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Antimicrobial preservatives are used as functional excipients in multidose formulations of biological therapeutics to destroy or inhibit the growth of microbial contaminants, which may be introduced by repeatedly administering doses. Antimicrobial agents can also induce the biophysical instability of proteins and peptides, which presents a challenge in optimizing the drug product formulation. Elucidating the structural basis for aggregation aids in understanding the underlying mechanism and can offer valuable knowledge and rationale for designing drug substances and drug products; however, this remains largely unexplored due to the lack of high-resolution characterization. In this work, we utilize solution nuclear magnetic resonance (NMR) as an advanced biophysical tool to study an acylated 31-residue peptide, acyl-peptide A, and its interaction with commonly used antimicrobial agents, benzyl alcohol and

The post-attendee Uniform Resource Locator (URL) feature within the video conferencing application known as Zoom is often overlooked by digital forensic experts as a potential risk for malware transmission. However, with the ability to redirect webinar participants to any URL set by the host for the webinar, the post-attendee URL can be abused by bad actors to expose webinar participants to malicious websites or, in the worst-case scenario, force participants to download a file through the use of a direct download link URL. This study aims to showcase how this exploit can be replicated by creating an experimental environment involving four Windows 10 desktops running Zoom version 5.7.5 and creating a webinar with four user accounts acting as webinar participants and setting the post-attendee URL value to the URL of a website that contained a keylogger. In another trial, the same experimental environment was utilized, with the only difference being the post-attendee URL that was set to redirect webinar participants to a download link for a .jpg file. In both instances, every user account that joined the webinar via clicking on the invitation link that was emailed to each user account after registering for the webinar was redirected to the post-attendee URL regardless of their user account role. These results not only prove that the post-attendee URL can be exploited, but also provide insight as to how this type of attack can be prevented.

Identification of low-dose, low-molecular-weight, drug-like inhibitors of protein-protein interactions (PPIs) is a challenging area of research. Despite the challenges, the therapeutic potential of PPI inhibition has driven significant efforts toward this goal. Adding to recent success in this area, we describe herein our efforts to optimize a novel purine carboxylic acid-derived inhibitor of the HDM2-p53 PPI into a series of low-projected dose inhibitors with overall favorable pharmacokinetic and physical properties. Ultimately, a strategy focused on leveraging known binding hot spots coupled with biostructural information to guide the design of conformationally constrained analogs and a focus on efficiency metrics led to the discovery of

In 2007, high-deductible plans were added to the primarily nondeductible Kaiser Permanente Northern California (KPNC) integrated health plan, which had covered 100% of device and procedure costs of long-acting reversible contraception (LARC) for members regardless of prescription/visit copay amount. We hypothesized that nondeductible plans and prior LARC use decreased unintended pregnancy.The purpose of this study was to determine if health plan design (nondeductible vs. deductible) and LARC use before pregnancy were associated with pregnancy intention.In this retrospective cohort study, women aged 15-44 as of the index date of June 30, 2010 were followed from January 1, 2010 to December 31, 2012 for evidence of pregnancy (n = 65,989). Health plan design, copays, contraceptive method used most recently before the pregnancy, and self-reported pregnancy intention status (intended, mistimed, unwanted) were obtained from electronic medical records. Logistic regression models were developed to determine if various health plan designs, copays, or prior LARC use were associated with pregnancy intention, controlling for potential confounders such as age, race/ethnicity, marital status, education/income, parity, and comorbidities.In all models, LARC use before pregnancy versus non-LARC use was significantly related to intended pregnancies (all models: odds ratio [OR] = 2.26, 95% confidence interval [CI] 2.06-2.48). Women with deductible plans with healthcare spending accounts (HSA) were more likely to report intended pregnancies versus women with nondeductible plans (all models: OR = 1.2, 95% CI 1.04-1.30). In stratified analyses, high income/high education was a significant predictor of intended pregnancy regardless of race/ethnicity.LARC use before pregnancy and having an HSA were associated with intended pregnancy.

To identify the prevalence of comorbidities in pregnant women and examine the incremental costs of these conditions on the care for mothers and their newborns.This was a retrospective comparative cohort study of women ages 15-49 years with a documented live-birth delivery using de-identified claims from the MarketScan Research Commercial Claims and Encounters database incurred between January 1, 2007, and December 31, 2011. Total health care costs from date of first pregnancy-related claim through 3 months postdelivery were reported; pregnancy-related comorbidities prior to the pregnancy diagnosis were identified and categorized in the 12 months prior to the pregnancy diagnosis, and costs associated with each condition were compiled. A subset of newborns was matched to their mothers using a unique family identifier and their costs were captured for the three months following birth. Comparisons of costs for both mothers and newborns were made using both unadjusted and multivariate analyses between mothers with and without each condition.A total of 322,141 women with live births were identified; 135,572 of these mothers were linked to their newborn(s). Prevalent conditions included back disorders (8.9%), mental disorders (6.5%), headache (5.5%), allergic rhinitis (5.5%), and osteoarthritis (4.8%). Diabetes (0.97%) and hypertension (1.9%) were associated with the highest adjusted incremental costs of care in both mothers ($6,211 [95% confidence interval 5,720-6,702] and $3,367 [95% CI 2,935-3,799] respectively) and newborns ($2,067 [95% CI 1,515-2618]; and $1,210 [95% CI 725-1,695] respectively). The two most common conditions, back disorders and mental disorders, were associated with unadjusted costs of $1,895/$978 (mothers/infants) and $2,097/$1,902 (mothers/infants) respectively.Preexisting conditions common in pregnant women may result in additional resource utilization and costs for both mothers and newborns.

Centaurus A, with its gas-rich elliptical host galaxy, NGC 5128, is the nearest radio galaxy at a distance of 3.8 Mpc. Its proximity allows us to study the interaction between an active galactic nucleus, radio jets, and molecular gas in great detail. We present ALMA observations of low J transitions of three CO isotopologues, HCN, HCO$^{+}$, HNC, CN, and CCH toward the inner projected 500 pc of NGC 5128. Our observations resolve physical sizes down to 40 pc. By observing multiple chemical probes, we determine the physical and chemical conditions of the nuclear interstellar medium of NGC 5128. This region contains molecular arms associated with the dust lanes and a circumnuclear disk (CND) interior to the molecular arms. The CND is approximately 400 pc by 200 pc and appears to be chemically distinct from the molecular arms. It is dominated by dense gas tracers while the molecular arms are dominated by $^{12}$CO and its rare isotopologues. The CND has a higher temperature, elevated CN/HCN and HCN/HNC intensity ratios, and much weaker $^{13}$CO and C$^{18}$O emission than the molecular arms. This suggests an influence from the AGN on the CND molecular gas. There is also absorption against the AGN with a low velocity complex near the systemic velocity and a high velocity complex shifted by about 60 km s$^{-1}$. We find similar chemical properties between the CND in emission and both the low and high velocity absorption complexes implying that both likely originate from the CND. If the HV complex does originate in the CND, then that gas would correspond to gas falling toward the supermassive black hole.

Objectives: The gene expression classifier (GEC, Afirma) reclassifies as molecularly benign approximately one half of thyroid nodule fine-needle aspiration (FNA) biopsies with an initial indeterminate cytopathology diagnosis, facilitating clinical monitoring in lieu of diagnostic thyroid surgery. This study evaluated the long-term management patterns and thyroid surgery rates of GEC benign patients compared to a control group of cytopathology benign patients and also described the costs of thyroid surgery. Methods: This retrospective cohort study used laboratory test results linked to payer medical claims data. Patients who underwent FNA biopsy between 1 January 2011 and 31 July 2013 were selected. GEC benign patients were matched 1:3 to cytopathology benign patients on biopsy year, gender, nodule size and age. Outcomes measured included thyroid-related follow-up clinic visits, ultrasound examinations and surgeries. Results: Out of 2059 patients, matched groups consisting of 201 GEC benign patients and 603 cytopathology benign patients were evaluated over an average follow-up of 20 months. The proportions of GEC benign and cytopathology benign patients that underwent thyroid surgery (11.4% versus 10.1%, p = 0.594), and received a follow-up ultrasound exam (60.2% versus 61.7%, p = 0.706), respectively, were not significantly different. Average thyroid-related medical cost for the surgical episode and during 6 months following surgery were $10,432.00 (SD $8301) and $10,939.00 (SD $9656) respectively. Limitations: The study cohort included only patients whose diagnostic laboratory test results and administrative claims data were uniquely identifiable and could be linked on multiple identifiers; the rigorous matching and patient selection algorithms utilized improved the robustness and internal validity of the study. Claims were used as a proxy for clinical utilization without chart review confirmation. Conclusion: Patients with GEC and cytopathology benign diagnoses were managed similarly. The majority of patients in both groups did not undergo surgery and were managed with usual care, consisting of clinical follow-up and ultrasound exams.

To study the economic burden of pregnancy in the US, common complications during pregnancy, and the incremental costs attributable to these complications.A retrospective comparative cohort study was conducted of pregnant women aged 15-49 years using de-identified medical and pharmacy claims from the Truven Health MarketScan Commercial Claims and Encounters database incurred between January 1, 2007 and December 31, 2011. The total healthcare costs are reported (adjusted to 2011 dollars) from the date of the first pregnancy-related claim through to 3 months post-delivery and these costs were compared to matched controls of non-pregnant women. Pregnancy-related complications were categorized, and the incremental costs associated with each complication were estimated using multivariate analyses.A total of 322,141 eligible women with live births were studied. Compared to matched controls, the average costs of care for pregnant women were nearly $13,000 higher through 3 months post-delivery. A total of 46.9% of women had at least one pre-specified pregnancy complication; the most commonly observed were fetal abnormality (24.7%) and early or threatened labor (16.3%). Multiple gestation (1.9%) resulted in the highest adjusted incremental cost ($12,212; 95% CI = 11,298, 13,216); hypertension ($6152; 95% CI = 5312, 6992) and diabetes ($5081; 95% CI = 4244, 5918) were also among those complications that led to high incremental costs of care.Pregnancy and delivery are frequently compounded by complications that lead to increased costs and resource utilization.

The aim of this study is examine the impact of pregnancy and delivery complications on the healthcare costs of newborns during the first 3 months of life. We conducted a retrospective cohort study of newborns born to women ages 15-49 using de-identified medical and pharmacy claims from the Truven Health MarketScan Commercial Claims and Encounters database incurred between January 1, 2007 and December 31, 2011. Total healthcare costs and resource utilization were examined and compared for the first 3 months of life between cohorts of newborns either with or without evidence of categorized maternal complications. Incremental costs were also determined using multivariable analysis for the conditions found to be the most prevalent in the study population. A total of 137,040 infants were studied, 75.4% of which were born to mothers who had experienced at least one complication during pregnancy or delivery. Fetal abnormalities (26.2%), early or threatened labor (16.6%), and hemorrhage (10.8%) were the most frequently observed complications. Diabetes (8.0%) and hypertension (7.7%) were also common, with the majority of other conditions present in 1% or less of the study population. Adjusted analyses found significant differences for seven conditions where incremental costs ranged from $987 to $10,287. Complications are common during pregnancy and delivery and some complications may lead to increased healthcare costs for newborns immediately following birth.

Few data exist on the distribution of pharmaceutical costs for inpatient surgical procedures across different drug categories (eg, analgesia, anti-infectives). The goals of this study were to categorize pharmaceuticals administered to patients after joint replacement surgery and then to take the hospital[apos ]s perspective and quantify the pharmacy cost of delivering postoperative analgesia to these patients. Two hundred ninety-eight patients undergoing unilateral hip replacement (n [equals] 145), unilateral knee replacement (n [equals] 121), or bilateral knee replacement (n [equals] 32) were studied retrospectively. For each patient, we determined what hospital resources (eg, supplies) were utilized by each patient in each of 12 different hospital departments. This was done to determine what fraction of overall hospital costs was incurred as a result of pharmacy. Then, we classified the hundreds of items (from acetaminophen to warfarin) included as pharmacy costs into 1 of the following categories: postoperative epidural analgesia, opioids, nonopioids, respiratory, gastrointestinal, naloxone, anti-infective, anticoagulant/antiplatelets, miscellaneous, cardiovascular, pharmacist clinical intervention, intravenous fluids, and benzodiazepines. The pharmacy costs for epidural analgesia, opioids, and nonopioids were summed to compute the fraction of pharmacy costs attributed to postoperative analgesia. The results showed that 3.3% (95% confidence interval [lsqb ]CI[rsqb ], 2.7% to 3.6%) of total hospitalization costs were pharmacy costs, which averaged $560 (95% CI, $500 to $620) for hip replacement, $595 (95% CI, $551 to $639) for knee replacement, and $922 (95% CI, $588 to $1256) for bilateral knee replacement surgery. An average of 9.9% (95% CI, 7.37% to 12.43%) of total pharmacy costs for the 3 surgery types were for postoperative epidural analgesia, whereas opioids averaged 19.9% (95% CI, 18.67% to 21.13%), and nonopioids averaged 0.8% (95% CI 0.65% to 0.95%) of pharmacy costs. Thus, analgesics accounted for approximately 31% of pharmacy costs. The pharmacy cost of delivering postoperative analgesia to patients undergoing joint replacement surgery represents 1% of the total costs of surgery. Almost two thirds of the analgesic costs were for opioids. [copy ] 2003 by the American Pain Society

Perfusion chromatography is uniquely characterized by the flow of a portion of the column eluent directly through the resin in the packed bed. The benefits of this phenomenon and some of the properties of perfusive resins have been described before, and can be summarized as enhanced mass transport to interior binding sites. Here we extend the understanding of this phenomenon by comparing resins with different pore size distributions. Resins are chosen to give approximately the same specific pore volumes (as shown in the characterization section) but the varying contribution of large pores is used to control the amount of liquid flowing through the beads. POROS R1 has the largest contribution of throughpores, and therefore the greatest intraparticle flow. POROS R2 has a lower contribution of throughpores, and a higher surface area coming from a greater population of diffusive pores, but still shows significant mass transport enhancements relative to a purely diffusive control. Oligo R3 is dominated by a high population of diffusive pores, and is used comparatively as a non-perfusive resin. Although the pore size distribution can be engineered to control mass transport rates, the resulting surface area is not the only means by which binding capacity can be controlled. Surface coatings are employed to increase binding capacity without fundamentally altering the mass transport properties. Models are used to describe the amount of flow transecting the beads, and comparisons of coated resins to uncoated (polystyrene) resins leads to the conclusion that these coatings do not obstruct the throughpore structures. This is an important conclusion since the binding capacity of the coated product, in some cases, is shown to be over 10-fold higher than the precursor polystyrene scaffold (i.e., POROS R1 or POROS R2).

The cost of pregnancy is increasing over time despite the decline in pregnancy rates. To fully elucidate and evaluate the cost drivers of pregnancy in the US for payers, a systematic review was conducted to understand the main cost components and primary factors that contribute to the direct costs of pregnancy, pregnancy-related complications and unintended pregnancy among women of childbearing age (15–44 years). We performed electronic searches in the PubMed database from January 2000 to December 2012, and major women’s health and pharmacoeconomics conference proceedings from 2011 to 2012. The systematic review is comprised of studies that reported pregnancy, pregnancy-related complications, unplanned pregnancy, and pregnancy-induced monetary costs. The review excluded narrative reports, systematic reviews, model-derived cost of pregnancy papers, non-US-based studies, and reports based solely on expert opinions. Two reviewers independently applied the inclusion criteria and assessed the quality of the data collected. Disagreements between reviewers were resolved by consensus or by arbitration through a third party, with reference to the original sources. We collected information on the study design and outcomes for each included study. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines in designing, performing, and reporting of the systematic review. We identified 40 studies from electronic and handsearching methods. We classified studies based on the primary research topic focusing on the overall cost of pregnancy (N = 10), cost of pregnancy-related complications (N = 26), cost of unintended pregnancy (N = 2), cost of planned pregnancy (N = 1), or cost of pregnancy by facilities (N = 1). In the quality assessment, randomized, non-randomized, and retrospective database studies had low to moderate risk of bias. We determined primary cost drivers based on the highest cost reported in each study. The identified cost drivers were inpatient care, pregnancy delivery, multiple births, complicated cesarean sections, high-risk pregnancy, preterm birth, low birth weight, complications due to conditions such as hypertension, diabetes, anemia, and cancer, and in vitro fertilization. In 2008, the overall mean cost per hospital stay for pregnancy-related incidence ranged from $3,306 to $9,234 in 2012 dollars. The mean cost of pregnancy-related complications that led to preterm birth was as high as $326,953 for an infant born at 25 weeks. It is estimated that over 50 % of live births were unintended in the US. The difference in the cost of unintended pregnancy and intended pregnancy was approximately $536 million. One limitation of the systematic review was the exclusion of model-based cost studies which were excluded because of the high level of variation and heterogeneity across sources of reported cost. Another limitation of the review is that the cost of pregnancy perspective is restricted to the US. Preventing pregnancy-related complications and reducing unintended pregnancies may lower the overall economic burden of pregnancy on the US health care system.

A Van Deemter equation modeling columns packed with spherical monodisperse perfusive media was utilized to calculate the predicted values of the effective pore diffusivity ( D p ) and split ratio (α) of columns packed with POROS® and Oligo R3™ media. The validity of the model was established by calculating consistent values of D p and α for lysozyme, α-chymotrypsinogen A and IgG using columns packed with POROS ion-exchange media. The split ratio was shown to be dependent on the pore structure of the media and not the eluite. The technique allows quantitative measurements of α and D p , and is applicable for both perfusive and diffusive media.

In multiple sclerosis (MS) the individual disease courses are very heterogeneous among patients and biomarkers for setting the diagnosis and the estimation of the prognosis for individual patients would be very helpful. For this purpose, we are developing a multidisciplinary method and workflow for the quantitative, spatial, and spatiotemporal analysis and characterization of MS lesion patterns from MRI with geostatistics.We worked on a small data set involving three synthetic and three real-world MS lesion patterns, covering a wide range of possible MS lesion configurations. After brain normalization, MS lesions were extracted and the resulting binary 3-dimensional models of MS lesion patterns were subject to geostatistical indicator variography in three orthogonal directions.By applying geostatistical indicator variography, we were able to describe the 3-dimensional spatial structure of MS lesion patterns in a standardized manner. Fitting a model function to the empirical variograms, spatial characteristics of the MS lesion patterns could be expressed and quantified by two parameters. An orthogonal plot of these parameters enabled a well-arranged comparison of the involved MS lesion patterns.This method in development is a promising candidate to complement standard image-based statistics by incorporating spatial quantification. The work flow is generic and not limited to analyzing MS lesion patterns. It can be completely automated for the screening of radiological archives.

We report 1.3 cm and 6 cm continuum observations toward the massive proto-stellar candidate G11.11-0.12P1 using the Karl G. Jansky Very Large Array (VLA). We detect a string of four unresolved radio continuum sources coincident with the mid-IR source in G11P1. The continuum sources have positive spectral indices consistent with a thermal (free-free) ionized jet. The most likely origin of the ionized gas are shocks due to the interaction of a stellar wind with the surrounding high-density material. We also present NIR United Kingdom Infrared Telescope (UKIRT) archival data which show an extended structure detected only at K-band (2.2 $\mu$m), which is oriented perpendicular to the jet, and that may be scattered light from a circumstellar disk around the massive protostar. Our observations plus the UKIRT archival data thus provide new evidence that a disk/jet system is present in the massive protostellar candidate located in the G11.11-0.12P1 core., Comment: Accepted for publication in the ApJ; 5 figures

Poster Presentation Objective To examine the prevalence of maternal comorbidities and their effect on pregnancy, delivery, and newborn‐related health care costs. Design Retrospective comparative cohort database analysis. Setting Truven Health MarketScan Commercial Claims and Encounters Database, 2007 to 2011. Sample Women aged 15 to 49 with commercial health care insurance, a medical claim of live birth, and continuous medical and drug benefit coverage 12 months before the first medical claim for pregnancy and 3 months following the birth. Methods Comorbid conditions among women with live births were identified during the 12 months prior to the first pregnancy claim (index date) using an adaptation of the AHRQ Clinical Classification. Women and their newborns were linked using a unique family identifier; the first live‐birth event in the study period was retained for analysis. Medical (inpatient and outpatient) and pharmacy costs accrued between the index date and the day before delivery for the mothers and 3 months following delivery for the mothers and newborns were assessed. Health care utilization and costs were descriptively analyzed for the women with one or more prespecified comorbidity and compared to women without the comorbidity during pregnancy and 3 months following delivery. The incremental pregnancy or newborn costs associated with the comorbidity were assessed using multivariable regression controlling for maternal demographics, all comorbidities evaluated, and compared to mothers without comorbidities. Results A total of 322,141 mothers with live births were included in the database. Of these, 135,572 were linked to 137,040 newborns after applying the inclusion criteria. The most prevalent comorbidities among all mothers included back disorders (9.5%), mental disorders (excluding psychoses; 6.4%), allergic rhinitis (5.9%), headache/migraine (5.6%), osteoarthritis (4.9%), hypertension (2.1%), and diabetes (1.1%). The estimated costs of care for mothers without a comorbid condition and their newborns were $10,221 ( SE = 219) and $1,653 ( SE = 171), respectively. The presence of maternal nongestational diabetes and hypertension were associated with the highest incremental costs of care in the mother ($6,211 [CI 5,720‐6,702] and $3,367 [CI 2,935‐3,799], respectively) and newborn ($2,067 [CI 1,515‐2,618] and $1,210 [CI 725‐1,695], respectively). Inpatient care was the largest single contributor to incremental costs across all comorbidities. Conclusion/Implications for Nursing Practice Particular comorbidities lead to significant incremental costs of care for the mother during pregnancy and the newborn. Comorbidities with the highest cost represent opportunities for additional focus that may potentially improve care and reduce costs.

The p53 tumor suppressor oligomerization domain, a dimer of two primary dimers, is an independently folding domain whose subunits consist of a beta-strand, a tight turn and an alpha-helix. To evaluate the effect of hydrophobic side-chains on three-dimensional structure, we substituted residues Phe341 and Leu344 in the alpha-helix with other hydrophobic amino acids. Substitutions that resulted in residue 341 having a smaller side-chain than residue 344 switched the stoichiometry of the domain from tetrameric to dimeric. The three-dimensional structure of one such dimer was determined by multidimensional NMR spectroscopy. When compared with the primary dimer of the wild-type p53 oligomerization domain, the mutant dimer showed a switch in alpha-helical packing from anti-parallel to parallel and rotation of the alpha-helices relative to the beta-strands. Hydrophobic side-chain size is therefore an important determinant of a protein fold.

We report the detection of a 22GHz water maser line in the nearest (D~3.8Mpc) radio galaxy Centaurus A using the Australia Telescope Compact Array (ATCA). The line is centered at a velocity of ~960kms-1, which is redshifted by about 400kms-1 from the systemic velocity. Such an offset, as well as the width of ~120kms-1, could be consistent with either a nuclear maser arising from an accretion disk of the central supermassive black hole, or for a jet maser that is emitted from the material that is shocked near the base of the jet in Centaurus\,A. The best spatial resolution of our ATCA data constrains the origin of the maser feature within 10cm-3, which indicates substantial mass entrainment of surrounding gas into the propagating jet material.

We present Atacama Large Millimeter/submillimeter Array (ALMA) and Australia Telescope Compact Array (ATCA) data of molecular absorption lines toward the bright central core of the prominent, nearby (d ∼ 3.8 Mpc) radio galaxy Centaurus A, at 13, 7, 3, and 1mm wavelengths. The line of sight crosses the prominent dust lane and continues through the disk and eventually through gas that may be very close to the central supermassive black hole. The goal of our survey is to determine the physical conditions of the gas via analyses of molecular line tracers including molecular abundances and excitation conditions that are sensitive to changes in temperature, density, ionization, and shocks. This study allows us to derive the physical processes that are shaping each molecular environment.

Grafted “narrow reject” pulse shapes, whicch were shown previously to be capable of uniformly exciting a wide range of resonance frequencies with a sharp null directly on resonance for solvent suppression, are combined to generate multiple-pulse sequences. In particular, we show that two-dimensional solvent-suppressed spectra can be obtained with such pulses. This is the first application of pulse Grafting to high-resolution, multiple-pulse NMR spectroscopy.