Oxidation of tertiary amine-derivatized surfaces to control protein adhesion

Selective oxidation of omega-tertiary amine self-assembled thiol monolayers to tertiary amine N-oxides is shown to transform the adhesion of model proteins lysozyme and fibrinogen upon them. Efficient preparation of both secondary and tertiary linker amides as judged by X-ray photoelectron spectroscopy (XPS) and water droplet contact angle was achieved with an improved amide bond formation on gold quartz crystal microbalance (QCM) sensors using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate methanaminium uronium (HATU). Oxidation with hydrogen peroxide was similarly assessed, and adhesion of lysozyme and fibrinogen from phosphate buffered saline was then assayed by QCM and imaged by AFM. Tertiary amine-functionalized sensors adsorbed multilayers of aggregated lysozyme, whereas tertiary amine N-oxides and triethylene glycol-terminated monolayers are consistent with small protein aggregates. The surface containing a dimethylamine N-oxide headgroup and ethyl secondary amide linker showed the largest difference in adsorption of both proteins. Oxidation of tertiary amine decorated surfaces therefore holds the potential for selective deposition of proteins and cells through masking and other patterning techniques

A Search for Exozodiacal Clouds with Kepler

Planets embedded within dust disks may drive the formation of large scale clumpy dust structures by trapping dust into resonant orbits. Detection and subsequent modeling of the dust structures would help constrain the mass and orbit of the planet and the disk architecture, give clues to the history of the planetary system, and provide a statistical estimate of disk asymmetry for future exoEarth-imaging missions. Here we present the first search for these resonant structures in the inner regions of planetary systems by analyzing the light curves of hot Jupiter planetary candidates identified by the Kepler mission. We detect only one candidate disk structure associated with KOI 838.01 at the 3-sigma confidence level, but subsequent radial velocity measurements reveal that KOI 838.01 is a grazing eclipsing binary and the candidate disk structure is a false positive. Using our null result, we place an upper limit on the frequency of dense exozodi structures created by hot Jupiters. We find that at the 90% confidence level, less than 21% of Kepler hot Jupiters create resonant dust clumps that lead and trail the planet by ~90 degrees with optical depths >~5*10^-6, which corresponds to the resonant structure expected for a lone hot Jupiter perturbing a dynamically cold dust disk 50 times as dense as the zodiacal cloud.Comment: 22 pages, 6 figures, Accepted for publication in Ap

Let the sun shine in: effects of ultraviolet radiation on invasive pneumococcal disease risk in Philadelphia, Pennsylvania

BACKGROUND: Streptococcus pneumoniae is a common cause of community acquired pneumonia and bacteremia. Excess wintertime mortality related to pneumonia has been noted for over a century, but the seasonality of invasive pneumococcal disease (IPD) has been described relatively recently and is poorly understood. Improved understanding of environmental influence on disease seasonality has taken on new urgency due to global climate change. METHODS: We evaluated 602 cases of IPD reported in Philadelphia County, Pennsylvania, from 2002 to 2007. Poisson regression models incorporating seasonal smoothers were used to identify associations between weekly weather patterns and case counts. Associations between acute (dayto- day) environmental fluctuations and IPD occurrence were evaluated using a case-crossover approach. Effect modification across age and sex strata was explored, and meta-regression models were created using stratum-specific estimates for effect. RESULTS: IPD incidence was greatest in the wintertime, and spectral decomposition revealed a peak at 51.0 weeks, consistent with annual periodicity. After adjustment for seasonality, yearly increases in reporting, and temperature, weekly incidence was found to be associated with clear-sky UV index (IRR per unit increase in index: 0.70 [95% CI 0.54-0.91]). The effect of UV index was highest among young strata and decreased with age. At shorter time scales, only an association with increases in ambient sulphur oxides was linked to disease risk (OR for highest tertile of exposure 0.75, 95% CI 0.60 to 0.93). CONCLUSION: We confirmed the wintertime predominance of IPD in a major urban center. The major predictor of IPD in Philadelphia is extended periods of low UV radiation, which may explain observed wintertime seasonality. The mechanism of action of diminished light exposure on disease occurrence may be due to direct effects on pathogen survival or host immune function via altered 1,25-(OH)2-vitamin-D metabolism. These findings may suggest less diminution in future IPD risk with climate change than would be expected if wintertime seasonality was driven by temperature

Rapid 20th century warming reverses 900-year cooling in the Gulf of Maine

The Gulf of Maine, located in the western North Atlantic, has undergone recent, rapid ocean warming but the lack of long-term, instrumental records hampers the ability to put these significant hydrographic changes into context. Here we present multiple 300-year long geochemical records (oxygen, nitrogen, and previously published radiocarbon isotopes) measured in absolutely-dated Arctica islandica shells from the western Gulf of Maine. These records, in combination with climate model simulations, suggest that the Gulf of Maine underwent a long-term cooling over most of the last 1000 years, driven primarily by volcanic forcing and North Atlantic ocean dynamics. This cooling trend was reversed by warming beginning in the late 1800s, likely due to increased atmospheric greenhouse gas concentrations and changes in western North Atlantic circulation. The climate model simulations suggest that the warming over the last century was more rapid than almost any other 100-year period in the last 1000 years in the region

Rapid detection of snakes modulates spatial orienting in infancy

Recent evidence for an evolved fear module in the brain comes from studies showing that adults, children and infants detect evolutionarily threatening stimuli such as snakes faster than non-threatening ones. A decisive argument for a threat detection system efficient early in life would come from data showing, in young infants, a functional threat-detection mechanism in terms of “what” and “where” visual pathways. The present study used a variant of Posner’s cuing paradigm, adapted to 7–11-month-olds. On each trial, a threat-irrelevant or a threat-relevant cue was presented (a flower or a snake, i.e., “what”). We measured how fast infants detected these cues and the extent to which they further influenced the spatial allocation of attention (“where”). In line with previous findings, we observed that infants oriented faster towards snake than flower cues. Importantly, a facilitation effect was found at the cued location for flowers but not for snakes, suggesting that these latter cues elicit a broadening of attention and arguing in favour of sophisticated “what–where” connections. These results strongly support the claim that humans have an early propensity to detect evolutionarily threat-relevant stimuli

No excess harms from sustained-release morphine: A randomised placebo-controlled trial in chronic breathlessness

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. Objectives: We aimed to identify and evaluate: (1) treatment-emergent adverse events (TEAE (worse or new since baseline)) and the subgroup of severe TEAEs in a placebo-controlled 7-day randomised trial of regular, low-dose, sustained-release oral morphine for chronic breathlessness and (2) clinical characteristics associated with TEAE. Methods: Safety analysis of trial data. Adults with chronic breathlessness (modified Medical Research Council breathlessness score ≥2) due to heart or lung disease, or cancer, not on regular opioids were eligible. Symptoms associated with opioids (TEAE of special interest) were systematically sought using Common Terminology Criteria for Adverse Events (CTCAE) grading. Other harms could be reported at any time. The relationship between characteristics and presence of ≥1 TEAE of special interest was explored using univariable logistic regression analyses. Results: 1449/5624 (26%) Adverse Events from 279 participants were TEAE of which 150/1449 (10%) were severe (CTCAE grades 3-5). 1086/5624 (75%) were events of special interest of which 41/1086 (4%) were severe. Compared with placebo, morphine was not associated with more TEAE or severe TEAE of special interest (TEAE: OR 0.53, 95% CI 0.21 to 1.38, p=0.20; severe TEAE: OR 0.96, 95% CI 0.27 to 3.41, p=0.95) nor with CTCAE severity grade (χ2=4.39, p=0.50). Among the 26/150 (17%) with severe TEAEs, study withdrawal was more common in the morphine arm (18/26 (69%) morphine arm; 8/26 (30%) placebo arm). None of the severe TEAEs was a respiratory harm. Conclusions: Severe morphine-associated toxicity was uncommon and not associated with study arm. Clinical consequences were minor and self-limiting. Trial registration number: ACTRN126000806268

Pharmacist Contributions to the U.S. Health Care System

Objective: The overall goal for this study was to conduct a segment analysis of the pharmacist workforce during 2009 based upon time spent in medication providing and in patient care services. Methods: Data for this study were obtained from the 2009 National Pharmacist Workforce Survey in which a random sample of 3,000 pharmacists was selected. Cluster analysis was used for identifying pharmacist segments and descriptive statistics were used for describing and comparing segments.Results: Of the 2,667 surveys that were presumed to be delivered to a pharmacist, 1,395 were returned yielding a 52.3% overall response rate. Of these, 1,200 responses were usable for cluster analysis. Findings from this study revealed five segments ofpharmacists: (1) Medication Providers, (2) Medication Providers who also Provide Patient Care, (3) Other Activity Pharmacists, (4) Patient Care Providers Who also Provide Medication, and (5) Patient Care Providers. The results showed that, in 2009, 41% of U.S. pharmacists were devoted wholly to medication providing (Medication Providers). Forty-three percent of pharmacists contributed significantly to patient care service provision (Medication Providers who also Provide Patient Care, Patient Care Providers who also Provide Medication, and Patient Care Providers) and the remaining 16% (Other Activity Pharmacists) contributed most of their time to business / organization management, research, education, and other health-system improvement activities. Conclusions: Based on the findings, we propose that the pharmacy profession currently has, and will continue to build, capacity for contributing to the U.S. health care system in new roles for which they have been identified. However, as shifts in professional roles occur, a great deal of capacity is required related to new service provision. Resources are scarce, so an understanding of the most appropriate timing for making such changes can lead to cost-effective use of limited resources for improving patient care

Monitoring metabolic responses to chemotherapy in single cells and tumors using nanostructure-initiator mass spectrometry (NIMS) imaging

BACKGROUND: Tissue imaging of treatment-induced metabolic changes is useful for optimizing cancer therapies, but commonly used methods require trade-offs between assay sensitivity and spatial resolution. Nanostructure-Initiator Mass Spectrometry imaging (NIMS) permits quantitative co-localization of drugs and treatment response biomarkers in cells and tissues with relatively high resolution. The present feasibility studies use NIMS to monitor phosphorylation of 3(′)-deoxy-3(′)-fluorothymidine (FLT) to FLT-MP in lymphoma cells and solid tumors as an indicator of drug exposure and pharmacodynamic responses. METHODS: NIMS analytical sensitivity and spatial resolution were examined in cultured Burkitt’s lymphoma cells treated briefly with Rapamycin or FLT. Sample aliquots were dispersed on NIMS surfaces for single cell imaging and metabolic profiling, or extracted in parallel for LC-MS/MS analysis. Docetaxel-induced changes in FLT metabolism were also monitored in tissues and tissue extracts from mice bearing drug-sensitive tumor xenografts. To correct for variations in FLT disposition, the ratio of FLT-MP to FLT was used as a measure of TK1 thymidine kinase activity in NIMS images. TK1 and tumor-specific luciferase were measured in adjacent tissue sections using immuno-fluorescence microscopy. RESULTS: NIMS and LC-MS/MS yielded consistent results. FLT, FLT-MP, and Rapamycin were readily detected at the single cell level using NIMS. Rapid changes in endogenous metabolism were detected in drug-treated cells, and rapid accumulation of FLT-MP was seen in most, but not all imaged cells. FLT-MP accumulation in xenograft tumors was shown to be sensitive to Docetaxel treatment, and TK1 immunoreactivity co-localized with tumor-specific antigens in xenograft tumors, supporting a role for xenograft-derived TK1 activity in tumor FLT metabolism. CONCLUSIONS: NIMS is suitable for monitoring drug exposure and metabolite biotransformation with essentially single cell resolution, and provides new spatial and functional dimensions to studies of cancer metabolism without the need for radiotracers or tissue extraction. These findings should prove useful for in vitro and pre-clinical studies of cancer metabolism, and aid the optimization of metabolism-based cancer therapies and diagnostics

Pandemic (H1N1) 2009 Risk for Frontline Health Care Workers

To determine whether frontline health care workers (HCWs) are at greater risk for contracting pandemic (H1N1) 2009 than nonclinical staff, we conducted a study of 231 HCWs and 215 controls. Overall, 79 (17.7%) of 446 had a positive antibody titer by hemagglutination inhibition, with 46 (19.9%) of 231 HCWs and 33 (15.3%) of 215 controls positive (OR 1.37, 95% confidence interval 0.84–2.22). Of 87 participants who provided a second serum sample, 1 showed a 4-fold rise in antibody titer; of 45 patients who had a nose swab sample taken during a respiratory illness, 7 had positive results. Higher numbers of children in a participant’s family and working in an intensive care unit were risk factors for infection; increasing age, working at hospital 2, and wearing gloves were protective factors. This highly exposed group of frontline HCWs was no more likely to contract pandemic (H1N1) 2009 influenza infection than nonclinical staff, which suggests that personal protective measures were adequate in preventing transmission