Stability enhancing N-Terminal PEGylation of oxytocin exploiting different polymer architectures and conjugation approaches

Oxytocin, a cyclic nine amino acid neurohypophyseal hormone therapeutic, is effectively used in the control of postpartum hemorrhaging (PPH) and is on the WHO List of Essential Medicines. However, oxytocin has limited shelf life stability in aqueous solutions, particularly at temperatures in excess of 25 °C and injectable aqueous oxytocin formulations require refrigeration (<8 °C). This is particularly problematic in the hot climates often found in many developing countries where daytime temperatures can exceed 40 °C and where reliable cold-chain storage is not always achievable. The purpose of this study was to develop N-terminal amine targeted PEGylation strategies utilizing both linear PEG and polyPEG “comb” polymers as an effective method for stabilizing solution formulations of this peptide for prolonged storage in the absence of efficient cold-chain storage. The conjugation chemistries investigated herein include irreversible amine targeted conjugation methods utilizing NHS ester and aldehyde reductive amination chemistry. Additionally, one reversible conjugation method using a Schiff base approach was explored to allow for the release of the native peptide, thus, ensuring that biological activity remains unaffected. The reversibility of this approach was investigated for the different polymer architectures, alongside a nonpolymer oxytocin analogue to monitor how pH can tune native peptide release. Elevated temperature degradation studies of the polymer conjugates were evaluated to assess the stability of the PEGylated analogues in comparison to the native peptide in aqueous formulations to mimic storage conditions in developing nations and regions where storage under appropriate conditions is challenging

CyberKnife with Tumor Tracking: An Effective Treatment for High-Risk Surgical Patients with Stage I Non-Small Cell Lung Cancer

Published data suggests that wedge resection for stage I non-small cell lung cancer (NSCLC) is associated with improved overall survival compared to stereotactic body radiation therapy. We report CyberKnife outcomes for high-risk surgical patients with biopsy-proven stage I NSCLC. PET/CT imaging was completed for staging. Three-to-five gold fiducial markers were implanted in or near tumors to serve as targeting references. Gross tumor volumes (GTVs) were contoured using lung windows; the margins were expanded by 5 mm to establish the planning treatment volume (PTV). Treatment plans were designed using a mean of 156 pencil beams. Doses delivered to the PTV ranged from 42 to 60 Gy in three fractions. The 30 Gy isodose contour extended at least 1 cm from the GTV to eradicate microscopic disease. Treatments were delivered using the CyberKnife system with tumor tracking. Examination and PET/CT imaging occurred at 3 month follow-up intervals. Forty patients (median age 76) with a median maximum tumor diameter of 2.6 cm (range, 1.4–5.0 cm) and a mean post-bronchodilator percent predicted forced expiratory volume in 1 s (FEV1) of 57% (range, 21–111%) were treated. A median dose of 48 Gy was delivered to the PTV over 3–13 days (median, 7 days). The 30 Gy isodose contour extended a mean 1.9 cm from the GTV. At a median 44 months (range, 12–72 months) follow-up, the 3 year Kaplan–Meier locoregional control and overall survival estimates compare favorably with contemporary wedge resection outcomes at 91 and 75%, respectively. CyberKnife is an effective treatment approach for stage I NSCLC that is similar to wedge resection, eradicating tumors with 1–2 cm margins in order to preserve lung function. Prospective randomized trials comparing CyberKnife with wedge resection are necessary to confirm equivalence

CyberKnife with Tumor Tracking: An Effective Treatment for High-Risk Surgical Patients with Single Peripheral Lung Metastases

Standard treatment for operable patients with single peripheral lung metastases is metastasectomy. We report mature CyberKnife outcomes for high-risk surgical patients with biopsy proven single peripheral lung metastases. Twenty-four patients (median age 73 years) with a mean maximum tumor diameter of 2.5 cm (range, 0.8–4.5 cm) were treated over a 6-year period extending from September 2004 to September 2010 and followed for a minimum of 1 year or until death. A mean dose of 52 Gy (range, 45–60 Gy) was delivered to the prescription isodose line in three fractions over a 3–11 day period (mean, 7 days). At a median follow-up of 20 months, the 2-year Kaplan–Meier local control and overall survival rates were 87 and 50%, respectively. CyberKnife with fiducial tracking is an effective treatment for high-risk surgical patients with single small peripheral lung metastases. Trials comparing CyberKnife with metastasectomy for operable patients are necessary to confirm equivalence

Improving patient notification of solid abdominal viscera incidental findings with a standardized protocol

BACKGROUND: The increasing use of computed tomography (CT) scans in the evaluation of trauma patients has led to increased detection of incidental radiologic findings. Incidental findings (IFs) of the abdominal viscera are among the most commonly discovered lesions and can carry a risk of malignancy. Despite this, patient notification regarding these findings is often inadequate. METHODS: We identified patients who underwent abdominopelvic CTs as part of their trauma evaluation during a recent 1-year period (9/2011-8/2012). Patients with IFs of the kidneys, liver, adrenal glands, pancreas and/or ovaries had their charts reviewed for documentation of the lesion in their discharge paperwork or follow-up. A quality improvement project was initiated where patients with abdominal IFs were verbally informed of the finding, it was noted on their discharge summary and/or were referred to specialists for evaluation. Nine months after the implementation of the IF protocol, a second chart review was performed to determine if the rate of patient notification improved. RESULTS: Of 1,117 trauma patients undergoing abdominopelvic CT scans during the 21 month study period, 239 patients (21.4%) had 292 incidental abdominal findings. Renal lesions were the most common (146 patients, 13% of all patients) followed by hepatic (95/8.4%) and adrenal (38/3.4%) lesions. Pancreatic (10/0.9%) and ovarian lesions (3/0.3%) were uncommon. Post-IF protocol implementation patient notification regarding IFs improved by over 80% (32.4% vs. 17.7% pre-protocol, p = 0.02). CONCLUSION: IFs of the solid abdominal organs are common in trauma patients undergoing abdominopelvic CT scan. Patient notification regarding these lesions is often inadequate. A systematic approach to the documentation and evaluation of incidental radiologic findings can significantly improve the rate of patient notification

Results from a natural experiment: initial neighbourhood investments do not change objectively-assessed physical activity, psychological distress or perceptions of the neighbourhood

Abstract Background Few studies have assessed objectively measured physical activity (PA), active transportation, psychological distress and neighborhood perceptions among residents of a neighborhood before and after substantial improvements in its physical environment. Also, most research-to-date has employed study designs subject to neighborhood selection, which may introduce bias in reported findings. We built upon a previously enrolled cohort of households from two low-income predominantly African American Pittsburgh neighborhoods, matched on socio-demographic composition including race/ethnicity, income and education. One of the two neighborhoods received substantial neighborhood investments over the course of this study including, but not limited to public housing development and greenspace/landscaping. We implemented a natural experiment using matched intervention and control neighborhoods and conducted pre-post assessments among the cohort. Our comprehensive assessments included accelerometry-based PA, active transportation, psychological distress and perceptions of the neighborhood, with assessments conducted both prior to and following the neighborhood changes. In 2013, we collected data from 1003 neighborhood participants and in 2016, we re-interviewed 676 of those participants. We conducted an intent to treat analysis, with a difference-in-difference estimator using attrition weighting to account for nonresponse between 2013 and 2016. In addition, we derived an individual-level indicator of exposure to neighbourhood investment and estimated effect of exposure to investment on the same set of outcomes using covariate-adjusted models. Results We observed no statistically significant differences in activity, psychological distress, satisfaction with one’s neighborhood as a place to live or any of the other measures we observed prior to and after the neighborhood investments between the intervention and control neighborhoods or those exposed vs not exposed to investments. Conclusions Using this rigorous study design, we observed no significant changes in the intervention neighborhood above and beyond secular trends present in the control neighborhood. Although neighborhood investment may have other benefits, we failed to see improvement in PA, psychological distress or related outcomes in the low-income African American neighborhoods in our study. This may be an indication that improvements in the physical environment may not directly translate into improvements in residents’ physical activity or health outcomes without additional individual-level interventions. It is also possible that these investments were not dramatic enough to spur change within the three year period. Additional studies employing similar design with other cohorts in other settings are needed to confirm these results. Trial registration Trial Registration is not applicable since we did not prospectively assign individuals to a health-related intervention.https://deepblue.lib.umich.edu/bitstream/2027.42/148333/1/12966_2019_Article_793.pd

KELT-2Ab: A Hot Jupiter Transiting the Bright (V=8.77) Primary Star of a Binary System

We report the discovery of KELT-2Ab, a hot Jupiter transiting the bright (V=8.77) primary star of the HD 42176 binary system. The host is a slightly evolved late F-star likely in the very short-lived "blue-hook" stage of evolution, with \teff=6148\pm48{\rm K}, $\log{g}=4.030_{-0.026}^{+0.015}$ and \feh=0.034\pm0.78. The inferred stellar mass is $M_*=1.314_{-0.060}^{+0.063}$\msun\ and the star has a relatively large radius of $R_*=1.836_{-0.046}^{+0.066}$\rsun. The planet is a typical hot Jupiter with period $4.11379\pm0.00001$ days and a mass of $M_P=1.524\pm0.088$\mj\ and radius of $R_P=1.290_{-0.050}^{+0.064}$\rj. This is mildly inflated as compared to models of irradiated giant planets at the $\sim$4 Gyr age of the system. KELT-2A is the third brightest star with a transiting planet identified by ground-based transit surveys, and the ninth brightest star overall with a transiting planet. KELT-2Ab's mass and radius are unique among the subset of planets with $V<9$ host stars, and therefore increases the diversity of bright benchmark systems. We also measure the relative motion of KELT-2A and -2B over a baseline of 38 years, robustly demonstrating for the first time that the stars are bound. This allows us to infer that KELT-2B is an early K-dwarf. We hypothesize that through the eccentric Kozai mechanism KELT-2B may have emplaced KELT-2Ab in its current orbit. This scenario is potentially testable with Rossiter-McLaughlin measurements, which should have an amplitude of $\sim$44 m s$^{-1}$.Comment: 9 pages, 2 tables, 4 figures. A short video describing this paper is available at http://www.youtube.com/watch?v=wVS8lnkXXlE. Revised to reflect the ApJL version. Note that figure 4 is not in the ApJL versio

KELT-3b: A Hot Jupiter Transiting a V=9.8 Late-F Star

We report the discovery of KELT-3b, a moderately inflated transiting hot Jupiter with a mass of 1.477 (-0.067, +0.066) M_J, and radius of 1.345 +/- 0.072 R_J, with an orbital period of 2.7033904 +/- 0.000010 days. The host star, KELT-3, is a V=9.8 late F star with M_* = 1.278 (-0.061, +0.063) M_sun, R_* = 1.472 (-0.067, +0.065) R_sun, T_eff = 6306 (-49, +50) K, log(g) = 4.209 (-0.031, +0.033), and [Fe/H] = 0.044 (-0.082, +0.080), and has a likely proper motion companion. KELT-3b is the third transiting exoplanet discovered by the KELT survey, and is orbiting one of the 20 brightest known transiting planet host stars, making it a promising candidate for detailed characterization studies. Although we infer that KELT-3 is significantly evolved, a preliminary analysis of the stellar and orbital evolution of the system suggests that the planet has likely always received a level of incident flux above the empirically-identified threshold for radius inflation suggested by Demory & Seager (2011).Comment: 12 pages, 12 figures, accepted to Ap