Bacterial factors required for Streptococcus pneumoniae coinfection with influenza A virus.

BACKGROUND: Streptococcus pneumoniae is a common cause of post-influenza secondary bacterial infection, which results in excessive morbidity and mortality. Although 13-valent pneumococcal conjugate vaccine (PCV13) vaccination programs have decreased the incidence of pneumococcal pneumonia, PCV13 failed to prevent serotype 3 pneumococcal disease as effectively as other vaccine serotypes. We aimed to investigate the mechanisms underlying the co-pathogenesis of influenza virus and serotype 3 pneumococci. METHODS: We carried out a genome-wide screening of a serotype 3 S. pneumoniae transposon insertion mutant library in a mouse model of coinfection with influenza A virus (IAV) to identify the bacterial factors required for this synergism. RESULTS: Direct, high-throughput sequencing of transposon insertion sites identified 24 genes required for both coinfection and bacterial infection alone. Targeted deletion of the putative aminotransferase (PA) gene decreased bacterial growth, which was restored by supplementation with methionine. The bacterial burden in a coinfection with the PA gene deletion mutant and IAV in the lung was lower than that in a coinfection with wild-type pneumococcus and IAV, but was significantly higher than that in an infection with the PA gene deletion mutant alone. These data suggest that IAV infection alters host metabolism to benefit pneumococcal fitness and confer higher susceptibility to pneumococcal infection. We further demonstrated that bacterial growth was increased by supplementation with methionine or IAV-infected mouse lung homogenates. CONCLUSIONS: The data indicates that modulation of host metabolism during IAV infection may serve as a potential therapeutic intervention against secondary bacterial infections caused by serotype 3 pneumococci during IAV outbreaks in the future.

Romosozumab in postmenopausal women with low bone mineral density.

BACKGROUND: Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. The monoclonal antibody romosozumab binds to sclerostin and increases bone formation. METHODS: In a phase 2, multicenter, international, randomized, placebo-controlled, parallel-group, eight-group study, we evaluated the efficacy and safety of romosozumab over a 12-month period in 419 postmenopausal women, 55 to 85 years of age, who had low bone mineral density (a T score of -2.0 or less at the lumbar spine, total hip, or femoral neck and -3.5 or more at each of the three sites). Participants were randomly assigned to receive subcutaneous romosozumab monthly (at a dose of 70 mg, 140 mg, or 210 mg) or every 3 months (140 mg or 210 mg), subcutaneous placebo, or an open-label active comparator--oral alendronate (70 mg weekly) or subcutaneous teriparatide (20 µg daily). The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Secondary end points included percentage changes in bone mineral density at other sites and in markers of bone turnover. RESULTS: All dose levels of romosozumab were associated with significant increases in bone mineral density at the lumbar spine, including an increase of 11.3% with the 210-mg monthly dose, as compared with a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide. Romosozumab was also associated with large increases in bone mineral density at the total hip and femoral neck, as well as transitory increases in bone-formation markers and sustained decreases in a bone-resorption marker. Except for mild, generally nonrecurring injection-site reactions with romosozumab, adverse events were similar among groups. CONCLUSIONS: In postmenopausal women with low bone mass, romosozumab was associated with increased bone mineral density and bone formation and with decreased bone resorption. (Funded by Amgen and UCB Pharma; ClinicalTrials.gov number, NCT00896532.).

A PDMS-based cylindrical hybrid lens for enhanced fluorescence detection in microfluidic systems.

Microfluidic systems based on fluorescence detection have been developed and applied for many biological and chemical applications. Because of the tiny amount of sample in the system; the induced fluorescence can be weak. Therefore, most microfluidic systems deploy multiple optical components or sophisticated equipment to enhance the efficiency of fluorescence detection. However, these strategies encounter common issues of complex manufacturing processes and high costs. In this study; a miniature, cylindrical and hybrid lens made of polydimethylsiloxane (PDMS) to improve the fluorescence detection in microfluidic systems is proposed. The hybrid lens integrates a laser focusing lens and a fluorescence collecting lens to achieve dual functions and simplify optical setup. Moreover, PDMS has advantages of low-cost and straightforward fabrication compared with conventional optical components. The performance of the proposed lens is first examined with two fluorescent dyes and the results show that the lens provides satisfactory enhancement for fluorescence detection of Rhodamine 6G and Nile Red. The overall increments in collected fluorescence signal and detection sensitivity are more than 220% of those without lens, and the detection limits of Rhodamine 6G and Nile red are lowered to 0.01 µg/mL and 0.05 µg/mL, respectively. The hybrid lens is further applied to the detection of Nile red-labeled Chlorella vulgaris cells and it increases both signal intensity and detection sensitivity by more than 520%. The proposed hybrid lens also dramatically reduces the variation in detected signal caused by the deviation in incident angle of excitation light.

Genomic analysis of penicillin-binding proteins and recombination events in an emerging amoxicillin- and meropenem-resistant PMEN3 (Spain9V-3, ST156) variant in Taiwan and comparison with global descendants of this lineage.

From 2008 to 2020, the Taiwan National Notifiable Disease Surveillance System database demonstrated that the incidence of non-vaccine serotype 23A invasive pneumococcal disease (IPD) approximately doubled. In this study, 276 non-repetitive pneumococcal clinical isolates were collected from two medical centers in Taiwan between 2019 and 2021. Of these 267 pneumococci, 60 were serotype 23A. Among them, 50 (83%) of serotype 23A isolates belonged to the sequence type (ST) 166 variant of the Spain9V-3 clone. Pneumococcal 23A-ST166 isolates were collected to assess their evolutionary relationships using whole-genome sequencing. All 23A-ST166 isolates were resistant to amoxicillin and meropenem, and 96% harbored a novel combination of penicillin-binding proteins (PBPs) (1a:2b:2x):15:11:299, the newly identified PBP2x-299 in Taiwan. Transformation of the pbp1a, pbp2b, and pbp2x alleles into the ß-lactam-susceptible R6 strain revealed that PBP2x-299 and PBP2b-11 increased the MIC of ceftriaxone and meropenem by 16-fold, respectively. Prediction analysis of recombination sites in PMEN3 descendants (23A-ST166 in Taiwan, 35B-ST156 in the United States, and 11A-ST838/ST6521 in Europe) showed that adaptive evolution involved repeated, selectively favored convergent recombination in the capsular polysaccharide synthesis region, PBPs, murM, and folP genome sites. In the late 13-valent pneumococcal conjugate vaccine era, PMEN3 continuously displayed an evolutionary capacity for global dissemination and persistence, increasing IPD incidence, leading to an offset in the decrease of pneumococcal conjugate vaccine serotype-related diseases, and contributing to high antibiotic resistance. A clonal shift with a highly ß-lactam-resistant non-vaccine serotype 23A, from ST338 to ST166, increased in Taiwan. ST166 is a single-locus variant of the Spain9V-3 clone, which is also called the PMEN3 lineage. All 23A-ST166 isolates, in this study, were resistant to amoxicillin and meropenem, and 96% harbored a novel combination of penicillin-binding proteins (PBPs) (1a:2b:2x):15:11:299. PBP2x-299 and PBP2b-11 contributed to the increasing MIC of ceftriaxone and meropenem, respectively. Prediction analysis of recombination sites in PMEN3 descendants showed that adaptive evolution involved repeated, selectively favored convergent recombination in the capsular polysaccharide synthesis region, PBPs, murM, and folP genome sites. In the late 13-valent pneumococcal conjugate vaccine era, PMEN3 continuously displays the evolutionary capacity for dissemination, leading to an offset in the decrease of pneumococcal conjugate vaccine serotype-related diseases and contributing to high antibiotic resistance.

Romosozumab Enhances Vertebral Bone Structure in Women With Low Bone Density.

Romosozumab monoclonal antibody treatment works by binding sclerostin and causing rapid stimulation of bone formation while decreasing bone resorption. The location and local magnitude of vertebral bone accrual by romosozumab and how it compares to teriparatide remains to be investigated. Here we analyzed the data from a study collecting lumbar computed tomography (CT) spine scans at enrollment and 12 months post-treatment with romosozumab (210 mg sc monthly, n = 17), open-label daily teriparatide (20 µg sc, n = 19), or placebo (sc monthly, n = 20). For each of the 56 women, cortical thickness (Ct.Th), endocortical thickness (Ec.Th), cortical bone mineral density (Ct.bone mineral density (BMD)), cancellous BMD (Cn.BMD), and cortical mass surface density (CMSD) were measured across the first lumbar vertebral surface. In addition, color maps of the changes in the lumbar vertebrae structure were statistically analyzed and then visualized on the bone surface. At 12 months, romosozumab improved all parameters significantly over placebo and resulted in a mean vertebral Ct.Th increase of 10.3% versus 4.3% for teriparatide, an Ec.Th increase of 137.6% versus 47.5% for teriparatide, a Ct.BMD increase of 2.1% versus a -0.1% decrease for teriparatide, and a CMSD increase of 12.4% versus 3.8% for teriparatide. For all these measurements, the differences between romosozumab and teriparatide were statistically significant (p < 0.05). There was no significant difference between the romosozumab-associated Cn.BMD gains of 22.2% versus 18.1% for teriparatide, but both were significantly greater compared with the change in the placebo group (-4.6%, p < 0.05). Cortical maps showed the topographical locations of the increase in bone in fracture-prone areas of the vertebral shell, walls, and endplates. This study confirms widespread vertebral bone accrual with romosozumab or teriparatide treatment and provides new insights into how the rapid prevention of vertebral fractures is achieved in women with osteoporosis using these anabolic agents. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

A retrospective study to investigate racial and ethnic variations in the treatment of psoriasis with etanercept.

OBJECTIVES: Psoriasis is a chronic inflammatory condition that occurs worldwide; however, few studies have examined this condition in non-Caucasian populations. The purpose of this study was to investigate racial/ethnic differences in demographics, psoriasis severity, efficacy, safety, and health-related quality of life in patients treated with etanercept using data from the Etanercept Assessment of Safety and Effectiveness (EASE) in Psoriasis trial. PATIENTS AND METHODS: This is an investigator-initiated evaluation of data from the EASE study. RESULTS: The study included 2511 patients (Caucasian n=2164; Hispanic/Latino n=173; African American n=98; Asian n=76). Although baseline Physicians' Global Assessment (PGA) scores were similar, we found significant baseline differences in patient characteristics, prior therapy, percentage of body surface area (%BSA) affected and Dermatology Life Quality Index (DLQI) scores between the groups. At baseline, the Caucasian group had the longest disease duration (19 years), but the lowest percentage of BSA involvement (28%). The Asian group had the highest percentage of BSA involvement (41%). Baseline DLQI score was lowest for Caucasians (12.0) and highest for Hispanic/Latinos (14.6). At week 12, response to therapy was similar in all ethnic/racial groups. The BSA involvement was reduced by more than 50 percent for all groups, but remained significantly higher for the Asian group (17%) than for the Caucasian (13%; P=0.0105) and African American groups (13%; P=0.0461). At week 12, the mean Asian DLQI score of 5.2 was significantly higher (worse) than scores for the Caucasian (3.5; P=0.0001) and Hispanic/Latino groups (3.8; P=0.028). For both percentage of BSA and DLQI, differences among racial/ethnic groups in the percentage improvement from baseline were not statistically significant. Adverse event rates were similar for the groups. CONCLUSIONS: Patient characteristics at enrollment differed among ethnic groups, but no significant racial/ethnic differences were found in safety or efficacy of etanercept. However, racial/ethnic differences in the impact of psoriasis on quality of life were observed.

A randomized controlled trial of low-dose hormone therapy on myocardial ischemia in postmenopausal women with no obstructive coronary artery disease: results from the National Institutes of Health/National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: Compared with men, women have more evidence of myocardial ischemia with no obstructive coronary artery disease. Although low endogenous estrogen levels are associated with endothelial dysfunction, the role of low-dose hormone therapy has not been fully evaluated. We postulate that a 12-week duration of low-dose hormone replacement therapy is associated with myocardial ischemia and endothelial dysfunction. METHODS AND RESULTS: Using a multicenter, randomized, placebo-controlled design, subjects were randomized to receive either 1 mg norethindrone/10 microg ethinyl estradiol or placebo for 12 weeks. Chest pain and menopausal symptoms, cardiac magnetic resonance spectroscopy, brachial artery reactivity, exercise stress testing, and psychosocial questionnaires were evaluated at baseline and exit. Recruitment was closed prematurely because of failure to recruit after publication of the Women's Health Initiative hormone trial. Of the 35 women who completed the study, there was less frequent chest pain in the treatment group compared with the placebo group (P = .02) at exit. Women taking 1 mg norethindrone/10 microg ethinyl estradiol also had significantly fewer hot flashes/night sweats (P = .003), less avoidance of intimacy (P = .05), and borderline differences in sexual desire and vaginal dryness (P = .06). There were no differences in magnetic resonance spectroscopy, brachial artery reactivity, compliance, or reported adverse events between the groups. CONCLUSIONS: These data suggest that low-dose hormone therapy improved chest pain symptoms, menopausal symptoms, and quality of life, but did not improve ischemia or endothelial dysfunction. Given that it was not possible to enroll the prespecified sample size, these results should not be considered definitive.

Flavanone and diphenylpropane glycosides and glycosidic acyl esters from Viscum articulatum.

Seven new compounds including three flavanone glycosides, visartisides A-C (1-3), three glycoside acyl esters, visartisides D-F (4-6), and one diphenylpropane glycoside, (4'-hydroxy-2',3',6',3''-tetramethoxy-1,3-diphenylpropane)-4''-O-beta-d-glucopyranoside (7), along with four known flavanone glycosides (8-11) were isolated from the leaves and stems of Viscum articulatum. The structure elucidation of 1-7 was based on spectroscopic data analysis. Biological evaluation showed that 1, 2, and 10 exhibited antioxidant activity using a DPPH method and that compounds 1, 3, and 11 were active in a lipopolysaccharide-induced nitric oxide assay.

Numerical analysis of local non-equilibrium heat transfer in layered spherical tissue during magnetic hyperthermia.

A solid multi-layered concentric sphere with Gaussian space source is considered as the tissue model for magnetic hyperthermia treatment. The generalized dual-phase-lag model of bioheat transfer is used to describe the behavior of heat transport in tissue in the hyperthermia treatment process for accounting the local non-equilibrium effect. The effects of blood perfusion with the transient temperature are included in the tissue model. The hybrid numerical scheme based on Laplace transform, change of variables, and the modified discretization technique is extended to solve the present problem. The analytical solution for constant heat generation in the inner sphere is presented and evidences the accuracy and rationality of the present numerical results. In an ideal hyperthermia treatment, all the diseased tissues should be selectively heated without affecting any healthy tissue. Attempting to achieve the ideal temperature distribution, the thermal dose is estimated at the specified condition. The corresponding thermal efficacy of tumor damage has also been assessed based on the Arrenius equation.

Synthetic Naphthofuranquinone Derivatives Are Effective in Eliminating Drug-Resistant Candida albicans in Hyphal, Biofilm, and Intracellular Forms: An Application for Skin-Infection Treatment.

Candida albicans is the most common cause of fungal infection. The emergence of drug resistance leads to the need for novel antifungal agents. We aimed to design naphthofuranquinone analogs to treat drug-resistant C. albicans for topical application on cutaneous candidiasis. The time-killing response, agar diffusion, and live/dead assay of the antifungal activity were estimated against 5-fluorocytosine (5-FC)- or fluconazole-resistant strains. A total of 14 naphthofuranquinones were compared for their antifungal potency. The lead compounds with hydroxyimino (TCH-1140) or O-acetyl oxime (TCH-1142) moieties were the most active agents identified, showing a minimum inhibitory concentration (MIC) of 1.5 and 1.2 µM, respectively. Both compounds were superior to 5-FC and fluconazole for killing planktonic fungi. Naphthofuranquinones efficiently diminished the microbes inside and outside the biofilm. TCH-1140 and TCH-1142 were delivered into C. albicans-infected keratinocytes to eradicate intracellular fungi. The compounds did not reduce the C. albicans burden inside the macrophages, but the naphthofuranquinones promoted the transition of fungi from the virulent hypha form to the yeast form. In the in vivo skin mycosis mouse model, topically applied 5-FC and TCH-1140 reduced the C. albicans load from 1.5 × 106 to 5.4 × 105 and 1.4 × 105 CFU, respectively. The infected abscess diameter was significantly decreased by TCH-1140 (3-4 mm) as compared to the control (8 mm). The disintegrated skin-barrier function induced by the fungi was recovered to the baseline by the compound. The data support the potential of TCH-1140 as a topical agent for treating drug-resistant C. albicans infection without causing skin irritation.

The Droplet-Size Effect Of Squalene@cetylpyridinium Chloride Nanoemulsions On Antimicrobial Potency Against Planktonic And Biofilm MRSA.

BACKGROUND: It is important to explore the interaction between antibacterial nanoparticles and microbes for understanding bactericidal activity and developing novel applications. It is possible that the nanoparticulate size can govern the antibacterial potency. PURPOSE: The purpose of this study was to evaluate the antimicrobial and antibiofilm properties of cetylpyridinium chloride (CPC)-decorated nanoemulsions against methicillin-resistant Staphylococcus aureus (MRSA). METHODS: The droplet size could be adjusted by varying the percentage of squalene, the main ingredient of the oily core. RESULTS: We fabricated cationic nanoemulsions of three different sizes, 55, 165, and 245 nm. The nanoemulsions showed greater storage stability than the self-assembled CPC micelles. The tested nanoemulsions exhibited more antimicrobial activity against Gram-positive bacteria than Gram-negative bacteria and fungi. The killing of MRSA was mainly induced by direct cell-membrane damage. This rupture led to the leakage of cytoplasmic DNA and proteins. The nanoemulsions might also degrade the DNA helix and disturb protein synthesis. The proteomic analysis indicated the significant downregulation of DNA-directed RNA polymerase (RNAP) subunits ß and ß'. The antibacterial effect of nanoemulsions increased with decreasing droplet size in the biofilm MRSA but not planktonic MRSA. The small-sized nanoemulsions had potent antibiofilm activity that showed a colony-forming unit (CFU) reduction of 10-fold compared with the control. The loss of total DNA concentration also negatively correlated with the nanoemulsion size. CONCLUSION: The present report established a foundation for the development of squalene@CPC nanosystems against drug-resistant S. aureus.

Multidimensional Developments and Free-Play Movement Tracking in 30- to 36-Month-Old Toddlers With Autism Spectrum Disorder Who Were Full Term.

BACKGROUND: Few studies have investigated multidimensional developments and free-play movement performance in toddlers with an early diagnosis of autism spectrum disorder (ASD). OBJECTIVE: This study compared cognitive, motor, and behavioral developments and free-play movement performance in toddlers with ASD who were full term (FT-ASD), toddlers who were full term and are typically developing (FT-TD), and toddlers who were born preterm and had a very low birth weight (VLBW-PT). DESIGN: This was a prospective cross-sectional study. METHODS: Forty-five 30- to 36-month-old age-matched toddlers were recruited and divided into FT-ASD, FT-TD, and VLBW-PT groups. Their developments were examined using the Mullen Scales of Early Learning; the Peabody Developmental Motor Scales, Second Edition; the Child Behavior Checklist for Ages 1.5 to 5; and the Repetitive Behavior Scale-Revised. In addition, the toddlers' free-play movements were tracked in laboratory settings using an automatic movement tracking system. RESULTS: Toddlers with FT-ASD exhibited lower cognitive and motor scores and a higher degree of behavioral problems compared with toddlers with FT-TD or VLBW-PT. Furthermore, the movement tracking data in a free-play setting revealed that toddlers with FT-ASD displayed a higher degree of turning velocity, a higher moving time, and a higher frequency of moving toward the peripheral region compared with toddlers with FT-TD or VLBW-PT. Moreover, several motor developmental and movement-tracking indicators were found to correlate with behavioral problems and cognitive scores in toddlers with FT-ASD. LIMITATIONS: The study results may have been affected by the small sample size, the cross-sectional design, and tracking only the whole body without subtle movements or segmental motions. CONCLUSIONS: The findings suggest varied aspects of co-occurring developmental conditions and movement-based problems in toddlers with FT-ASD. Using standardized and sensitive measures for the early assessment of perceptuo-motor impairments is necessary for timely early intervention for such toddlers.

Utilization of narrow-band ultraviolet light B therapy and etanercept for the treatment of psoriasis (UNITE): efficacy, safety, and patient-reported outcomes.

BACKGROUND: Moderate to severe psoriasis is a significant inflammatory disease that frequently requires systemic therapies to effectively treat the underlying disorder. Etanercept and narrow-band ultraviolet light B (NB-UVB) are widely used to treat this disease. OBJECTIVE: To evaluate the effectiveness, tolerability, and patient-reported outcomes of combination etanercept plus NB-UVB phototherapy in moderate to severe plaque psoriasis. METHODS: This 12-week, single-arm, open-label study evaluated the combination of etanercept 50 mg twice weekly and NB-UVB thrice weekly in 86 patients. The primary outcome measure was > or =75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75). Other measures included PASI 90, PASI 100, and the Dermatology Life Quality Index (DLQI). RESULTS: At week 12, 26.0% achieved PASI 100, 58.1% achieved PASI 90, and 84.9% of patients achieved PASI 75. Mean improvement from baseline in DLQI was 84.4%. No unexpected, untoward adverse events were noted. CONCLUSIONS: A 12-week course of etanercept plus NB-UVB phototherapy was well tolerated and produced clinically meaningful improvements in signs and symptoms of moderate to severe plaque psoriasis and in patient-reported outcomes. Further investigation of the safety and efficacy of the use of such combination for this indication in controlled clinical trials would be of interest.

An inverse problem of estimating the heat source in tapered optical fibers for scanning near-field optical microscopy.

A conjugate gradient method based on inverse algorithm is applied in this study to estimate the unknown space- and time-dependent heat source in aluminum-coated tapered optical fibers for scanning near-field optical microscopy, by reading the transient temperature data at the measurement positions. No prior information is available on the functional form of the unknown heat source in the present study; thus, it is classified as the function estimation in inverse calculation. The accuracy of the inverse analysis is examined by using the simulated exact and inexact temperature measurements. Results show that an excellent estimation on the heat source and temperature distributions in the tapered optical fiber can be obtained for all the test cases considered in this study.

An inverse problem in estimating the laser irradiance and thermal damage in laser-irradiated biological tissue with a dual-phase-lag model.

The aim of this study is to solve an inverse heat conduction problem to estimate the unknown time-dependent laser irradiance and thermal damage in laser-irradiated biological tissue from the temperature measurements taken within the tissue. The dual-phase-lag model is considered in the formulation of heat conduction equation. The inverse algorithm used in the study is based on the conjugate gradient method and the discrepancy principle. The effect of measurement errors and measurement locations on the estimation accuracy is also investigated. Two different examples of laser irradiance are discussed. Results show that the unknown laser irradiance and thermal damage can be predicted precisely by using the present approach for the test cases considered in this study.

Effects of Romosozumab Compared With Teriparatide on Bone Density and Mass at the Spine and Hip in Postmenopausal Women With Low Bone Mass.

Romosozumab, a monoclonal antibody that binds sclerostin, has a dual effect on bone by increasing bone formation and reducing bone resorption, and thus has favorable effects in both aspects of bone volume regulation. In a phase 2 study, romosozumab increased areal BMD at the lumbar spine and total hip as measured by DXA compared with placebo, alendronate, and teriparatide in postmenopausal women with low bone mass. In additional analyses from this international, randomized study, we now describe the effect of romosozumab on lumbar spine and hip volumetric BMD (vBMD) and BMC at month 12 as assessed by QCT in the subset of participants receiving placebo, s.c. teriparatide (20 µg once daily), and s.c. romosozumab (210 mg once monthly). QCT measurements were performed at the lumbar spine (mean of L1 and L2 entire vertebral bodies, excluding posterior processes) and hip. One year of treatment with romosozumab significantly increased integral vBMD and BMC at the lumbar spine and total hip from baseline, and compared with placebo and teriparatide (all p < 0.05). Trabecular vertebral vBMD improved significantly and similarly from baseline (p < 0.05) with both romosozumab (18.3%) and teriparatide (20.1%), whereas cortical vertebral vBMD gains were larger with romosozumab compared with teriparatide (13.7% versus 5.7%, p < 0.0001). Trabecular hip vBMD gains were significantly larger with romosozumab than with teriparatide (10.8% versus 4.2%, p = 0.01), but were similar for cortical vBMD (1.1% versus -0.9%, p = 0.12). Cortical BMC gains were larger with romosozumab compared with teriparatide at both the spine (23.3% versus 10.9%, p < 0.0001) and hip (3.4% versus 0.0%, p = 0.03). These improvements are expected to result in strength gains and support the continued clinical investigation of romosozumab as a potential therapy to rapidly reduce fracture risk in ongoing phase 3 studies. © 2016 American Society for Bone and Mineral Research.

Children's residential exposure to chlorpyrifos: application of CPPAES field measurements of chlorpyrifos and TCPy within MENTOR/SHEDS-Pesticides model.

The comprehensive individual field-measurements on non-dietary exposure collected in the Children's-Post-Pesticide-Application-Exposure-Study (CPPAES) were used within MENTOR/SHEDS-Pesticides, a physically based stochastic human exposure and dose model. In this application, however, the model was run deterministically. The MENTOR/SHEDS-Pesticides employed the CPPAES as input variables to simulate the exposure and the dose profiles for seven children over a 2-week post-application period following a routine residential and professional indoor crack-and-crevice chlorpyrifos application. The input variables were obtained from a personal activity diary, microenvironmental measurements and personal biomonitoring data obtained from CPPAES samples collected from the individual children and in their homes. Simulation results were compared with CPPAES field measured values obtained from the children's homes to assess the utility of the different microenvironmental data collected in CPPAES, i.e. indicator toys and wipe samplers to estimate aggregate exposures that can be result from one or more exposure pathways and routes. The final analyses of the database involved comparisons of the actual data obtained from the individual biomarker samples of a urinary metabolite of chlorpyrifos (TCPy) and the values predicted by MENTOR/SHEDS-Pesticides using the CPPAES-derived variables. Because duplicate diet samples were not part of the CPPAES study design, SHEDs-Pesticides simulated dose profiles did not account for the dietary route. The research provided more confidence in the types of data that can be used in the inhalation and dermal contact modules of MENTOR/SHEDS-Pesticides to predict the pesticide dose received by a child. It was determined that we still need additional understanding about: (1) the types of activities and durations of activities that result in non-dietary ingestion of pesticides and (2) the influence of dietary exposures on the levels of TCPy found in the urine.

Vibration sensitivity of the scanning near-field optical microscope with a tapered optical fiber probe.

In this paper the Rayleigh-Ritz method was used to study the scanning near-field optical microscope (SNOM) with a tapered optical fiber probe's flexural and axial sensitivity to vibration. Not only the contact stiffness but also the geometric parameters of the probe can influence the flexural and axial sensitivity to vibration. According to the analysis, the lateral and axial contact stiffness had a significant effect on the sensitivity of vibration of the SNOM's probe, each mode had a different level of sensitivity and in the first mode the tapered optical fiber probe was the most acceptive to higher levels of flexural and axial vibration. Generally, when the contact stiffness was lower, the tapered probe was more sensitive to higher levels of both axial and flexural vibration than the uniform probe. However, the situation was reversed when the contact stiffness was larger. Furthermore, the effect that the probe's length and its tapered angle had on the SNOM's probe axial and flexural vibration were significant and these two conditions should be incorporated into the design of new SNOM probes.

The development of a physiologically-based pharmacokinetic model using the distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the tissues of the eastern oyster (Crassostrea virginica).

A physiologically-based pharmacokinetic model (PBPK) was developed to describe the kinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the eastern oyster (Crassostrea virginica). The estimated t(1/2) of elimination for a bolus dose of TCDD in C. virginica is approximately 14-24 days based on both the experimental data and the PBPK model. The highest dioxin concentration reached during 28-days was in the digestive gland followed by the mantle, gonad, hemolymph, gill, adductor muscle, and the kidney/heart. A binding protein for 2,3,7,8-TCDD had been reported in the literature for both the digestive gland and gonad. Incorporating a binding component in the model resulted in a better fit for the data. The PBPK model predicted the distribution and the elimination concentrations for 2,3,7,8-TCDD within each of the tissue compartments. This model will serve as a useful tool for predicting the kinetics of other persistent organic pollutants as well as, allow for a more refined ecological risk assessment by estimating dioxin concentrations in sensitive tissues such as the gonad.

Estimation of surface heat flux and temperature distributions in a multilayer tissue based on the hyperbolic model of heat conduction.

In this study, an inverse algorithm based on the conjugate gradient method and the discrepancy principle is applied to solve the inverse hyperbolic heat conduction problem in estimating the unknown time-dependent surface heat flux in a skin tissue, which is stratified into epidermis, dermis, and subcutaneous layers, from the temperature measurements taken within the medium. Subsequently, the temperature distributions in the tissue can be calculated as well. The concept of finite heat propagation velocity is applied to the modeling of the bioheat transfer problem. The inverse solutions will be justified based on the numerical experiments in which two different heat flux distributions are to be determined. The temperature data obtained from the direct problem are used to simulate the temperature measurements. The influence of measurement errors on the precision of the estimated results is also investigated. Results show that an excellent estimation on the time-dependent surface heat flux can be obtained for the test cases considered in this study.