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This study aimed to estimate the cost-effectiveness of the use of recombinant zoster vaccine (RZV) (Shingrix), which protects against herpes zoster (HZ), among immunocompromised adults aged 19 to 49 years, as a contribution to deliberations of the Advisory Committee on Immunization Practices. Hematopoietic cell transplant (HCT) recipients experience a high incidence of HZ, and the efficacy of RZV in preventing HZ has been studied in clinical trials. The cost-effectiveness model calculated incremental cost-effectiveness ratios that compared vaccination with RZV with a no vaccination strategy among adults aged 19 to 49 years. Costs and outcomes were calculated until age 50 years using the healthcare sector perspective and summarized as cost per quality-adjusted life-year (QALY) gained. The base case represents HCT recipients, with scenario analyses representing persons with other immunocompromising conditions, including hematologic malignancies, human immunodeficiency virus, and autoimmune and inflammatory conditions. Uncertainty was investigated using univariate, multivariate, and probabilistic sensitivity analyses. Base-case results indicated vaccination with RZV would avert approximately 35% of HZ episodes and complications, while saving approximately 11% of net costs. Compared with no vaccination, vaccination of HCT recipients with RZV generated cost-savings (ie, lower costs and improved health) in the base case and in 81% of simulations in the probabilistic analysis. In scenario analyses, vaccination cost US dollar ($) 9500/QALY among patients with hematologic malignancies, $79 000/QALY among persons living with human immunodeficiency virus, and $208 000/QALY among persons with selected autoimmune and inflammatory conditions. Generally favorable economic estimates supported recommendations for vaccination of immunocompromised adults with RZV to prevent episodes of HZ and related complications. • In a cost-effectiveness analysis, the use of recombinant zoster vaccine (RZV) among adults aged 19 to 49 years who received a hematopoietic cell transplant was found to be cost-saving in the base-case scenario and in most sensitivity analyses. Scenario analyses investigating persons with other selected immunocompromising conditions resulted in a wide range of economic values. • Generally favorable economic estimates further support that vaccination of immunocompromised adults with RZV should be a clinical priority to prevent episodes of herpes zoster and related complications. • In October 2021, RZV (Shingrix) was recommended for use among immunocompromised adults aged ≥ 19 years. [ABSTRACT FROM AUTHOR]

Investigations of individual differences in how safe people feel in their social lives have typically used single-item measures or indirect measures. To examine the multifaceted nature of perceived personal safety more comprehensively, we introduce a novel measurement model of perceived personal safety, validated over the course of 8 studies (5 main and 3 supplementary studies; total N = 4390). Three distinct factors capturing variance in perceived personal safety emerged, Feeling of Safety (i.e., experiencing security in day-to-day life), Fear of Crime (i.e., being afraid of victimization), and Safety Confidence (i.e., trusting one's own ability to remain safe). Studies 1–3 introduce a newly developed multidimensional model, providing evidence for its face and construct validity. Studies 4 A-4B suggest that the feeling of safety facet specifically relate to better mental health outcomes, even across the span of one year. Study 5 explored the cross-national validity of this model across four different European countries. Contrary to past conceptualizations, perceived personal safety appears to be multidimensional, with different facets affecting our lives in distinct ways. • A multidimensional, three-factor model of perceived personal safety is validated • Feelings of safety measure levels of safety in familiar, day-to-day environments • Fear of crime captures perceived threat from victimization from different crimes • Safety confidence measures a person's perception that they can protect themselves • Relationships with mental well-being and demographic indicators are highlighted [ABSTRACT FROM AUTHOR]

• Private insurance reimbursements for recombinant zoster vaccine averaged $149 in 2018. • Reimbursement rates varied across states. Most reimbursements exceeded $140 in 2018. • Reimbursement rates may be important to consider for vaccination providers and programs. A two-dose series of the recombinant zoster vaccine (RZV, Shingrix) was licensed by the Food and Drug Administration in 2017 and recommended by the Advisory Committee on Immunization Practices in 2018 for adults in the United States age 50 years and older. Despite the health benefits of shingles vaccination, coverage has remained low, with financial barriers among healthcare providers identified as one potential factor. This study estimates the reimbursement levels for RZV among a large sample of privately insured individuals in the US from the 2018 IBM® MarketScan® Commercial Claims and Encounters database. Of 198,534 claims for an RZV dose, the mean reimbursement was $149. Most claims (83%) exceeded $140, which was the private sector vaccine price reported on the CDC vaccine price list in April 2018. These results can be useful for providers considering procuring RZV and for state immunization programs considering ways to improve vaccination coverage. [ABSTRACT FROM AUTHOR]

The Community Preventive Services Task Force (CPSTF) has recommended several interventions that have been demonstrated to be effective at increasing vaccination coverage. Conduct a systematic review to examine the costs of interventions designed to increase vaccination coverage among children and adolescents in the United States. PubMed, EconLit, Embase, and Cochrane. Peer-reviewed articles from January 1, 2009 to August 31, 2019. Studies were identified with systematic searches of the literature, reviewed for inclusion criteria, abstracted for data on intervention, target population, costs, and risk of bias. Cost measures were reported as costs per child in the target population, costs per vaccinated child, incremental costs per vaccinated child, and costs per vaccine dose administered. Results were stratified by intervention type, vaccine, and age group. Thirty-seven studies were identified for full-text review. Across all interventions and age groups, the cost per child ranged from $0.10 to $537.38, and the incremental cost per vaccinated child ranged from $6.52 to $5,098.57. Provider assessment and feedback interventions had the lowest (median) cost per child ($0.17) and a healthcare system-based combined intervention with multiple components had the lowest (median) incremental cost per vaccinated child ($26.65). A community-based combined intervention with multiple components had the highest median cost per child ($537.38) and the highest median incremental cost per vaccinated child ($5,098.57). A small number of included intervention types and inconsistent cost definition. There is substantial variability in the costs of CPSTF-recommended interventions. [ABSTRACT FROM AUTHOR]

Introduction: Improving the utilization of preventive care among adolescents is important for achieving individual-level and population-level health goals. The Healthcare Effectiveness Data and Information Set reports data submitted by managed care health plans, capturing a large number of individuals in the U.S.Methods: Using Healthcare Effectiveness Data and Information Set from 2018, mean performance levels were calculated for 5 preventive care measures among adolescents. Differences in performance between states that use Healthcare Effectiveness Data and Information Set or Health Plan Accreditation and those that use neither were estimated. Analysis was conducted in January-July 2020.Results: The sample included data from 39 states, with 32 that use Healthcare Effectiveness Data and Information Set or Health Plan Accreditation and 7 that do not. Adolescent vaccination coverage was 28% for the complete human papillomavirus series, 81% for meningococcal, and 88% for tetanus, diphtheria, and acellular pertussis. Access to a primary care practitioner (a 2-year measure) was 91%, and well-care visits (a 1-year measure) were 50%. When compared with states that do not use Healthcare Effectiveness Data and Information Set or Health Plan Accreditation, the mean performance of states that used either Healthcare Effectiveness Data and Information Set or Health Plan Accreditation was statistically significantly higher for 4 of the 5 assessed measures.Conclusions: Healthcare Effectiveness Data and Information Set measures can help public health officials to monitor progress toward health goals, such as Healthy People 2020, and identify poorly performing health plans and types of preventive services in greatest need of improvement. States using Healthcare Effectiveness Data and Information Set or Health Plan Accreditation were associated with better performance in some adolescent measures, which suggests that health plan accountability may have a role in achieving health outcomes and could be an important area for future research. [ABSTRACT FROM AUTHOR]

• Both refrigerator and freezer compartments of household-grade combination storage units do not perform as well as household-grade stand-alone or purpose-built storage units. • Performance estimates support current vaccine storage and handling guidelines to minimize the use of household-grade combination storage units, particularly the freezer compartments. To evaluate the ability of different types of vaccine storage units to maintain appropriate temperatures for the storage of vaccines and to characterize deviations from recommended temperatures. Continuous temperature monitoring devices, or digital data loggers, from vaccine providers who participated in a continuous temperature monitoring pilot project. We computed descriptive statistics on the percentage of runtime with an out-of-range temperature, or excursion, for different storage unit types (freezers and refrigerators) and for different storage unit grades (household-grade combination, household-grade stand alone, and purpose-built or pharmaceutical grade). We developed frequency histograms for the percentage of storage unit runtime outside of the normal range. We plotted the duration and temperature extrema for identified excursions. Analyses were stratified by storage unit type and grade. Household-grade combination units underperformed relative to household-grade stand-alone and purpose-built units. Among refrigerators, household-grade combination units operated in the normal temperature range an average of 98.9% of their observed runtime, which was lower than 99.4% (p value = 0.038) for household-grade stand-alone and 99.9% (p value < 0.001) for purpose-built units. Among freezers, household-grade combination units operated in the normal temperature range an average of 95.0% of their observed runtime, which was lower than 99.3% (p value < 0.001) for household-grade stand-alone units and 99.7% (p value < 0.001) for purpose-built units. These findings, in particular the underperformance of household-grade combination units relative to household-grade stand-alone and purpose-built units, support current CDC recommendations to avoid the use of household-grade combination storage units when possible. [ABSTRACT FROM AUTHOR]

Abstract Advanced cognitive capabilities enable humans to solve even complex tasks by representing and processing internal models of manipulation actions and their effects. Consequently, humans are able to plan the effect of their motions before execution and validate the performance afterwards. In this work, we derive an analog approach for robotic wiping actions which are fundamental for some of the most frequent household chores including vacuuming the floor, sweeping dust, and cleaning windows. We describe wiping actions and their effects based on a qualitative particle distribution model. This representation enables a robot to plan goal-oriented wiping motions for the prototypical wiping actions of absorbing, collecting and skimming. The particle representation is utilized to simulate the task outcome before execution and infer the real performance afterwards based on haptic perception. This way, the robot is able to estimate the task performance and schedule additional motions if necessary. We evaluate our methods in simulated scenarios, as well as in real experiments with the humanoid service robot Rollin' Justin. [ABSTRACT FROM AUTHOR]

Abstract Silica nanoparticles are widely used platform materials for the immobilization of proteins to realize applications in biomedicine and biotechnology. We here report on the use of a highly delicate protein for the systematic evaluation of routes for the surface modification of multifunctional silica nanoparticles. To investigate how surface immobilization methods affect the functionality of surface-bound proteins, we constructed a novel fusion protein, dubbed FlipHOB, that combines the glucose sensor protein FLIP with a variant of the commercially-available self-ligating Halo-tag. As indicated by the spectroscopic properties and sensing capabilities of FlipHOB, the oriented immobilization of this protein through its HOB tag domain or DNA-directed immobilization were superior over the non-directional statistical immobilization via glutardialdehyde-mediated cross-coupling. Immobilization through double-stranded DNA bridges also allows for the triggered disassembly of FlipHOB nanosensors and the controlled recovery of the sensor protein. We demonstrate that the nanosensors are functional in in vitro settings and can be used for imaging in vivo. We believe that our results show generic strategies and provide essential guidelines for the development of protein-based nanoparticle sensors for applications in the life sciences. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Highlights • Published studies report favorable cost-effectiveness profiles for adult vaccinations. • Some influenza, pneumococcal, and Td/Tdap evaluations report cost-savings. • Adult vaccines can prevent substantial morbidity, disability and death. Abstract Background Coverage levels for many recommended adult vaccinations are low. The cost-effectiveness research literature on adult vaccinations has not been synthesized in recent years, which may contribute to low awareness of the value of adult vaccinations and to their under-utilization. We assessed research literature since 1980 to summarize economic evidence for adult vaccinations included on the adult immunization schedule. Methods We searched PubMed, EMBASE, EconLit, and Cochrane Library from 1980 to 2016 and identified economic evaluation or cost-effectiveness analysis for vaccinations targeting persons aged ≥18 years in the U.S. or Canada. After excluding records based on title and abstract reviews, the remaining publications had a full-text review from two independent reviewers, who extracted economic values that compared vaccination to "no vaccination" scenarios. Results The systematic searches yielded 1688 publications. After removing duplicates, off-topic publications, and publications without a "no vaccination" comparison, 78 publications were included in the final analysis (influenza = 25, pneumococcal = 18, human papillomavirus = 9, herpes zoster = 7, tetanus-diphtheria-pertussis = 9, hepatitis B = 9, and multiple vaccines = 1). Among outcomes assessing age-based vaccinations, the percent indicating cost-savings was 56% for influenza, 31% for pneumococcal, and 23% for tetanus-diphtheria-pertussis vaccinations. Among age-based vaccination outcomes reporting $/QALY, the percent of outcomes indicating a cost per QALY of ≤$100,000 was 100% for influenza, 100% for pneumococcal, 69% for human papillomavirus, 71% for herpes zoster, and 50% for tetanus-diphtheria-pertussis vaccinations. Conclusions The majority of published studies report favorable cost-effectiveness profiles for adult vaccinations, which supports efforts to improve the implementation of adult vaccination recommendations. [ABSTRACT FROM AUTHOR]

Highlights • Overall, studies were transparent, e.g. inclusion of a clearly stated study perspective. • For consistency, we examined the frequency of particular model characteristics. • We find opportunity for improvement in costs included and sensitivity analyses. • We find these presentations contribute beneficially to the ACIP policy-making process. Abstract We identified 16 Advisory Committee on Immunization Practices (ACIP) presentations from 2012 to 2016 that indicated 'cost' or 'economic' content. Characteristics were reviewed, abstracted, and tabulated to quantify and assess the transparency and consistency of economic evidence presented to ACIP. To assess transparency, we documented if each study identified author affiliation, conflicts of interest, study limitations, a clearly described model structure and other model attributes. To assess consistency, we identified the frequency of specific modeling choices, including the perspective, types of health outcomes considered, inclusion of specific types of costs, discount rate, and use of sensitivity analyses. Our results indicate that the content in these presentations appear to be transparent overall and consistent in several important areas, such as study perspective and health outcomes. However, we find the inclusion of particular types of direct costs, indirect costs, program costs, and sensitivity analyses are areas that could improve consistency. [ABSTRACT FROM AUTHOR]

Background Vaccination coverage is typically measured as the proportion of individuals who have received recommended vaccine doses by the date of assessment. This approach does not provide information about receipt of vaccines by the recommended age, which is critical for ensuring optimal protection from vaccine-preventable diseases (VPDs). Objective To assess vaccination timeliness in the Federated States of Micronesia (FSM), and the projected impact of suboptimal vaccination in the event of an outbreak. Methods Timeliness of the 4 th dose of diphtheria, tetanus, and acellular pertussis vaccine (DTaP) and 1 st dose of measles, mumps, and rubella vaccine (MMR) among children 24–35 months was assessed in FSM. Both doses are defined as on time if administered from 361 through 395 days in age. Timeliness was calculated by one-way frequency analysis, and dose delays, measured in months after recommended age, were described using inverse Kaplan-Meier analysis. A time-series susceptible-exposed-infected-recovery (TSEIR) model simulated measles outbreaks in populations with on time and late vaccination. Results Total coverage for the 4 th dose of DTaP ranged from 36.6% to 98.8%, and for the 1 st dose of MMR ranged from 80.9% to 100.0% across FSM states. On time coverage for the 4 th dose of DTaP ranged from 3.2% to 52.3%, and for the 1 st dose of MMR ranged from 21.1% to 66.9%. Maximum and median dose delays beyond the recommended age varied by state. TSEIR models predicted 10.8–13.7% increases in measles cases during an outbreak based on these delays. Conclusions In each of the FSM states, a substantial proportion of children received DTaP and MMR doses outside the recommended timeframe. Children who receive vaccinations later than recommended remain susceptible to VPDs during the period they remain unvaccinated, which may have a substantial impact on health systems during an outbreak. Immunization programs should consider vaccination timeliness in addition to coverage as a measure of susceptibility to VPDs in young children. [ABSTRACT FROM AUTHOR]

We present the results of an investigation of the prompt-gamma emission from an interaction of a proton beam with phantom materials. Measurements were conducted with a novel setup allowing the precise selection of the investigated depth in the phantom, featuring three different materials composed of carbon, oxygen and hydrogen. We studied two beam energies of 70.54 and 130.87 MeV and two detection angles: 90° and 120°. The results are presented in form of profiles of the prompt-gamma yield as a function of depth. In the analysis we focused on the transitions with the largest cross sections: 12 C 4.44 → g.s. and 16 O 6.13 → g.s. . We compare the profiles obtained under various irradiation conditions, with emphasis on the shape of the distal fall-off. The results are also compared to calculations including different cross-section models. They are in agreement with the model exploiting published cross-section data, but the comparison with the Talys model shows discrepancies. [ABSTRACT FROM AUTHOR]

OX40 is a member of the tumor necrosis factor (TNF) receptor family and a potent co-stimulatory pathway that when triggered can enhance T-cell memory, proliferation and anti-tumor activity in patients with metastatic cancer. Ongoing investigations at our institution have demonstrated that OX40 expressing T cells are found in abundance in the tumors of patients with advanced stage head and neck squamous cell carcinoma (HNSCC). This has led to the initiation of human clinical trials investigating OX40-directed therapy for patients with HNSCC in both the metastatic and curative setting. The purpose of this review is to explore what is known about OX40 signaling and discuss how this pathway potentially can be modulated to improve outcome for patients with HNSCC. [ABSTRACT FROM AUTHOR]

Conservationists recognise that remote sensing can make a substantial contribution to their effort to monitor the environment to better understand and reduce the impact of anthropogenic activities. However, often it is perceived that the needs of the terrestrial conservation community are not being met by the remote sensing community. The first step to bridging this gap is the improved communication between both communities, and the compilation of a list of needs and best practises for conservation applications. Here we review five recent workshops that help to answer the broad question “What conservationists need and want from remote sensing”. We identify recurring requests, and consider potential ways forward for the conservation and remote sensing communities to start to deliver data or tools to address these needs. [ABSTRACT FROM AUTHOR]

Global virtual teams are examined.

Abstract: This paper examines optimal input allocations in the context of a seawater desalination reverse osmosis (SWRO) system used to produce municipal water. The objective of this research is to better understand the effects on the total costs and the input portfolio of a SWRO system from changes in water quality, daily operations schedule, and input prices. A cost-minimization model is developed, a production function is estimated, and sensitivity analyses are conducted. The results indicate that lower total system costs are associated with warm-weather water quality parameters and lower input prices. Conditional findings indicate a range of system characteristics that yield, in optimality, moderate levels of both capital and hourly operations. This finding is due to the substitution between capital and daily-hours of operation. Additionally, an interruptible (or off-peak) electrical power supply regime is evaluated and determined to contribute to lower system costs under realistic conditions. [Copyright &y& Elsevier]

Abstract: This paper provides a theoretical review of self-rated competences questionnaires. This topic is influenced by the ongoing world-wide reform of higher education, which has led to a focus on the learner outcomes of higher education. Consequently, questionnaires on self-rated competences have increasingly been employed. However, self-ratings are often criticised for their lack of validity. Our intention is to outline some principles of good questionnaire design and to use these principles to contrast questionnaires on self-rated competences. We begin with an overview of research about questionnaire design. Then we introduce seven questionnaires and portray them in terms of their design characteristics. A comparison reveals some significant points: biographical data need to be handled more carefully, and there is an overuse of vague and abstract language. On the positive side, all of the questionnaires that were examined provide reliable sub-scales covering important facets of competences. [Copyright &y& Elsevier]

The standard definition of a prolonged pregnancy is 42 completed weeks of gestation. The incidence of prolonged pregnancy varies depending on the criteria used to define gestational age at birth. It is estimated that 4 to 19% of pregnancies reach or exceed 42 weeks gestation. Several studies that have used very large computerized databases of well-dated pregnancies provided insights into the incidence and nature of adverse perinatal outcome such as an increased fetal and neonatal mortality as well as increased fetal and maternal morbidity in prolonged pregnancy. Fetal surveillance may be used in an attempt to observe the prolonged pregnancy while awaiting the onset of spontaneous labor. This article reviews the different methodologies and protocols for fetal surveillance in prolonged pregnancies. On the one hand, false-positive tests commonly lead to unnecessary interventions that are potentially hazardous to the gravida. On the other hand, to date, no program of fetal testing has been shown to completely eliminate the risk of stillbirth. [Copyright &y& Elsevier]

The IκB-Kinase (IKK) complex is a multisubunit protein complex crucial for signal-induced phosphorylation of the 1κB proteins and thus controls the activity of the transcription factor NF-κB. Besides the two kinases IKKα and IKKβ, the IKK complex contains NEMO/IKKγ, an additional subunit with regulatory and adaptor functions. NEMO not only confers structural stability to the IKK complex but also participates in the activation process of the IKK complex by linking the IKK subunits to upstream activators. In this study we analyze the IKKβ-mediated phosphorylation of the IKK-binding domain of NEMO. In vitro, IKKβ phosphorylates three serine residues in the domain of NEMO at positions 43,68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the IKK-binding domain plays an essential role for the formation and the function of the IKK complex. Thus, Ser68 phosphorylation attenuates the amino-terminal dimerization of NEMO as well as the IKKβ-NEMO interaction. In contrast, the NEMO-IKKα interaction was only mildly affected by the phosphorylation of Ser68. However, functional analysis revealed that Ser68 phosphorylation primarily affects the activity of IKKα. Furthermore, in complementation experiments of NEMO-deficient murine embryonic fibroblasts, a S68A-NEMO mutant enhanced, whereas a S68E mutant decreased, TNF-α-induced NF-κB activity, thus emphasizing the inhibitory role of the Ser68 phosphorylation on the signal-induced NF-κB activity. Finally, we provide evidence that the protein phosphatase PP2A is involved in the regulation of the Ser68-based mechanism. In summary, we provide evidence for a signal-induced phosphorylation-dependent alteration of the IKK complex emphasizing the dynamic nature of this multisubunit kinase complex. [ABSTRACT FROM AUTHOR]

Abstract: Toponym resolution is the task of linking place name instances in a text with spatial footprints, given the context in which they occur. Whereas a lot of work on the evaluation of temporal resolution is ongoing (e.g. [Setzer, A., & Gaizauskas, R. (2000). On the importance of annotating temporal event–event relations in text. In LREC 2000 Workshop on annotation standards for temporal information in natural language, Vol. 3 (pp. 1281–1286). Athens, Greece]), to date no reference resource is available to evaluate competing algorithms for toponym resolution. It is thus argued that a shareable, reusable evaluation resource is necessary. To this end, a new proposal for the markup of toponyms in text corpora with their referents and an associated tool data methodology are presented: the Toponym Resolution Markup Language (TRML) is an XML-based markup language, and TAME, the toponym annotation markup editor, is a tool that implements it. A novel evaluation resource is described which comprises a large-scale reference gazetteer server and a human-annotated news corpus in which toponyms are associated with latitude/longitude coordinates of the location they refer to. The reliability of the annotation task is established by determining inter-annotator agreement of the human annotators. [Copyright &y& Elsevier]

Few studies have examined the influence of the family on the course of chronic illness in African-Americans. We explore the relationship between family structure, defined as marital status and household composition, and patient survival. Patient gender was examined as a possible moderator in this relationship. Using data from a survey of 476 African-American end-stage renal disease (ESRD) patients, a significant association between household composition and patient survival was found. Results from Cox proportional hazards model, controlling for patient age, indicated that patients who live in 'complex' households (i.e. those with a partner and/or others) are at greater risk for shortened survival as compared to those who live alone or with a spouse/partner (p < 0.05). When we examined whether patient gender moderates this relationship, female patients who live in these households were found to be at 2 times greater risk for shortened survival (p < 0.01) than female patients who live alone or with their spouse/ partner only. Family structure was not significantly associated with survival in male patients. Discussion and implications of findings are addressed. [ABSTRACT FROM AUTHOR]

Furan and 2-methylfuran (2-MF) can form during food processing and accumulate in foods at various concentrations depending on processing technology and beverage/meal preparation methods applied prior to consumption. Here, we report a controlled dosimetry study with 20 volunteers (10 male, 10 female) to monitor dietary furan/2-MF exposure. The volunteers followed an eleven-day furan/2-MF-restricted diet in which they consumed freshly prepared coffee brew containing known amounts of furan and 2-MF on two separate occasions (250 mL and 500 mL on days 4 and 8, respectively). Urine was collected over the whole study period and analyzed for key metabolites derived from the primary oxidative furan metabolite cis -2-butene-1,4-dial (BDA) (i.e., Lys-BDA, AcLys-BDA and cyclic GSH-BDA) and the primary 2-MF metabolite acetylacrolein (AcA, 4-oxo-pent-2-enal) (i.e., Lys-AcA and AcLys-AcA). A previously established stable isotope dilution analysis (SIDA) method was utilized. Excretion kinetics revealed two peaks (at 0–2 and 24–36 h) for AcLys-BDA, Lys-BDA, AcLysAcA and LysAcA, whereas GSH-BDA showed a single peak. Notably, women on average excreted the metabolite GSH-BDA slightly faster than men, indicating gender differences. Overall, the study provided further insights into the spectrum of possible biomarkers of furan and 2-methyfuran metabolites occurring in the urine of volunteers after coffee consumption. [Display omitted] • We have performed a duplicate diet intervention study. • Volunteers consumed a furan/2-methylfuran reduced diet. • Urine samples and meal duplicates were collected. • Furan/2-methylfuran were analyzed in meals and coffee beverage. • Biomarkers of excretion were identified and quantitated. [ABSTRACT FROM AUTHOR]

Objectives: To prospectively assess rates and detailed predictors of morbidity and mortality among HIV-exposed uninfected children and HIV-unexposed children in Botswana in a more recent era.Study Design: We enrolled HIV-infected and HIV-uninfected mothers and their children in the prospective observational Tshipidi study at 2 sites (1 city and 1 village) in Botswana from May 2010-July 2012. Live-born children and their mothers were followed for 24 months postpartum. Detailed sociodemographic data, health, and psychosocial characteristics were collected at baseline and prospectively, and health outcomes ascertained. Mothers chose infant feeding method with counselling.Results: A total of 893 live-born HIV-uninfected children (436 HIV-exposed uninfected, 457 HIV-unexposed) were followed. HIV-infected mothers had a median CD4 count of 410 cells/mm3, 32% took 3-drug antiretroviral treatment during pregnancy, 67% took only zidovudine, and 1% took <2 weeks of any antiretrovirals antepartum. Twenty four-month vital status was available for 888 (99.4%) children. HIV-exposed uninfected children had a significantly higher risk of death compared with children of HIV-uninfected mothers (5.0% vs 1.8%) (adjusted hazard ratio 3.27, 95% CI 1.44-7.40). High collinearity between maternal HIV status and child feeding method precluded analysis of these factors as independent predictors of mortality. Preterm birth, low birth weight, and congenital anomaly were also associated with mortality (in separate analyses), but maternal socioeconomic factors, depression, substance use, and social support were not significant predictors.Conclusions: The strongest predictors of 24-month mortality among children in Botswana were HIV exposure and formula feeding, although the relative contribution of these factors to child health could not be separated. [ABSTRACT FROM AUTHOR]

Summary Despite significant progress in hepatitis C virus (HCV) protease inhibitor (PI) drug design, resistance remains a problem causing treatment failure. Double-substitution variants, notably Y56H/D168A, have emerged in patients who fail therapy with a PI-containing regimen. The resistance conferred by Asp168 substitutions has been well characterized and avoided in newer inhibitors. However, an additional mutation at Tyr56 confers resistance to even the most robust inhibitors. Here, we elucidate the molecular mechanisms of resistance for the Y56H/D168A variant against grazoprevir (and four analogs), paritaprevir, and danoprevir through inhibition assays, co-crystal structures, and molecular dynamics simulations. The PIs' susceptibility to Y56H/D168A varies, with those stacking on the catalytic His57 losing the most potency. For such inhibitors, the Y56H substitution disrupts favorable stacking interactions with the neighboring catalytic His57. This indirect mechanism of resistance threatens to cause multi-PI failure as all HCV PIs in clinical development rely on interactions with the catalytic triad. Graphical Abstract Highlights • Y56H/D168A variant causes high levels of resistance • The two mutations have interdependency in conferring resistance • Y56H causes disruption of stacking interactions with the catalytic His57 • Double mutations may confer cross-resistance to current PIs in clinical development The molecular mechanism of resistance for HCV NS3/4A protease inhibitors (PIs) against the clinically emerging Y56H/D168A variant is described by determining crystal structures of this double mutant and Y56H variant. Substitution at the neighboring Y56 disrupted critical stacking interactions with the catalytic His57, revealing a structural mechanism that threatens cross-resistance. [ABSTRACT FROM AUTHOR]