demonstrate that increased maximum standardized uptake value on pretreatment 18F-fluorodeoxyglucose-positron emission tomography correlates with epithelial-to-mesenchymal transition (EMT) gene expression. We derived and validated 3 major molecular groups, namely squamous epithelial, squamous mesenchymal, and adenocarcinoma, using prospectively collected institutional (n = 67) and publicly available (n = 304) data sets. Patients with tumors of the squamous mesenchymal subtype showed inferior survival outcomes compared with the other 2 molecular groups. High mesenchymal gene expression in cervical cancer cells positively correlated with the capacity to form spheroids and with resistance to radiation. CaSki organoids were radiation-resistant but sensitive to the glycolysis inhibitor, 2-DG. These experiments provide a strategy for response prediction by integrating large data sets, and highlight the potential for metabolic therapy to influence EMT phenotypes in cervical cancer

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Novel metrics for growth model selection

Abstract Background Literature surrounding the statistical modeling of childhood growth data involves a diverse set of potential models from which investigators can choose. However, the lack of a comprehensive framework for comparing non-nested models leads to difficulty in assessing model performance. This paper proposes a framework for comparing non-nested growth models using novel metrics of predictive accuracy based on modifications of the mean squared error criteria. Methods Three metrics were created: normalized, age-adjusted, and weighted mean squared error (MSE). Predictive performance metrics were used to compare linear mixed effects models and functional regression models. Prediction accuracy was assessed by partitioning the observed data into training and test datasets. This partitioning was constructed to assess prediction accuracy for backward (i.e., early growth), forward (i.e., late growth), in-range, and on new-individuals. Analyses were done with height measurements from 215 Peruvian children with data spanning from near birth to 2 years of age. Results Functional models outperformed linear mixed effects models in all scenarios tested. In particular, prediction errors for functional concurrent regression (FCR) and functional principal component analysis models were approximately 6% lower when compared to linear mixed effects models. When we weighted subject-specific MSEs according to subject-specific growth rates during infancy, we found that FCR was the best performer in all scenarios. Conclusion With this novel approach, we can quantitatively compare non-nested models and weight subgroups of interest to select the best performing growth model for a particular application or problem at hand

Epidemiology and risk factors of asthma-chronic obstructive pulmonary disease overlap in low- and middle-income countries

Background: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) represents the confluence of bronchial airway hyperreactivity and chronic airflow limitation and has been described as leading to worse lung function and quality of life than found with either singular disease process. Objective: We aimed to describe the prevalence and risk factors for ACO among adults across 6 low- and middle-income countries (LMICs). Methods: We compiled cross-sectional data for 11,923 participants aged 35 to 92 years from 4 population-based studies in 12 settings. We defined COPD as postbronchodilator FEV 1 /forced vital capacity ratio below the lower limit of normal, asthma as wheeze or medication use in 12 months or self-reported physician diagnosis, and ACO as having both. Results: The prevalence of ACO was 3.8% (0% in rural Puno, Peru, to 7.8% in Matlab, Bangladesh). The odds of having ACO were higher with household exposure to biomass fuel smoke (odds ratio [OR], 1.48; 95% CI, 0.98-2.23), smoking tobacco (OR, 1.28 per 10 pack-years; 95% CI, 1.22-1.34), and having primary or less education (OR, 1.35; 95% CI, 1.07-1.70) as compared to nonobstructed nonasthma individuals. ACO was associated with severe obstruction (FEV 1 %, <50; 31.6% of ACO vs 10.9% of COPD alone) and severe spirometric deficits compared with participants with asthma (−1.61 z scores FEV 1 ; 95% CI, −1.48 to −1.75) or COPD alone (−0.94 z scores; 95% CI, −0.78 to −1.10). Conclusions: ACO may be as prevalent and more severe in LMICs than has been reported in high-income settings. Exposure to biomass fuel smoke may be an overlooked risk factor, and we favor diagnostic criteria for ACO that include environmental exposures common to LMICs.Fil: Morgan, Brooks W.. University Johns Hopkins; Estados UnidosFil: Grigsby, Matthew R.. University Johns Hopkins; Estados UnidosFil: Siddharthan, Trishul. University Johns Hopkins; Estados UnidosFil: Chowdhury, Muhammad. International Centre For Diarrhoeal Disease Research ; BangladeshFil: Rubinstein, Adolfo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Gutierrez, Laura. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Irazola, Vilma. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Miranda, J. Jaime. Universidad Peruana Cayetano Heredia; PerúFil: Bernabe-Ortiz, Antonio. Universidad Peruana Cayetano Heredia; PerúFil: Alam, Dewan. University of York; Reino UnidoFil: Wise, Robert A.. University Johns Hopkins; Estados UnidosFil: Checkley, William. University Johns Hopkins; Estados Unido

Low Body Mass Index Is Associated with Higher Odds of COPD and Lower Lung Function in Low- and Middle-Income Countries

The relationship of body mass index (BMI) with lung function and COPD has been previously described in several high-income settings. However, few studies have examined this relationship in resource-limited settings where being underweight is more common. We evaluated the association between BMI and lung function outcomes across 14 diverse low- and middle-income countries. We included data from 12,396 participants aged 35-95 years and used multivariable regressions to assess the relationship between BMI with either COPD and lung function while adjusting for known risk factors. An inflection point was observed at a BMI of 19.8kg/m(2). Participants with BMI <19.8kg/m(2) had a 2.28 greater odds (95% CI 1.83-2.86) of having COPD and had a 0.21 (0.13-0.30) lower FEV1 and 0.34 (0.27-0.41) lower FEV1/FVC z-score compared to those with BMI 19.8kg/m(2). The association with lung function remained even after excluding participants with COPD. Individuals with lower BMI were more likely to have COPD and had lower lung function compared to those in higher BMI. The association with lung function remained positive even after excluding participants with COPD, suggesting that being underweight may also play a role in having worse lung function

Efficacy and toxicity of rectal cancer reirradiation using IMRT for patients who have received prior pelvic radiation therapy

Purpose: Locally recurrent rectal cancer may cause significant morbidity. Prior reports of rectal cancer reirradiation following local recurrence suggest treatment efficacy, with variable rates of late toxicity. Modern techniques including intensity modulated radiation therapy (IMRT) may improve the therapeutic index. We report outcomes for pelvic reirradiation as treatment for rectal cancer using IMRT. Methods and materials: The records of 31 patients undergoing reirradiation for rectal cancer between 2004 and 2013 were reviewed. All patients underwent IMRT using an accelerated hyperfractionation (39 Gy in 1.5-Gy fractions delivered twice daily, n=15) or once-daily fractionation technique (median dose, 30.4 Gy; range, 27-40 Gy in 15-22 fractions; n = 16). The median cumulative dose was 77 Gy (range, 59-113), and the median interval from prior pelvic radiation therapy was 39.8 months (range, 10.1-307.6). Treatment intent was palliative in 20 patients and neoadjuvant or adjuvant in 11 patients. Surgery was generally reserved for patients with an isolated local recurrence. Concurrent chemotherapy was administered for 25/31 patients, most frequently capecitabine (n=11) or continuous infusion 5-fluorouracil (n=10). Results: Median follow-up was 11.3 months. The prescribed treatment was completed in 29/31 patients (93.5%). Among 18 patients with symptoms attributable to recurrent disease, successful palliation was achieved in 10/18 (55.6%). The rate of grade 2 and grade 3 acute toxicities was 32.3% and 3.2%, respectively. Local control rates at 1 and 2 years were 61.3% and 47.3%, respectively. Median overall survival was 21.9 months, and 1-year survival was 66.7% for patients who had surgical resection versus 58.7% for those who did not (P = .0802). Conclusions: Rectal cancer reirradiation using IMRT is well-tolerated in the setting of prior pelvic radiation therapy. Given significant risk of local progression, further dose escalation may be warranted for patients with life expectancy exceeding 1 year