pH catalyzed pretreatment of corn bran for enhanced enzymatic arabinoxylan degradation.
Corn bran is mainly made up of the pericarp of corn kernels and is a byproduct stream resulting from the wet milling step in corn starch processing. Through statistic modeling this study examined the optimization of pretreatment of corn bran for enzymatic hydrolysis. A low pH pretreatment (pH 2, 150 °C, 65 min) boosted the enzymatic release of xylose and glucose and maximized biomass solubilization. With more acidic pretreatment followed by enzymatic hydrolysis the total xylose release was maximized (at pH 1.3) reaching ∼ 50% by weight of the original amount present in destarched corn bran, but the enzyme catalyzed xylose release was maximal after pretreatment at approx. pH 2. The total glucose release peaked after pretreatment of approx. pH 1.5 with an enzymatic release of approx. 68% by weight of the original amounts present in destarched corn bran. For arabinose the enzymatic release was negatively affected by the acidic pretreatment as labile arabinosyl-linkages were presumably hydrolysed directly during the pretreatment. A maximum of 60% arabinose release was achieved directly from the optimal (acidic) pretreatment. The total content of diferulic acids, supposedly involved in the cross-linking of the arabinoxylan polymers, decreased by both alkaline and acidic pretreatment pH, with the loss by alkaline pretreatments being highest. No direct correlation between the enzymatic release of xylose and the content of diferulic acids in the substrate could be verified. On the contrary the enzymatic release of xylose was significantly correlated to the total release of arabinose, indicating that the degree of arabinosyl-substitutions on the xylan backbone is an essential parameter for enzymatic hydrolysis of corn bran arabinoxylan.


New 99mTc Radiotracers for Myocardial Perfusion Imaging by SPECT.
Myocardial Perfusion Imaging (MPI) with radiotracers is an integral component in evaluation of the patients with known or suspected coronary artery diseases (CAD). 99mTc-Sestamibi and 99mTc-Tetrofosmin are commercial radiopharmaceuticals for MPI by single photon-emission computed tomography (SPECT). Despite their widespread clinical applications, they do not meet the requirements of an ideal perfusion imaging agent due to their inability to linearly track the regional myocardial blood flow rate at >2.5 mL/min/g. With tremendous development of CZT-based SPECT cameras over the past several years, the nuclear cardiology community has been calling for better perfusion radiotracers with improved extraction and biodistribution properties. This review will summarize recent research efforts on new cationic and neutral 99mTc radiotracers for SPECT MPI. The goal of these efforts is to develop a 99mTc radiotracer that can be used to detect perfusion defects at rest or under stress, determine the regional myocardial blood flow, and measure the perfusion and left ventricular function. The advantage of cationic radiotracers (e.g. 99mTc-Sestamibi) is their long myocardial retention because of the positive molecular charge and fast liver clearance kinetics. 99mTc-Teboroxime derivatives have a high initial heart uptake (high first-pass extraction fraction) due to their neutrality. 99mTc- 3SPboroxime is the most promising radiotracer for future clinical translation considering its initial heart uptake, myocardial retention time, liver clearance kinetics, heart/liver ratios and SPECT image quality. 99mTc-3SPboroximine is an excellent example of perfusion radiotracers, the heart uptake of which is largely relies on the regional blood flow. It is possible to use 99mTc-3SPboroximine for detection of perfusion defect(s), accurate quantification and determination of regional blood flow rate. Development of such a 99mTc radiotracer is of great clinical benefit for accurate diagnosis of CAD and assessing the risk of future hard events (e.g. heart attack and sudden death) in cardiac patients.


Overexpression of HO-1 protects against TNF-alpha-mediated airway inflammation by down-regulation of TNFR1-dependent oxidative stress.
Oxidative stresses are believed to play an important role in the induction of both cell adhesion molecules and pro-inflammatory cytokines, a key event in a variety of inflammatory processes. The enzyme heme oxygenase-1 (HO-1) functions as an antioxidant and serves to protect against tissue injury. In this study, we report that HO-1 was induced in cultured human tracheal smooth muscle cells after either treatment with a potent inducer of HO-1 activity, cobalt protoporphyrin IX, or infection with a recombinant adenovirus that carries the human HO-1 gene. Overexpression of HO-1 protected against tumor necrosis factor (TNF)-alpha-mediated airway inflammation via the down-regulation of oxidative stress, adhesion molecules, and interleukin-6 in both cultured human tracheal smooth muscle cells and the airways of mice. In addition, HO-1 overexpression inhibited TNF-alpha-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, adherence of THP-1 cells, generation of interleukin-6, p47(phox) translocation, and nuclear factor-kappaB activation. HO-1 overexpression also attenuated TNF-alpha-induced oxidative stress, which was abrogated in the presence of both the HO-1 inhibitor, zinc protoporphyrin IX, as well as a carbon monoxide scavenger. In addition, HO-1 overexpression reduced the formation of a TNFR1/c-Src/p47(phox) complex. These results suggest that HO-1 functions as a suppressor of TNF-alpha signaling, not only by inhibiting the expression of adhesion molecules and generation of interleukin-6, but also by diminishing intracellular reactive oxygen species production and nuclear factor-kappaB activation in both cultured human tracheal smooth muscle cells and the airways of mice.


Microbial reduction in wastewater treatment using Fe(3+) and Al(3+) coagulants and PAA disinfectant.
Wastewater is an important source of pathogenic enteric microorganisms in surface water and a major contaminating agent of drinking water. Although primary and secondary wastewater treatments reduce the numbers of microorganisms in wastewater, significant numbers of microbes can still be present in the effluent. The aim of this study was to test the feasibility of tertiary treatment for municipal wastewater treatment plants (WWTPs) using PIX (FeCl3) or PAX (AlCl3) coagulants and peracetic acid (PAA) the disinfectant to reduce microbial load in effluent. Our study showed that both PIX and PAX efficiently reduced microbial numbers. PAA disinfection greatly reduced the numbers of culturable indicator microorganisms (Escherichia coli, intestinal enterococci, F-specific RNA coliphages and somatic DNA coliphages). In addition, pathogenic microorganisms, thermotolerant Campylobacter, Salmonella and norovirus GI, were successfully reduced using the tertiary treatments. In contrast, clostridia, Legionella, rotavirus, norovirus GII and adenovirus showed better resistance against PAA compared to the other microorganisms. However, interpretation of polymerase chain reaction (PCR) analysis results will need further studies to clarify the infectivity of the pathogenic microbes. In conclusion, PIX and PAX flocculants followed by PAA disinfectant can be used as a tertiary treatment for municipal WWTP effluents to reduce the numbers of indicator and pathogenic microorganisms.


Prognostic factors and effects of early surgical drainage in patients with peritonsillar abscess.
Peritonsillar abscess is a frequently encountered otorhinolaryngological emergency, but the characteristics of patients with this disease have not been described in detail. The objective of this study was to delineate prognostic factors associated with peritonsillar abscess and the effects of early surgical drainage for the treatment of peritonsillar abscess. We conducted a retrospective analysis of the medical records of 240 consecutive patients with PTA during the period from 2007 to 2013. Univariate analysis indicated that the period between symptom onset and relief was significantly longer in patients with high levels of C-reactive protein (CRP) (>8.53 mg/dL, p = 0.0073) and without early surgical drainage of pus (p < 0.0001). Multivariate analysis identified both of these values as independently associated with longer duration of symptoms (high CRP, P < 0.0001; no early drainage, P < 0.0001). Univariate analysis indicated that the duration between symptom onset and complete recovery from the disease was significantly longer with age ≥40 years (P = 0.0004), no history of recurrent tonsillitis (P = 0.022), high CRP level (P = 0.0017), and no early surgical drainage of the abscess (P = 0.0014). Multivariate analysis identified older age (P = 0.0004), high CRP level (P = 0.0001), and no early drainage (P < 0.0001) as independently associated with longer duration between symptom onset and complete recovery. Early surgical drainage of the abscess is important for the treatment of peritonsillar abscess. Patients ≥40 years old with peritonsillar abscess and high CRP levels should be recognized as a high-risk group.


Mechanisms of nutrient attenuation in a subsurface flow riparian wetland.
Riparian wetlands are transition zones between terrestrial and aquatic environments that have the potential to serve as nutrient filters for surface and ground water due to their topographic location. We investigated a riparian wetland that had been receiving intermittent inputs of NO3- and PO4(3-) during storm runoff events to determine the mechanisms of nutrient attenuation in the wetland soils. Few studies have shown whether infrequent pulses of NO3- are sufficient to maintain substantial denitrifying communities. Denitrification rates were highest at the upstream side of the wetland where nutrient-rich runoff first enters the wetland (17-58 microg N2O-N kg soil(-1) h(-1)) and decreased further into the wetland. Carbon limitation for denitrification was minor in the wetland soils. Samples not amended with dextrose had 75% of the denitrification rate of samples with excess dextrose C. Phosphate sorption isotherms suggested that the wetland soils had a high capacity for P retention. The calculated soil PO4(3-) concentration that would yield an equilibrium aqueous P04(3-) concentration of 0.05 mg P L(-1) was found to be 100 times greater than the soil PO4(3-) concentration at the time of sampling. This indicated that the wetland could retain a large additional mass of PO4(3-) without increasing the dissolved P04(3-) concentrations above USEPA recommended levels for lentic waters. These results demonstrated that denitrification can be substantial in systems receiving pulsed NO3- inputs and that sorption could account for extensive PO4(3-) attenuation observed at this site.


Early clinical results following staged bilateral primary total shoulder arthroplasty.
The advantages of performing either a single- or 2-staged joint replacement has been reviewed extensively in the hip and knee arthroplasty literature, but far less data exist regarding total shoulder replacements. In the appropriate clinical setting, bilateral total shoulder arthroplasty yields excellent functional results with a low complication profile. We evaluated retrospectively the records of 13 consecutive patients (26 shoulders) who underwent staged bilateral primary total shoulder replacements by a single surgeon, with a minimum follow-up of 12 months for each side (range, 12.0-61.5). The interval between replacements averaged 7.4 months (range, 0.5-26.0). The mean unadjusted baseline Constant score for the first versus the second side was not significant (35 vs 41, P = .3). These scores improved to 73 and 72 by final follow-up (both P < .0001). Mean pain scores on the visual analog scale (VAS) improved from 6.9 to 0.9 (P < .0001). We found no difference in the estimated blood loss (EBL), operative time, or hospital length of stay (LOS) between the sides. Significantly higher mean scores were demonstrated in all components of the SF-36 questionnaire over a normalized cohort of U.S. age-matched males and females by final follow-up. All patients were satisfied with both procedures. Staged, bilateral total shoulder arthroplasty results in excellent functional outcomes and high satisfaction in subjective patient assessment. We currently recommend a minimum of 6 weeks between replacements to allow for appropriate tissue healing and rehabilitation. 4.


Molecular-genetic insights in paediatric T-cell acute lymphoblastic leukaemia.
Paediatric T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive malignancy of thymocytes that accounts for about 15% of ALL cases and for which treatment outcome remains inferior compared to B-lineage acute leukaemias. In T-ALL, leukemic transformation of maturating thymocytes is caused by a multistep pathogenesis involving numerous genetic abnormalities that drive normal T-cells into uncontrolled cell growth and clonal expansion. This review provides an overview of the current knowledge on onco- and tumor suppressor genes in T-ALL and suggests a classification of these genetic defects into type A and type B abnormalities. Type A abnormalities may delineate distinct molecular-cytogenetic T-ALL subgroups, whereas type B abnormalities are found in all major T-ALL subgroups and synergize with these type A mutations during T-cell pathogenesis.


Insulin stimulates lipoprotein lipase activity and synthesis in adipocytes from septic rats.
Gram-negative sepsis suppresses lipoprotein lipase (LPL) activity in adipose tissue which contributes, in part, to the altered clearance of triglycerides. The suppression in LPL activity occurs when plasma insulin concentrations are elevated and insulin-stimulated glucose utilization is impaired. This study was planned to evaluate whether the presence of insulin resistance was responsible for the decrease in adipose LPL activity. Adipocytes were isolated from epididymal fat pads 24 h after inducing sepsis in male Lewis rats by intravenous injection of 4 x 10(8) colonies of live Escherichia coli/100 g body wt. The decrease in heparin-releasable (HR) LPL activity in adipocytes from the septic rats was evident at the time of isolation and maintained in a 20-h culture. After overnight incubation with insulin (10(-8) M), HR LPL activity was stimulated to a greater extent in adipocytes from septic rats (298%) than in adipocytes from control rats (88%). The insulin stimulation of LPL activity during sepsis could not be attributed to insulin-like growth factor-I (IGF-I) as adipocytes from septic rats appeared to be IGF-I resistant. Insulin-treatment (10(-8) M) increased LPL synthesis 99% in adipocytes from control rats and 136% in adipocytes from septic rats. Insulin treatment also led to a 65 and 62% increase in LPL mass in adipocytes from control and septic rats, respectively. These findings indicate that the sepsis-induced decrease in adipose LPL is not due to insulin resistance with respect to LPL. The insulin stimulation of LPL activity in adipocytes from septic rats appears to be mediated by an increase in LPL synthesis.


Tumor accumulation and antitumor efficacy of docetaxel-loaded core-shell-corona micelles with shell-specific redox-responsive cross-links.
A robust core-shell-corona micelle bearing redox-responsive shell-specific cross-links was evaluated as a carrier of docetaxel (DTX) for cancer therapy. The polymer micelles of poly(ethylene glycol)-b-poly(L-lysine)-b-poly(L-phenylalanine) (PEG-PLys-PPhe) in the aqueous phase provided the three distinct functional domains: the PEG outer corona for prolonged circulation, the PLys middle shell for disulfide cross-linking, and the PPhe inner core for DTX loading. The shell cross-linking was performed by the reaction of disulfide-containing cross-linkers with Lys moieties in the middle shells. The shell cross-linking did not change the micelle size or the spherical morphology. The shell cross-linked micelles exhibited enhanced serum stability. The DTX release from the DTX-loaded disulfide cross-linked micelles (DTX-SSCLM) was facilitated by increasing the concentration of glutathione (GSH). At an intracellular GSH level, DTX release was facilitated due to the reductive cleavage of the disulfide cross-links in the shell domains. The in vivo tissue distribution and tumor accumulation of the DTX-SSCLM that were labeled with a near-infrared fluorescence (NIRF) dye, Cy5.5, were monitored in MDA-MB231 tumor-bearing mice. Non-invasive real-time optical imaging results indicated that the DTX-SSCLM exhibited enhanced tumor specificity due to the prolonged stable circulation in blood and the enhanced permeation and retention (EPR) effect compared with the DTX-loaded non-cross-linked micelles (DTX-NCLM). The DTX-SSCLM exhibited enhanced therapeutic efficacy in tumor-bearing mice compared with free DTX and DTX-NCLM. The domain-specific shell cross-linking that is described in this work may serve as a useful guidance for enhancing the antitumor therapeutic efficacy of various polymer micelles and nano-aggregates.


Genome Detective Coronavirus Typing Tool for rapid identification and characterization of novel coronavirus genomes.
Genome Detective is a web-based, user-friendly software application to quickly and accurately assemble all known virus genomes from next generation sequencing datasets. This application allows the identification of phylogenetic clusters and genotypes from assembled genomes in FASTA format. Since its release in 2019, we have produced a number of typing tools for emergent viruses that have caused large outbreaks, such as Zika and Yellow Fever Virus in Brazil. Here, we present The Genome Detective Coronavirus Typing Tool that can accurately identify novel coronavirus (2019-nCoV) sequences isolated in China and around the world. The tool can accept up to 2,000 sequences per submission and the analysis of a new whole genome sequence will take approximately one minute. The tool has been tested and validated with hundreds of whole genomes from ten coronavirus species, and correctly classified all of the SARS-related coronavirus (SARSr-CoV) and all of the available public data for 2019-nCoV. The tool also allows tracking of new viral mutations as the outbreak expands globally, which may help to accelerate the development of novel diagnostics, drugs and vaccines.


The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein.
Sortilin belongs to a growing family of multiligand type-1 receptors with homology to the yeast receptor Vps10p. Based on structural features and sortilin's intracellular predominance, we have proposed it to be a sorting receptor for ligands in the synthetic pathway as well as on the cell membrane. To test this hypothesis we examine here the cellular trafficking of chimeric receptors containing constructs of the sortilin tail. We report that sorting signals conforming to YXX and dileucine motifs mediate rapid endocytosis of sortilin chimeras, which subsequently travel to the trans-Golgi network, showing little or no recycling. Furthermore, we found that cation-independent mannose 6-phosphate receptor (MPR300)-sortilin chimeras, expressed in mannose 6-phosphate receptor knockout cells, were almost as efficient as MPR300 itself for transport of newly synthesized beta-hexosaminidase and beta-glucuronidase to lysosomes, and established that the sortilin tail contains potent signals for Golgi-endosome sorting. Finally, we provide evidence suggesting that sortilin is the first example of a mammalian receptor targeted by the recently described GGA family of cytosolic sorting proteins, which condition the Vps10p-mediated sorting of yeast carboxypeptidase Y.


Characteristics of asthma in the elderly.
Asthma occurs more frequently in the elderly than is usually appreciated and may, therefore, be underdiagnosed and undertreated. This study evaluated the relationship between asthma symptoms and the degree of airflow obstruction in elderly and young asthmatics. Fifteen young asthmatics (<65 yrs) (group A), 15 aged >65 yrs with onset of symptoms before 65 yrs (group B), and 15 aged >65 yrs with onset of symptoms after 65 yrs (group C), were studied. Patients used daily diary cards, during 2 weeks, to record inhaled beta2-agonist consumption and severity of asthma symptoms. Long-standing asthma was associated with a significantly lower forced expiratory volume in one second as compared with recent onset asthma. The asthma-symptom score was highest in group A, lower in group B and significantly lower in group C. When symptoms were related to the degree of obstruction (asthma index), it was higher in the young asthmatics than in both groups of elderly patients. In conclusion, elderly patients with long-standing asthma had more severe airway obstruction than patients with recently acquired disease. Older patients particularly those with long-standing disease complained less about asthma symptoms. Within the various groups of patients, subjective symptoms of asthma were negatively related to asthma duration.


Stochastic optimal control as a theory of brain-machine interface operation.
The closed-loop operation of brain-machine interfaces (BMI) provides a framework to study the mechanisms behind neural control through a restricted output channel, with emerging clinical applications to stroke, degenerative disease, and trauma. Despite significant empirically driven improvements in closed-loop BMI systems, a fundamental, experimentally validated theory of closed-loop BMI operation is lacking. Here we propose a compact model based on stochastic optimal control to describe the brain in skillfully operating canonical decoding algorithms. The model produces goal-directed BMI movements with sensory feedback and intrinsically noisy neural output signals. Various experimentally validated phenomena emerge naturally from this model, including performance deterioration with bin width, compensation of biased decoders, and shifts in tuning curves between arm control and BMI control. Analysis of the model provides insight into possible mechanisms underlying these behaviors, with testable predictions. Spike binning may erode performance in part from intrinsic control-dependent constraints, regardless of decoding accuracy. In compensating decoder bias, the brain may incur an energetic cost associated with action potential production. Tuning curve shifts, seen after the mastery of a BMI-based skill, may reflect the brain's implementation of a new closed-loop control policy. The direction and magnitude of tuning curve shifts may be altered by decoder structure, ensemble size, and the costs of closed-loop control. Looking forward, the model provides a framework for the design and simulated testing of an emerging class of BMI algorithms that seek to directly exploit the presence of a human in the loop.


Path integral-GC-AdResS simulation of a large hydrophobic solute in water: a tool to investigate the interplay between local microscopic structures and quantum delocalization of atoms in space.
We perform large scale quantum (path integral) molecular dynamics simulations of a C60-like molecule in water. The path integral (PI) technique allows for the description of the delocalization of atoms in space and of its consequences on the structure and dynamics of the hydrogen bonding network around the solute. We then employ the adaptive resolution method GC-AdResS, which unambiguously defines the essential (necessary) degrees of freedom required for a certain property, to analyze the locality of the water structure around the solute. We show that the feature of locality is independent of the use of a quantum or classical model of water. However the water structure around the solute obtained from classical simulations is more ordered and rigid than the structure found in quantum simulations. With this study we mainly intend to show that GC-AdResS, besides its computational efficiency, can be used as a powerful tool of multiscale analysis; this capability, in turn, can be used to speculate about processes at larger scales. We make an example, whose current validity is restricted to the molecular models specifically used, regarding the possible role of quantum effects in the aggregation of fullerene-like molecules in water.


Effect of a Health System-Sponsored Mobile App on Perinatal Health Behaviors: Retrospective Cohort Study.
Pregnancy mobile apps are becoming increasingly popular, with parents-to-be seeking information related to their pregnancy and their baby through mobile technology. This increase raises the need for prenatal apps with evidence-based content that is personalized and reliable. Previous studies have looked at whether prenatal apps impact health and behavior outcomes among pregnant and postpartum individuals; however, research has been limited. The primary objective of this study is to assess whether the use of a health system-sponsored mobile app-Circle by Providence-aimed at providing personalized and reliable health information on pregnancy, postpartum recovery, and infant care is associated with improved health outcomes and increased healthy behaviors and knowledge among users. This observational study compared app users and app nonusers using a self-reported survey and electronic medical records. The study took place over 18 months and was conducted at Providence St. Joseph Health in Portland, Oregon. The sample included patients who received prenatal care at one of seven Providence clinics and had a live birth at a Providence hospital. Recruitment occurred on a rolling basis and only those who completed the survey were included. Survey respondents were separated into app users and app nonusers, and survey responses and clinical outcomes were compared across groups using univariate and adjusted multivariate logistic regression. A total of 567 participants were enrolled in the study-167 in the app user group and 400 in the nonuser group. We found statistically significant differences between the two groups for certain behavior outcomes: subjects who used the app had 75% greater odds of breastfeeding beyond 6 months postpartum (P=.012), were less likely to miss prenatal appointments (P=.046), and were 50% more likely to exercise 3 or more times a week during pregnancy (P=.04). There were no differences in nutritional measures, including whether they took prenatal vitamins, ate 5 fruits or vegetables a day, or drank caffeine. We found no differences in many of the infant care outcomes; however, there was an increase in awareness of "purple crying." Finally, there were no significant differences in measured clinical health outcomes, including cesarean births, length of hospital stays (in minutes), low birth weight infants, preterm births, small-for-gestational-age births, large-for-gestational-age births, and neonatal intensive care unit stays. The use of the Circle app, which provides access to personalized and evidence-based health information, was associated with an increase in certain healthy behaviors and health knowledge, although there was no impact on clinical health outcomes. More research is needed to determine the impact of mobile prenatal apps on healthy pregnancies, clinical health outcomes, and infant care.


The effect of ovariectomy on the skin flap viability and myeloperoxidase levels.
Estrogen could affect the rate and quality of wound healing in skin. We aimed to investigate the effects of ovariectomy on skin flap viability and myeloperoxidase (MPO) levels in a rat model. Estrogens have many important beneficial and protective roles in skin that they improve collagen content and quality, maintain skin thickness and enhance vascularization. It has been shown that estrogen supplementation accelerates cutaneous wound healing in elderly patients. Forty-eight cycling female Wistar albino rats were randomly divided into three groups (n = 16); ovariectomy (Group 1), sham (Group 2), and control (Group 3). Rats were subjected to bilateral ovariectomy in the Group 1, and only laparotomy in the Group 2. Twenty-one days later in the Group 1 and 2, a dorsal caudally based skin flap elevation was done. In the Group 3, the rats had a dorsal skin flap without any surgical intervention. Ten days later, the flaps were harvested for histopathologic examination and biochemical analyses. The rats in the Group 1 had significantly larger necrotic area and lower flap viability than in the Group 2 and 3 (p<0.05). Histopathologic examination showed that necrotic flap regions contained muscle necrosis with an abundant neutrophil infiltration, and severe edema in the Group 1. The MPO activity in the distal of skin flaps was significantly higher in the Group 1 compared to the Group 2 and 3 (p<0.05). This study shows that ovariectomy has deleterious effects on skin flap viability in a rat model (Tab. 1, Fig. 6, Ref. 44).


Acoustics of Emotional Prosody Produced by Prelingually Deaf Children With Cochlear Implants.
Purpose: Cochlear implants (CIs) provide reasonable levels of speech recognition quietly, but voice pitch perception is severely impaired in CI users. The central question addressed here relates to how access to acoustic input pre-implantation influences vocal emotion production by individuals with CIs. The objective of this study was to compare acoustic characteristics of vocal emotions produced by prelingually deaf school-aged children with cochlear implants (CCIs) who were implanted at the age of 2 and had no usable hearing before implantation with those produced by children with normal hearing (CNH), adults with normal hearing (ANH), and postlingually deaf adults with cochlear implants (ACI) who developed with good access to acoustic information prior to losing their hearing and receiving a CI. Method: A set of 20 sentences without lexically based emotional information was recorded by 13 CCI, 9 CNH, 9 ANH, and 10 ACI, each with a happy emotion and a sad emotion, without training or guidance. The sentences were analyzed for primary acoustic characteristics of the productions. Results: Significant effects of Emotion were observed in all acoustic features analyzed (mean voice pitch, standard deviation of voice pitch, intensity, duration, and spectral centroid). ACI and ANH did not differ in any of the analyses. Of the four groups, CCI produced the smallest acoustic contrasts between the emotions in voice pitch and emotions in its standard deviation. Effects of developmental age (highly correlated with the duration of device experience) and age at implantation (moderately correlated with duration of device experience) were observed, and interactions with the children's sex were also observed. Conclusion: Although prelingually deaf CCI and postlingually deaf ACI are listening to similar degraded speech and show similar deficits in vocal emotion perception, these groups are distinct in their productions of contrastive vocal emotions. The results underscore the importance of access to acoustic hearing in early childhood for the production of speech prosody and also suggest the need for a greater role of speech therapy in this area.


One-step enzymatic hydrolysis of starch using a recombinant strain of Saccharomyces cerevisiae producing alpha-amylase, glucoamylase and pullulanase.
A recombinant strain of Saccharomyces cerevisiae was constructed that contained the genes encoding a bacterial alpha-amylase (AMY1), a yeast glucoamylase (STA2) and a bacterial pullulanase (pulA). The Bacillus amyloliquefaciens alpha-amylase and S. cerevisiae var. diastaticus glucoamylase genes were expressed in S. cerevisiae using their native promoters and the encoded enzymes secreted under direction of their native leader sequences. In contrast, the Klebsiella pneumoniae pullulanase gene was placed under the control of the yeast alcohol dehydrogenase gene promoter (ADC1P) and secreted using the yeast mating pheromone alpha-factor secretion signal (MF alpha 1S). Transcription termination of the pullulanase gene was effected by the yeast tryptophan synthase gene terminator (TRP5T), whereas termination of the glucoamylase and alpha-amylase genes was directed by their native terminators. Pullulanase (PUL1) produced by recombinant yeasts containing ADC1P MF alpha 1S pulA TRP5T (designated PUL1) was further characterized and compared to its bacterial counterpart (PulA). The different genes were introduced into S. cerevisiae in different combinations and the various amylolytic Saccharomyces transformants compared to Schwanniomyces occidentalis. Introduction of PUL1 into a S. cerevisiae strain containing both STA2 and AMY1, resulted in 99% assimilation of starch.


A Guide to Mass Spectrometry-Based Quantitative Proteomics.
Proteomics has become an attractive science in the postgenomic era, given its capacity to identify up to thousands of molecules in a single, complex sample and quantify them in an absolute and/or relative manner. The use of these techniques enables understanding of cellular and molecular mechanisms of diseases and other biological conditions, as well as identification and screening of protein biomarkers. Here we provide a straightforward, up-to-date compilation and comparison of the main quantitation techniques used in comparative proteomics such as in vitro and in vivo stable isotope labeling and label-free techniques. Additionally, this chapter includes common methods for data acquisition in proteomics and some appropriate methods for data processing. This compilation can serve as a reference for scientists who are new to, or already familiar with, quantitative proteomics.


Isolation and analysis of Mycobacterium tuberculosis mycolic acids.
Mycolic acids are an important constituent of the mycobacterial cell wall. Changes in the structure or composition of mycolic acids have been associated with modification of cell wall permeability and attenuation of pathogenic Mycobacterium tuberculosis strains. This unit describes the isolation of M. tuberculosis mycolic acids and their analysis by either thin-layer chromatography or high-performance liquid chromatography. Both techniques have been extensively used to study (1) mycolic acid biosynthesis, (2) the role of mycolic acids in mycobacterial virulence, (3) the effect of antituberculosis drugs targeting the cell wall, and (4) taxonomic purposes.


Metagenome-assembled genomes uncover a global brackish microbiome.
Microbes are main drivers of biogeochemical cycles in oceans and lakes. Although the genome is a foundation for understanding the metabolism, ecology and evolution of an organism, few bacterioplankton genomes have been sequenced, partly due to difficulties in cultivating them. We use automatic binning to reconstruct a large number of bacterioplankton genomes from a metagenomic time-series from the Baltic Sea, one of world's largest brackish water bodies. These genomes represent novel species within typical freshwater and marine clades, including clades not previously sequenced. The genomes' seasonal dynamics follow phylogenetic patterns, but with fine-grained lineage-specific variations, reflected in gene-content. Signs of streamlining are evident in most genomes, and estimated genome sizes correlate with abundance variation across filter size fractions. Comparing the genomes with globally distributed metagenomes reveals significant fragment recruitment at high sequence identity from brackish waters in North America, but little from lakes or oceans. This suggests the existence of a global brackish metacommunity whose populations diverged from freshwater and marine relatives over 100,000 years ago, long before the Baltic Sea was formed (8000 years ago). This markedly contrasts to most Baltic Sea multicellular organisms, which are locally adapted populations of freshwater or marine counterparts. We describe the gene content, temporal dynamics and biogeography of a large set of new bacterioplankton genomes assembled from metagenomes. We propose that brackish environments exert such strong selection that lineages adapted to them flourish globally with limited influence from surrounding aquatic communities.


Direct evidence for DNA bending at the lambda replication origin.
Replication initiation in bacteriophage lambda appears to require wrapping of origin DNA on an approximately 50 angstrom radius in or around the complex with the initiator protein O. Since short lengths of DNA are not that flexible, it may be that runs of coherently spaced deoxyadenylate residues constitute bend sites in the ori sequence that facilitate the process. Earlier data showed that ori DNA has electrophoretic anomalies characteristic of bend sites and that these are augmented by initiator protein binding. Here origin bending is examined by direct measurement of the ability of polymerized ori sequences to form small circles. The smallest circles observed (84 residues) are compatible with the required radius of curvature. Bend sites within the O protein binding sites, bend sites in the spacers between them, plus the inherent flexibility of non-bent DNA in the origin may all contribute to origin bending. The data also show that a bend site is required for O protein binding to DNA.


Perceived barriers and facilitators of using dietary modification for CKD prevention among African Americans of low socioeconomic status: a qualitative study.
Factors influencing the use of dietary interventions for modification of CKD risk among African Americans have not been well-explored. We assessed perceived barriers and facilitators of CKD prevention through dietary modifications among African Americans with low socioeconomic status (SES) and at high risk for CKD. We conducted a qualitative study involving three 90 minute focus groups of low SES (limited education, unemployed, uninsured, or income<$25,000/year) African American residents of Baltimore, Maryland (N=17), who were aged 18-60 years, with no known history of CKD and (1) a family history of end stage renal disease and (2) self-reported diabetes, hypertension, cardiovascular disease, HIV or obesity. A trained moderator asked a series of 21 closed and open-ended questions. Group sessions were recorded, transcribed, and two independent investigators reviewed transcripts to identify common themes. Participants' mean (SD) age was 39.8 (12.4) years. Most (59%) were female and earned <$5,000/year (71%). One quarter (24%) had self-reported diabetes and over half had hypertension (53%). Few (12%) perceived their CKD risk as high. Perceived barriers to CKD prevention through dietary change included the expense and unavailability of healthy foods, family member preferences, convenience of unhealthy foods, and inability to break lifelong habits. They identified vouchers for healthy foods, family-based interventions, nutritional counseling and group gatherings for persons interested in making dietary changes as acceptable facilitators of dietary CKD prevention efforts. Low SES African Americans at high risk for CKD had limited perception of their risk but they identified multiple barriers and potential facilitators of CKD prevention via dietary modifications which can inform future studies and public health interventions.


Light and Scanning Electron Microscopic Studies of Unionicola tetrafurcatus (Acari: Unionicolidae) Infecting Four Freshwater Bivalve Species and Histopathological Effect On Its Hosts.
Water mites of the genus Unionicola are the most common symbionts of freshwater bivalves. During the current investigation, a total of 120 live freshwater mussels representing 5 species, Corbicula fluminea (Veneroida), Coelatura aegyptiaca (Unionoidea), Mutela rostrata, and Chambardia rubens (Mutelidae), were collected from 2 localities in Tura (Helwan Governorate) and El Kanater (Qaluobiya Governorate), Egypt. Only 3 of the 4 bivalve species listed are considered freshwater bivalves (members of Unionoidea). Corbicula fluminea belong to the family Cyrenidae within Veneroida. Collected mussels were dissected and examined for the presence of unionicolid mites. It was found that 30.83% (37/120) were infected with a single mite species, Unionicola tetrafurcatus (Unionicolidae). The highest prevalence was observed during the summer with 83.33% (25/30) whereas the least was observed in autumn, i.e., 33.33% (10/30). Mites were recovered from the gills, gonads, and visceral mass of mussel hosts. Gills of host mussels were the primary site of oviposition for Unionicola mites. Smaller bivalves in size had significantly greater numbers of mites than did larger ones in size. Numbers of mites per host species was variable and the highest prevalence level of 83.33% (25/30) was recorded in Cor. fluminea while the lowest one of 16.66% (5/30) was found in Ch. rubens. Morphological and morphometric characterizations of mites revealed some differences between the present species and other related Unionicola. Histopathological responses of host mussels to the eggs, larvae, and cuticular remnants of U. tetrafurcatus were also studied. Therefore, the present study demonstrated that freshwater bivalves have a new host and locality records for infection with U. tetrafurcatus. Future studies are recommended to include advanced molecular characteristics for these mites.


Patterns of survival in patients with recurrent follicular lymphoma: a 20-year study from a single center.
To examine outcome of treatment for patients with recurrent follicular lymphoma. Two hundred twelve newly diagnosed follicular lymphoma patients were studied. One hundred seventy-nine were initially treated successfully. Recurrent or progressive lymphoma developed in 116. Treatment was given according to disease stage and current protocols, mostly with single alkylating agents. A policy of repeated lymph node and bone marrow biopsy was pursued. The overall median survival duration was 9 years, with a median follow-up duration of 12 years. Following recurrence, the median survival duration was 4 1/2 years. Only eight of 116 patients with recurrent disease died of causes unrelated to lymphoma. The overall response rate to first re-treatment was 78% and showed slight decline with successive recurrences, reaching 48% after the fourth treatment. The median duration of second remission was 13 months, (v 31 months for first remission), with the only significant predictive factor being quality of remission. Multivariate analysis showed only age at recurrence and number of prior treatments to correlate with survival after first recurrence. Survival after second remission was only correlated with age and quality of response: Kaplan-Meier estimates gave 53% of patients reaching second complete remission alive 10 years later, compared with 28% in partial remission. Age and previous and continuing responsiveness of follicular lymphoma to therapy are the principal determinants of survival following recurrence. Improvement in survival with new treatments will be demonstrated most readily in older patients, while more intensive approaches should be tested in younger patients in whom remission is achieved with difficulty.


Relationship between serum levels of superoxide dismutase activity and subsequent risk of cancer mortality: Findings from a nested case-control study within the Japan Collaborative Cohort Study.
Superoxide dismutases (SODs) are antioxidant enzymes that play a role in the defense system of the body. They may be involved in protection against carcinogenesis processes. In the present study, we investigate the association between serum SOD activity and the risk of deaths due to all cancers combined, based on a nested case-control study within the Japan Collaborative Cohort Study of 914 cancer deaths and 2,739 matched controls. Blood samples were obtained at the baseline and stored at -80 degrees C until analysis for SOD levels. Serum levels of SODs were divided into quartiles, with the first quartile used as the reference. A conditional logistic model was used to estimate odds ratios (ORs) for total cancer mortality associated with serum SOD quartile levels. The adjusted ORs and 95% confidence intervals (CIs) for the second, third and fourth SOD quartiles were 0.96 (95%CI: 0.77-1.19), 1.18 (0.92-1.51), and 1.32 (1.04-1.69), respectively. In analyses stratified by observation period, the adjusted ORs of the respective quartiles were 0.81 (95%CI: 0.60-1.08), 0.98 (0.70-1.37), and 1.28 (0.92-1.79) for the period from the baseline to 1994; and the adjusted ORs were 1.18 (95%CI: 0.85-1.63), 1.47 (1.04-2.10), and 1.41 (1.00-2.04) for the period after 1994. To conclude, we found a slightly positive association between serum SOD level and the risk of all cancer mortality in the present study. Elevated serum SOD levels might reflect a response to oxidative stress, and then may predict a state of excess reactive oxygen species in the carcinogenesis process. Detailed studies of associations between serum SOD levels and cancers in specific sites should now be performed, with attention to particular tumour types.


Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D.
Calcitriol, the hormonally active form of vitamin D, is being evaluated in clinical trials as an anti-cancer agent. Calcitriol exerts multiple anti-proliferative, pro-apoptotic, and pro-differentiating actions on various malignant cells and retards tumor growth in animal models of cancer. Calcitriol also exhibits several anti-inflammatory effects including suppression of prostaglandin (PG) action, inhibition of p38 stress kinase signaling, and the subsequent production of pro-inflammatory cytokines and inhibition of NF-κB signaling. Calcitriol also decreases the expression of aromatase, the enzyme that catalyzes estrogen synthesis in breast cancer, both by a direct transcriptional repression and indirectly by reducing PGs, which are major stimulators of aromatase transcription. Other important effects include the suppression of tumor angiogenesis, invasion, and metastasis. These calcitriol actions provide a basis for its potential use in cancer therapy and chemoprevention. We summarize the status of trials involving calcitriol and its analogs, used alone or in combination with known anti-cancer agents.


Macrophage-targeted lipid nanoparticle delivery of microRNA-146a to mitigate hemorrhagic shock-induced acute respiratory distress syndrome.
The pro-inflammatory response of alveolar macrophages to injurious physical forces during mechanical ventilation is regulated by the anti-inflammatory microRNA, miR-146a. Increasing miR-146a expression to supraphysiologic levels using untargeted lipid nanoparticles reduces ventilator-induced lung injury, but requires a high initial dose of miR-146a making it less clinically applicable. In this study, we developed mannosylated lipid nanoparticles that can effectively mitigate lung injury at the initiation of mechanical ventilation with lower doses of miR-146a. We used a physiologically relevant humanized in vitro co-culture system to evaluate the cell-specific targeting efficiency of the mannosylated lipid nanoparticle. We discovered that mannosylated lipid nanoparticles preferentially deliver miR-146a to alveolar macrophages and reduce force-induced inflammation in vitro . Our in vivo study using a clinically relevant mouse model of hemorrhagic shock-induced acute respiratory distress syndrome demonstrated that delivery of a low dose miR-146a (0.1 nmol) using mannosylated lipid nanoparticles dramatically increases miR-146a in mouse alveolar macrophages and decreases lung inflammation. These data suggest that mannosylated lipid nanoparticles may have therapeutic potential to mitigate lung injury during mechanical ventilation.


A Review of Best Practices for Monitoring and Improving Inpatient Pediatric Patient Experiences.
Achieving high-quality patient-centered care requires assessing patient and family experiences to identify opportunities for improvement. With the Child Hospital Consumer Assessment of Healthcare Providers and Systems Survey, hospitals can assess performance and make national comparisons of inpatient pediatric experiences. However, using patient and family experience data to improve care remains a challenge. We reviewed the literature on best practices for monitoring performance and undertaking activities aimed at improving pediatric patient and family experiences of inpatient care. We searched PubMed, Cumulative Index to Nursing and Allied Health Literature, and PsychINFO. We included (1) English-language peer-reviewed articles published from January 2000 to April 2019; (2) articles based in the United States, United Kingdom, or Canada; (3) articles focused on pediatric inpatient care; (4) articles describing pediatric patient and family experiences; and (5) articles including content on activities aimed at improving patient and family experiences. Our review included 25 articles. Two researchers reviewed the full article and abstracted specific information: country, study aims, setting, design, methods, results, Quality Improvement (QI) initiatives performed, internal reporting description, best practices, lessons learned, barriers, facilitators and study implications for clinical practice, patient-experience data collection, and QI activities. We noted themes across samples and care settings. We identified 10 themes of best practice. The 4 most common were (1) use evidence-based approaches, (2) maintain an internal system that communicates information and performance on patient and family experiences to staff and hospital leadership, (3) use experience survey data to initiate and/or evaluate QI interventions, and (4) identify optimal times (eg, discharge) and modes (eg, print) for obtaining patient and family feedback. These correspond to adult inpatient best practices. Both pediatric and adult inpatient best practices rely on common principles of culture change (such as evidence-based clinical practice), collaborative learning, multidisciplinary teamwork, and building and/or supporting a QI infrastructure that requires time, money, collaboration, data tracking, and monitoring. QI best practices in both pediatric and adult inpatient settings commonly rely on identifying drivers of overall ratings of care, rewarding staff for successful implementation, and creating easy-to-use and easy-to-access planning and QI tools for staff.


Contraceptive vaginal rings releasing Nestorone and ethinylestradiol: a 1-year dose-finding trial.
In a multicenter 1-year trial of contraceptive vaginal rings (rings) involving 150 women, three dose combinations of the progestin Nestorone (NES) and ethinylestradiol (EE) were compared with respect to effectiveness, safety and acceptability. Mean in vitro drug release rates for the three doses were 150 and 15, 150 and 20 and 200 and 15 microg/day of NES and EE, respectively. Each ring remained in situ for 21 days, removed for 7 days and then reinserted for a total of 13 cycles of use. We studied ring performance with respect to pregnancy and other termination events, adverse events, the extent of ovulation inhibition, serum drug levels and bleeding control. We also assessed the rings' effects on the vagina using a standardized colposcopy procedure. Seventy-two percent of the women completed the 1-year (> or = 350 days) study. In studied cycles, luteal activity (progesterone > or = 10 nmol/L) was noted in 17%, 7% and 12% of subjects with monitored cycles at the 150/15, 150/20 and 200/15 doses, respectively (p = .34). Two pregnancies occurred, both in subjects using the 200/15 microg/day ring. Breakthrough bleeding during ring use averaged about 2 days/year and breakthrough bleeding and spotting averaged about 7 days/year. In the entire trial, only two women discontinued because of bleeding problems. Medical conditions, chiefly vaginal problems, personal reasons and device loss or repeated expulsion were the principal reasons given for study discontinuation. Vaginal and cervical colposcopy, conducted with standardized techniques and standardized interpretations, revealed no elevated event incidence attributable to ring use. Clinical performance and adverse event profiles indicate that each of these 1-year NES/EE rings, used on a 21-day-in and 7-day-out regimen, provided women effective, acceptable and safe long-acting contraception under their own control.


Alzheimer's disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits.
Tau transgenic mice are valuable models to investigate the role of tau protein in Alzheimer's disease and other tauopathies. However, motor dysfunction and dystonic posture interfering with behavioral testing are the most common undesirable effects of tau transgenic mice. Therefore, we have generated a novel mouse model (THY-Tau22) that expresses human 4-repeat tau mutated at sites G272V and P301S under a Thy1.2-promotor, displaying tau pathology in the absence of any motor dysfunction. THY-Tau22 shows hyperphosphorylation of tau on several Alzheimer's disease-relevant tau epitopes (AT8, AT100, AT180, AT270, 12E8, tau-pSer396, and AP422), neurofibrillary tangle-like inclusions (Gallyas and MC1-positive) with rare ghost tangles and PHF-like filaments, as well as mild astrogliosis. These mice also display deficits in hippocampal synaptic transmission and impaired behavior characterized by increased anxiety, delayed learning from 3 months, and reduced spatial memory at 10 months. There are no signs of motor deficits or changes in motor activity at any age investigated. This mouse model therefore displays the main features of tau pathology and several of the pathophysiological disturbances observed during neurofibrillary degeneration. This model will serve as an experimental tool in future studies to investigate mechanisms underlying cognitive deficits during pathogenic tau aggregation.


Stimulation of sodium-dependent phosphate transport and signaling mechanisms induced by basic fibroblast growth factor in MC3T3-E1 osteoblast-like cells.
Physiological and pathological observations indicate that basic fibroblast growth factor (bFGF) is an important regulator of osteoblastic cell differentiation and in particular of cranial ossification. Experimental evidence suggests that inorganic phosphate (Pi) transport could be an important function of bone matrix calcification. In the present study, we address the influence of bFGF on Pi transport activity in MC3T3-E1 osteoblast-like cells derived from mouse calvaria. The results indicate that bFGF is a potent and selective stimulator of sodium-dependent Pi transport in these cells. The change in Pi transport activity induced by bFGF depends on transcription and translation and corresponds to a change in the maximum velocity of the Pi transport system (Vmax). These observations suggest that enhanced Pi transport activity in response to bFGF may result from insertion of newly synthesized Pi transporters into the plasma membrane. A selective inhibitor of fibroblast growth factor receptor (FGFR) tyrosine kinase, SU5402, blunted the stimulation of Pi transport induced by bFGF. It also prevented the increase in protein tyrosine phosphorylation induced by bFGF, including phosphorylation of FGFR-1, FGFR-2, phospholipase C-gamma (PLC-gamma), and Shc as well as the recruitment of the Grb2/Sos signaling complex. In addition, bFGF-induced the activation of the mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase (ERK) and p38, effects that were prevented by SU5402. Both the protein kinase C (PKC) inhibitor calphostin C and PKC down-regulation suppressed the stimulatory effect of bFGF on Pi transport. Selective inhibitors of ERK and p38 MAP kinases slightly reduced this cellular response with a significant effect observed with the highest concentration of the p38 MAP kinase inhibitor. In conclusion, the results of this study indicate that bFGF selectively stimulates Pi transport in calvaria-derived osteoblastic cells. The main signaling mechanism responsible for this effect involves tyrosine phosphorylation of PLC-gamma and activation of PKC, with a possible contribution of the p38 MAP kinase pathway.


The Helicobacter Eradication Aspirin Trial (HEAT): A Large Simple Randomised Controlled Trial Using Novel Methodology in Primary Care.
Clinical trials measuring the effect of an intervention on clinical outcomes are more influential than those investigating surrogate measures but are costly. We developed methods to reduce costs substantially by using existing data in primary care systems, to ask whether Helicobacter pylori eradication would reduce the incidence of hospitalisation for ulcer bleeding in aspirin users. The Helicobacter Eradication Aspirin Trial (HEAT) is a National Institute of Health Research-funded, double-blind placebo controlled randomised trial of the effects of H. pylori eradication on subsequent ulcer bleeding in infected individuals taking aspirin daily, conducted in practices across the whole of England, Wales and Northern Ireland. A bespoke web-based trial management system developed for the trial (and housed within the secure NHS Data Network) communicates directly with the HEAT Toolkit software downloaded at participating practices, which issues queries searching entry criteria (≥ 60 years, on chronic aspirin ≤ 325 mg daily, not on anti-ulcer therapy or non-steroidal anti-inflammatory drugs) for GP review of eligibility. Trial participation is invited using a highly secure automated online mail management system. Interested patients are seen once for consent and breath testing. Those with a positive test are randomised to eradication treatment (lansoprazole, clarithromycin, metronidazole) or placebo, with drug sent by post. Events are tracked by upload of accumulating information in the GP database, patient contact, review of National Hospital Episode Statistics and Office of National Statistics data. HEAT is the largest Clinical Research Network-supported drug trial, with 115,660 invitation letters sent from 850 practices, 22,922 volunteers, and 3038 H. pylori positive patients randomised to active or placebo treatment after 2.5 years of recruitment. 178 practices have performed their first follow-up data search to identify 21 potential endpoints to date. HEAT is important medically, because aspirin is so widely used, and methodologically, as a successful trial would show that large-scale studies of important clinical outcomes can be conducted at a fraction of the cost of those conducted by industry, which in turn will help to ensure that trials of primarily medical rather than commercial interest can be conducted successfully in the UK.


Self-reported Home Exercise Adherence: A Validity and Reliability Study Using Concealed Accelerometers.
Accurate measurement of adherence to prescribed exercise programs is essential. Diaries and self-report rating scales are commonly used, yet little evidence exists to demonstrate their validity and reliability. To examine the concurrent validity of adherence to home strengthening exercises measured by (1) exercise diaries and (2) a self-report rating scale, compared to adherence measured using an accelerometer concealed in an ankle cuff weight. Test-retest reliability of the self-report rating scale was also assessed. In this clinical measurement study, 54 adults aged 45 years or older with self-reported chronic knee pain were prescribed a home quadriceps-strengthening program. Over 12 weeks, participants completed paper exercise diaries and, at appointments every 2 weeks, rated their adherence on an 11-point numeric rating scale. A triaxial accelerometer was concealed in the ankle cuff weight used for exercises. Self-reported adherence rating scale data over each 2-week period were analyzed using descriptive statistics, the Wilcoxon signed-rank test, and a Bland-Altman plot to assess agreement, Spearman correlations for validity, and intraclass correlation coefficients for test-retest reliability. Exercise adherence was significantly overestimated in diaries during the 12 weeks (diary median, 220 exercises; accelerometer, 176; P<.001) and was moderately correlated with accelerometer data (r = 0.52; 95% confidence interval: 0.26, 0.69). A Bland-Altman plot indicated large between-participant variability in agreement between these measures. Self-reported adherence showed poor to fair correlations with accelerometer data (mean r = 0.23-0.39), and less than acceptable reliability (intraclass correlation coefficient = 0.79; lower 1-sided 95% confidence limit, 0.68). Exercise diaries showed questionable validity and variable levels of agreement compared with accelerometer-measured exercise completion. A self-reported adherence rating scale had limited validity and less than acceptable test-retest reliability. J Orthop Sports Phys Ther 2018;48(12):943-950. Epub 27 Jul 2018. doi:10.2519/jospt.2018.8275.


The influence of stroke unit rehabilitation on functional recovery from stroke.
Shorter lengths of hospital stay in stroke units could be due to quicker functional recovery or mechanisms of expediting hospital discharge. Stroke survivors with an intermediate prognosis at 2 weeks after stroke (n = 146) were randomized for management in a stroke rehabilitation unit or in general wards. Barthel scores were monitored at weekly intervals until hospital discharge. The duration and type of physiotherapy and occupational therapy received by patients in either setting were also recorded. The rate of change of Barthel scores, therapy input, and the duration of hospital stay were compared between the two settings. Neurological deficits and median initial Barthel scores were comparable between patients in the stroke unit (n = 73) and general wards (n = 68). Median discharge Barthel score of patients managed in the stroke unit was significantly higher than that of patients managed in general wards (15 versus 12). Median Barthel scores in the stroke unit group rose rapidly after 2 weeks, reaching a plateau at 6 weeks. The change in median Barthel score in patients in general wards was significantly slower, reaching a plateau at 12 weeks despite similar therapy input. There was a significant delay in discharging stroke patients in general wards (20 weeks) compared with those in the stroke unit (6 weeks). Functional recovery is significantly greater and more rapid in a stroke rehabilitation unit compared with general wards despite similar therapy input. These units also shorten hospital lengths of stay by expediting appropriate discharges.


Raman imaging of heme metabolism in situ in macrophages and Kupffer cells.
Herein, we provide the Raman imaging results for different stages of erythrophagocytosis of senescent red blood cells executed by isolated murine primary Kupffer cells and a murine macrophage cell line (RAW 264.7). Images were recorded with the use of 488 and 532 nm excitation lines. The use of Resonance Raman spectroscopy allowed the visualization of the heme metabolism and tracking of the systemic iron recycling process inside isolated murine Kupffer cells and RAW.264 cells. Because of the application of the different experimental assays, the erythrophagocytosis in two types of cells was presented and associated with the presence of different forms of oxidized and degradative derivatives of hemoglobin species. Moreover, we observed an increase of lipid level and later formation of lipid droplets during the erythrophagocytosis process inside RAW 264.7 macrophages and murine Kupffer cells.


Spatial Distribution and Fuzzy Health Risk Assessment of Trace Elements in Surface Water from Honghu Lake.
Previous studies revealed that Honghu Lake was polluted by trace elements due to anthropogenic activities. This study investigated the spatial distribution of trace elements in Honghu Lake, and identified the major pollutants and control areas based on the fuzzy health risk assessment at screening level. The mean total content of trace elements in surface water decreased in the order of Zn (18.04 μg/L) > Pb (3.42 μg/L) > Cu (3.09 μg/L) > Cr (1.63 μg/L) > As (0.99 μg/L) > Cd (0.14 μg/L), within limits of Drinking Water Guidelines. The results of fuzzy health risk assessment indicated that there was no obvious non-carcinogenic risk to human health, while carcinogenic risk was observed in descending order of As > Cr > Cd > Pb. As was regarded to have the highest carcinogenic risk among selected trace elements because it generally accounted for 64% of integrated carcinogenic risk. Potential carcinogenic risk of trace elements in each sampling site was approximately at medium risk level (10-5 to 10-4). The areas in the south (S4, S13, and S16) and northeast (S8, S18, and S19) of Honghu Lake were regarded as the risk priority control areas. However, the corresponding maximum memberships of integrated carcinogenic risk in S1, S3, S10-S13, S15, and S18 were of relatively low credibility (50-60%), and may mislead the decision-makers in identifying the risk priority areas. Results of fuzzy assessment presented the subordinate grade and corresponding reliability of risk, and provided more full-scale results for decision-makers, which made up for the deficiency of certainty assessment to a certain extent.


Leishmania PNUTS discriminates between PP1 catalytic subunits through an RVxF-ΦΦ-F motif and polymorphisms in the PP1 C-tail and catalytic domain.
Phosphoprotein phosphatase 1 (PP1) associates with specific regulatory subunits to achieve, among other functions, substrate selectivity. Among the eight PP1 isotypes in Leishmania, PP1-8e associates with the regulatory protein PNUTS along with the structural factors JBP3 and Wdr82 in the PJW/PP1 complex that modulates RNA polymerase II (pol II) phosphorylation and transcription termination. Little is known regarding interactions involved in PJW/PP1 complex formation, including how PP1-8e is the selective isotype associated with PNUTS. Here, we show that PNUTS uses an established RVxF-ΦΦ-F motif to bind the PP1 catalytic domain with similar interfacial interactions as mammalian PP1-PNUTS and noncanonical motifs. These atypical interactions involve residues within the PP1-8e catalytic domain and N and C terminus for isoform-specific regulator binding. This work advances our understanding of PP1 isoform selectivity and reveals key roles of PP1 residues in regulator binding. We also explore the role of PNUTS as a scaffold protein for the complex by identifying the C-terminal region involved in binding JBP3 and Wdr82 and impact of PNUTS on the stability of complex components and function in pol II transcription in vivo. Taken together, these studies provide a potential mechanism where multiple motifs within PNUTS are used combinatorially to tune binding affinity to PP1, and the C terminus for JBP3 and Wdr82 association, in the Leishmania PJW/PP1 complex. Overall, our data provide insights in the formation of the PJW/PP1 complex involved in regulating pol II transcription in divergent protozoans where little is understood.


Will Nanotechnology Bring New Hope for Gene Delivery?
The high mortality rates of cancer patients receiving standard treatments emphasize the crucial need for alternative treatments. One promising strategy is to use organic nanoparticles (NPs) for gene delivery. Although multifunctional NPs theoretically have many desirable properties as gene vectors, there are several practical barriers to successful gene delivery. In this review we discuss the properties of NPs and overview in vitro and preclinical studies of organic NPs over the past 5 years. The results of recent clinical trials suggest that the NP field holds significant promise. The annual market value for successful gene delivery could exceed US$30 billion, and this will encourage researchers to study the application of NPs to therapeutic gene delivery.


Molecular mechanisms of pancreatic stone formation in chronic pancreatitis.
Chronic pancreatitis (CP) is a progressive inflammatory disease in which the pancreatic secretory parenchyma is destroyed and replaced by fibrosis. The presence of intraductal pancreatic stone(s) is important for the diagnosis of CP; however, the precise molecular mechanisms of pancreatic stone formation in CP were left largely unknown. Cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel expressed in the apical plasma membrane of pancreatic duct cells and plays a central role in [Formula: see text] secretion. In previous studies, we have found that CFTR is largely mislocalized to the cytoplasm of pancreatic duct cells in all forms of CP and corticosteroids normalizes the localization of CFTR to the proper apical membrane at least in autoimmune pancreatitis. From these observations, we could conclude that the mislocalization of CFTR is a cause of protein plug formation in CP, subsequently resulting in pancreatic stone formation. Considering our observation that the mislocalization of CFTR also occurs in alcoholic or idiopathic CP, it is very likely that these pathological conditions can also be treated by corticosteroids, thereby preventing pancreatic stone formation in these patients. Further studies are definitely required to clarify these fundamental issues.


Two-photon imaging with diffractive optical elements.
Two-photon imaging has become a useful tool for optical monitoring of neural circuits, but it requires high laser power and serial scanning of each pixel in a sample. This results in slow imaging rates, limiting the measurements of fast signals such as neuronal activity. To improve the speed and signal-to-noise ratio of two-photon imaging, we introduce a simple modification of a two-photon microscope, using a diffractive optical element (DOE) which splits the laser beam into several beamlets that can simultaneously scan the sample. We demonstrate the advantages of DOE scanning by enhancing the speed and sensitivity of two-photon calcium imaging of action potentials in neurons from neocortical brain slices. DOE scanning can easily improve the detection of time-varying signals in two-photon and other non-linear microscopic techniques.


Development and evaluation of a cultural competency training curriculum.
Increasing the cultural competence of physicians and other health care providers has been suggested as one mechanism for reducing health disparities by improving the quality of care across racial/ethnic groups. While cultural competency training for physicians is increasingly promoted, relatively few studies evaluating the impact of training have been published. We recruited 53 primary care physicians at 4 diverse practice sites and enrolled 429 of their patients with diabetes and/or hypertension. Patients completed a baseline survey which included a measure of physician culturally competent behaviors. Cultural competency training was then provided to physicians at 2 of the sites. At all 4 sites, physicians received feedback in the form of their aggregated cultural competency scores compared to the aggregated scores from other physicians in the practice. The primary outcome at 6 months was change in the Patient-Reported Physician Cultural Competence (PRPCC) score; secondary outcomes were changes in patient trust, satisfaction, weight, systolic blood pressure, and glycosylated hemoglobin. Multiple analysis of variance was used to control for differences patient characteristics and baseline levels of the outcome measure between groups. Patients had a mean of 2.8 + 2.2 visits to the study physician during the study period. Changes in all outcomes were similar in the "Training + Feedback" group compared to the "Feedback Only" group (PRPCC: 3.7 vs.1.8; trust: -0.7 vs. -0.2 ; satisfaction: 1.9 vs. 2.5; weight: -2.5 lbs vs. -0.7 lbs; systolic blood pressure: 1.7 mm Hg vs. 0.1 mm Hg; glycosylated hemoglobin 0.02% vs. 0.07%; p = NS for all). The lack of measurable impact of physician training on patient-reported and disease-specific outcomes in the current has several possible explanations, including the relatively limited nature of the intervention. We hope that the current study will help provide a basis for future studies, using more intensive interventions with different provider groups.


Ginsenosides block HIV protease inhibitor ritonavir-induced vascular dysfunction of porcine coronary arteries.
Human immunodeficiency virus (HIV) protease inhibitor ritonavir (RTV) may induce vascular dysfunction through oxidative stress. Ginsenosides have been shown to have potential benefits on the cardiovascular system through diverse mechanisms, including antioxidative property. The objective of this study was to determine whether ginsenosides could prevent coronary arteries from RTV-induced dysfunction. Porcine coronary artery rings were incubated with RTV and ginsenosides Rb1, Rc, and Re for 24 h. Vasomotor function was recorded by a myograph tension system. In response to the thromboxane A(2) analog U-46619, the contraction of the vessel rings was significantly reduced. When cocultured with Rb1, Rc, and Re, the contractility significantly increased. In response to bradykinin at 10(-5) M, the endothelium-dependent relaxation of vessel rings was significantly reduced by 59% for RTV compared with controls (P < 0.05). When cocultured with Rb1, Rc, and Re, the relaxation significantly increased 100%, 90%, and 134%, respectively, compared with the RTV-alone groups (P > 0.05). In response to sodium nitroprusside, RTV significantly reduced vasorelaxation. In addition, the endothelial nitric oxide synthase (eNOS) mRNA levels were significantly reduced by 78% for RTV group (P < 0.05) by real-time PCR analysis. The eNOS protein levels measured by Western blot analysis and nitrite concentrations measured by Griess assay were also decreased, whereas O(2)(-) production by lucigenin-enhanced chemiluminescence was significantly increased in the RTV-treated group. These effects of RTV were effectively blocked by ginsenosides. Thus HIV protease inhibitor RTV significantly impaired the vasomotor function of porcine coronary arteries. This effect may be mediated by the downregulation of eNOS and overproduction of O(2)(-). These results suggest that ginsenosides can effectively block RTV-induced vascular dysfunction.


Mapping the immune response to the outer domain of a human immunodeficiency virus-1 clade C gp120.
The outer domain (OD) of human immunodeficiency virus (HIV)-1 gp120 represents an attractive, if difficult, target for a beneficial immune response to HIV infection. Unlike the entire gp120, the OD is structurally stable and contains the surfaces that interact with both the primary and secondary cellular receptors. The primary strain-specific neutralizing target, the V3 loop, lies within the OD, as do epitopes for two cross-reactive neutralizing monoclonal antibodies (mAbs), b12 and 2G12, and the contact sites for a number of inhibitory lectins. The OD is poorly immunogenic, at least in the context of complete gp120, but purposeful OD immunization can lead to a substantial antibody response. Here, we map the antibody generated following immunization with a clade C OD. In contrast to published data for the clade B OD, the majority of the polyclonal response to the complete clade C OD is to the V3 loop; deletion of the loop substantially reduces immunogenicity. When the loop sequence was substituted for the epitope for 2F5, a well-characterized human cross-neutralizing mAb, a polyclonal response to the epitope was generated. A panel of mAbs against the clade C OD identified two mAbs that reacted with the loop and were neutralizing for clade C but not B isolates. Other mAbs recognized both linear and conformational epitopes in the OD. We conclude that, as for complete gp120, V3 immunodominance is a property of OD immunogens, that the responses can be neutralizing and that it could be exploited for the presentation of other epitopes.


Aromatic ortho-benzylation reveals an unexpected reductant.
The discovery of a novel arylpalladium(II) reduction enables the synthesis of diarylmethanes via reductive benzylation. Benzyl chlorides were found to be the major source of hydride, acting as an alkylating agent and an aprotic surrogate for benzyl alcohol. This represents the first example of an arylpalladium(II) reduction mediated by a benzyl halide.


Neurofilament light chain: a specific serum biomarker of axonal damage severity in rat models of Chemotherapy-Induced Peripheral Neurotoxicity.
Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) is a severe and long-lasting side effect of anticancer therapy, which can severely impair patients' quality of life. It is a sensory and length-dependent neuropathy, which predominantly affects large myelinated fibers. Easy and reliable monitoring of CIPN in patients is still an unmet clinical need. Since increasing clinical evidence supports the potential use of neurofilament light chain (NfL) as a biomarker of axonal injury, in this study we measured serum NfL levels in animals chronically treated with cisplatin (CDDP) and paclitaxel (PTX), two antineoplastic drugs with different neuronal targets. Wistar rats were treated with CDDP (2 mg/kg i.p. twice/week for 4 weeks) or PTX (10 mg/kg i.v. once/week for 4 weeks). Repeated serum NfL quantification was obtained using the Single Molecule Array (Simoa) technology. The onset and progression of peripheral neurotoxicity were evaluated through neurophysiology, morphological assessments and intraepidermal nerve fibers density quantification. Our results showed that serum NfL measurements correlated with the severity of axonal damage. In fact, both treatments induced serum NfL increase, but higher levels were evidenced in PTX-treated animals, compared with CDDP-treated rats, affected by a milder neurotoxicity. Notably, also the timing of the NfL level increase was associated with the severity of morphological and functional alterations of axonal structure. Therefore, NfL could be a useful biomarker for axonal damage in order to follow the onset and severity of axonal degeneration and possibly limit the occurrence of serious PNS disease.


Ribozymes: a distinct class of metalloenzymes.
Ribozymes are an important new class of metalloenzymes that have an unlikely feature: they are made entirely of ribonucleic acid (RNA). Metal ions are essential for efficient chemical catalysis by ribozymes and are often required for the stabilization of ribozyme structure. Most ribozymes catalyze reactions at phosphorus centers through one of two major mechanistic pathways, and reaction has been observed at carbon centers. Creative experiments have revealed the position of metal ions in the active site of two ribozymes. The exploitation of variable metal geometry and reactivity has expanded ribozyme chemistry and has facilitated the application of in vitro selection for the creation of novel ribozymes.


Off-label use of the Angioseal vascular closure device for femoral arteriotomy: retrospective analysis of safety and efficacy.
Angioseal, an arteriotomy closure device (ACD), functions as a collagen plug that physically closes arteriotomy sites and can simultaneously induce platelet activation and aggregation. When used 'on-label', the safety and efficacy profile of Angioseal is superior compared with those of other ACDs. However, Angioseal is sometimes deployed in less than ideal situations. Therefore, we sought to assess the safety and efficacy of 'off-label' Angioseal use in patients undergoing femoral arteriotomies. We performed a retrospective review of all femoral arterial angiograms executed at our institution between 2008 and 2014. Patients whose femoral punctures did not fit the criteria for on-label Angioseal use were included, and were dichotomized based on vascular closure (off-label Angioseal vs manual compression). Of the 521 patients (1023 angiograms) reviewed, 303 (58.2%) patients had off-label Angioseal groin punctures. Mean patient age was 46.2±14.0 years, and 113 were men. 234 patients (77%) had off-label Angioseal deployment while 69 (22%) individuals received manual pressure, serving as controls. Demographic and procedural variables were nearly identical between the two groups but the Angioseal group comprised mostly patients that underwent neurointerventional procedures and thus received intraprocedural heparinization (41%) more often than the manual compression group (19%). The overall rate of major complications associated with off-label Angioseal deployment was low (<0.85%), and clinical complications were not independently associated with Angioseal use (OR 0.76 (95% CI 0.06 to 8.86); p=0.69). Off-label use of Angioseal was found to be safe and was not associated with an increased complication rate in our cohort.


Mechanism of spontaneous activity in afferent neurons of the zebrafish lateral-line organ.
Many auditory, vestibular, and lateral-line afferent neurons display spontaneous action potentials. This spontaneous spiking is thought to result from hair-cell glutamate release in the absence of stimuli. Spontaneous release at hair-cell resting potentials presumably results from Ca(V)1.3 L-type calcium channel activity. Here, using intact zebrafish larvae, we recorded robust spontaneous spiking from lateral-line afferent neurons in the absence of external stimuli. Consistent with the above assumptions, spiking was absent in mutants that lacked either Vesicular glutamate transporter 3 (Vglut3) or Ca(V)1.3. We then tested the hypothesis that spontaneous spiking resulted from sustained Ca(V)1.3 activity due to depolarizing currents that are active at rest. Mechanotransduction currents (I(MET)) provide a depolarizing influence to the resting potential. However, following block of I(MET), spontaneous spiking persisted and was characterized by longer interspike intervals and increased periods of inactivity. These results suggest that an additional depolarizing influence maintains the resting potential within the activation range of Ca(V)1.3. To test whether the hyperpolarization-activated cation current, I(h) participates in setting the resting potential, we applied I(h) antagonists. Both ZD7288 and DK-AH 269 reduced spontaneous activity. Finally, concomitant block of I(MET) and I(h) essentially abolished spontaneous activity, ostensibly by hyperpolarization outside of the activation range for Ca(V)1.3. Together, our data support a mechanism for spontaneous spiking that results from Ca(2+)-dependent neurotransmitter release at hair-cell resting potentials that are maintained within the activation range of Ca(V)1.3 channels through active I(MET) and I(h).


Making Sense of Patient-Generated Health Data for Interpretable Patient-Centered Care: The Transition from "More" to "Better".
The rise of health consumers and the accumulation of patient-generated health data (PGHD) have brought the patient to the centerstage of precision health and behavioral science. In this positional paper we outline an interpretability-aware framework of PGHD, an important but often overlooked dimension in health services. The aim is two-fold: First, it helps generate practice-based evidence for population health management; second, it improves individual care with adaptive interventions. However, how do we check if the evidence generated from PGHD is reliable? Are the evidence directly deployable in realworld applications? How to adapt behavioral interventions for each individual patient at the touchpoint given individual patients' needs? These questions commonly require better interpretability of PGHD-derived patient insights. Yet the definitions of interpretability are often underspecified. In the position paper, we outline an interpretability-aware framework to handle model properties and techniques that affect interpretability in the patient-centered care process. Throughout the positional paper, we contend that making sense of PGHD systematically in such an interpretability-aware framework is preferrable, because it improves on the trustworthiness of PGHD-derived insights and the consequent applications such as person-centered comparative effectiveness in patient-centered care.


An implementation science perspective on psychological science and cancer: what is known and opportunities for research, policy, and practice.
We discuss the role of implementation science in cancer and summarize the need for this perspective. Following a summary of key implementation science principles and lessons learned, we review the literature on implementation of cancer prevention and control activities across the continuum from prevention to palliative care. We identified 10 unique relevant reviews, four of which were specific to cancer. Multicomponent implementation strategies were found to be superior to single-component interventions, but it was not possible to draw conclusions about specific strategies or the range of conditions across which strategies were effective. Particular gaps identified include the need for more studies of health policies and reports of cost, cost-effectiveness, and resources required. Following this review, we summarize the types of evidence needed to make research findings more actionable and discuss emerging implementation science opportunities for psychological research on cancer prevention and control. These include innovative study designs (i.e., rapid learning designs, simulation modeling, comparative effectiveness, pragmatic studies, mixed-methods research) and measurement science (i.e., development of context-relevant measures; practical, longitudinal measures to gauge improvement; cost-effectiveness data; and harmonized patient report data). We conclude by identifying a few grand challenges for psychologists that if successfully addressed would accelerate integration of evidence into cancer practice and policy more consistently and rapidly.


[Effect of a protein-bound polysaccharide, PSK, on human hemopoietic progenitors].
Using in vitro clonal culture assays, we investigated the effects of PSK, a protein-bound polysaccharide derived from the cultured mycelium of CM101, Coriolus versicolor (Fr.) Quél in Basidiomycetes, on human hemopoietic progenitors. PSK alone did not stimulate colony formation by human bone marrow progenitors. Although 1-100 micrograms/ml of PSK had no effects on colony formation stimulated by erythropoietin and medium conditioned by phytohemagglutinin-stimulated leukocytes, more than 1 mg/ml of PSK inhibited all types of colony formation. In contrast, medium conditioned by PSK-stimulated leukocytes significantly stimulated formation of various types of colonies including erythroid bursts, granulocyte and/or macrophage colonies, eosinophil colonies, megakaryocyte colonies and mixed hemopoietic colonies. It is speculated that administration of the optimal dose of PSK can reduce the hematological suppression of antitumor drugs.


Emerging roles and mechanisms of ERK pathway mechanosensing.
The coupling between mechanical forces and modulation of cell signalling pathways is essential for tissue plasticity and their adaptation to changing environments. Whilst the number of physiological and pathological relevant roles of mechanotransduction has been rapidly expanding over the last decade, studies have been mostly focussing on a limited number of mechanosensitive pathways, which include for instance Hippo/YAP/TAZ pathway, Wnt/β-catenin or the stretch-activated channel Piezo. However, the recent development and spreading of new live sensors has provided new insights into the contribution of ERK pathway in mechanosensing in various systems, which emerges now as a fast and modular mechanosensitive pathway. In this review, we will document key in vivo and in vitro examples that have established a clear link between cell deformation, mechanical stress and modulation of ERK signalling, comparing the relevant timescale and mechanical stress. We will then discuss different molecular mechanisms that have been proposed so far, focussing on the epistatic link between mechanics and ERK and discussing the relevant cellular parameters affecting ERK signalling. We will finish by discussing the physiological and the pathological consequences of the link between ERK and mechanics, outlining how this interplay is instrumental for self-organisation and long-range cell-cell coordination.


Single-grain OSL chronologies for the Still Bay and Howieson's Poort industries and the transition between them: Further analyses and statistical modelling.
The chronology of the Still Bay (SB) and Howieson's Poort (HP) lithic industries remains an issue of keen interest because of the central role of these two phases of technological and behavioural innovation within the Middle Stone Age of southern Africa. Several dating studies have been conducted on SB and HP sites, including a pair published by the present authors and our colleagues in 2008 and 2013. These reported the results of systematically applying single-grain optically stimulated luminescence (OSL) dating procedures to 10 sites in South Africa, Lesotho and Namibia to constrain the timing of the start and end of the SB and HP and reveal the existence of a gap of several millennia between them. Alternative ages for these two industries have since been proposed by others for one of these South African sites (Diepkloof Rockshelter) and some concerns have been raised about the procedures used in our earlier studies to estimate the beta dose rates for a small number of samples. Here, we provide an update on our chronology for the SB and HP and address the issues raised about the methods that we used previously to estimate the beta dose rates and their associated uncertainties. To test the sensitivity of our new SB and HP ages to different underlying assumptions, we have run the same statistical model as that used in our 2008 and 2013 studies under three different scenarios. We show that the ages for the different samples are insensitive to how we analytically process or statistically model our data, and that our earlier conclusions about timing of the start and end of the SB and the HP and the probability of a gap between them remain true for two of the three scenarios. We conclude by bringing our study into the context of additional chronometric, stratigraphic and lithic technology studies that have been conducted in the intervening decade.


Association between alcohol advertising and beer drinking among adolescents.
To analyze the association between alcohol advertising and beer drinking among adolescents. A total of 1,115 students enrolled in the 7th and 8th grades of three public schools in São Bernardo do Campo, Southeastern Brazil, were interviewed in 2006. The independent variables were as follows: attention paid to alcohol advertisements, belief in the veracity of advertisements, affective response to advertisements and previous tobacco use, among others. The dependent variable was beer drinking in the last 30 days. Univariate and multiple logistic regression analyses were made. Age, importance given to religion and the presence of a bathroom in the home were used as control. Beer drinking in the last 30 days was associated with tobacco use (OR = 4.551), having a favorite alcoholic beverage brand (OR = 5.150), poor parental supervision (OR = 2.139), considering parties one goes to as similar to those seen in commercials (OR = 1.712), paying more attention to advertisements (OR = 1.563) and believing that advertisements tell the truth (OR = 2.122). This association remained, even in the presence of other variables associated with beer drinking. Alcohol advertisements are positively associated with recent beer drinking, because they remind adolescents of their own reality or make them believe in their veracity. Alcohol advertisement restrictions can be one way to prevent alcohol use and abuse by adolescents.


Vocational Identity and Ego Identity Status in Korean Nursing Students.
The purpose of this study was to investigate the association between vocational identity and ego identity status among Korean nursing students. The participants were 311 nursing students in South Korea who were attending either a 4-year bachelor's program or a 3-year diploma program. Data were collected using self-report questionnaires that addressed vocational identity, ego identity status, and demographic information. The data were analyzed using descriptive statistics, one-way analysis of variance, t test, and Chi-square test. In terms of ego identity status, 31.5% of nursing students were classified as being in diffusion status, followed by 28.3% in low profile moratorium status, 14.8% in moratorium status, 14.1% in foreclosure status, and 11.3% in achievement status. Vocational identity differed according to ego identity status; vocational identity among students who were in achievement status was higher than for those in all other statuses. Vocational identity also differed according to grade level and monthly family income. Ego identity status was related to the type of program enrolled in, grade level, and monthly family income. These findings show that nursing students in identity achievement status have secure and clear vocational identities. Further longitudinal and qualitative studies are needed to find out if identity formation among nursing students changes with age.


Assessing the global threat from Zika virus.
First discovered in 1947, Zika virus (ZIKV) infection remained a little-known tropical disease until 2015, when its apparent association with a considerable increase in the incidence of microcephaly in Brazil raised alarms worldwide. There is limited information on the key factors that determine the extent of the global threat from ZIKV infection and resulting complications. Here, we review what is known about the epidemiology, natural history, and public health effects of ZIKV infection, the empirical basis for this knowledge, and the critical knowledge gaps that need to be filled.


Prevalence and correlates of body image dissatisfaction in postmenopausal women.
Dissatisfaction with one's body image is widespread and can have serious health consequences; however, research about its prevalence and correlates in older women is limited. We analyzed data from 75,256 women participating in the Women's Health Initiative Observational Study, a longitudinal study of postmenopausal women's health. Measures used in the study were collected at baseline and/or the third year of follow-up between 1993 and 2002. The majority of participants (83%) in this study were dissatisfied with their bodies because they perceived themselves as heavier than their ideal. Overall, the multiple and significant correlates of body image dissatisfaction explained 36.2% of the variance in the body image dissatisfaction score, with body mass index (BMI) and change in BMI being the two most important contributors to explaining the variance. The results of this study suggest future research should focus on the utility of interventions to reduce dissatisfaction with body image in postmenopausal women that target either maintenance of a lower BMI through diet and exercise, and/or body acceptance. Further, future research should aim to identify factors in addition to body size that drive body image dissatisfaction.


Differential Progression of Dysphagia in Heredity and Sporadic Ataxias Involving Multiple Systems.
Sporadic ataxia affecting multiple systems, such as cerebellar, extrapyramidal, and autonomic systems, is known as multiple system atrophy cerebellar type (MSA-C), while similar multisystem involvements are seen in certain types of hereditary ataxia, such as spinocerebellar ataxia type 3 (SCA3). Dysphagia is a common symptom that can predispose to aspiration pneumonia, a major cause of death in patients with these diseases. Although the progressions of dysphagia in patients with MSA-C have been reported sporadically, those in SCA3 have not been reported. We retrospectively compared the results of repetitive videofluoroscopic examinations in patients with SCA3 (n = 6) and in those with MSA-C (n = 7). The result showed that the gross progression of dysphagia was significantly slower in patients with SCA3 than in those with MSA-C, but the maximum progression speeds were not significantly different. The dysphagia severities were not associated with impaired activity of daily living evaluated by the Barthel index in MSA-C, but were associated in SCA3. Despite the small number of patients enrolled, these data suggest that physicians should monitor swallowing functions in patients with SCA3 after mild dysphagia develops because it may progress as rapidly as it does in MSA-C.


Clinical applications of autologous cryoplatelet gel for the reconstruction of the maxillary sinus. A new approach for the treatment of chronic oro-sinusal fistula.
The authors report their clinical experience regarding an original method of surgical repair of oro-sinusal communications. From September 1999 to December 2003, 13 patients (7 male and 6 female patients; mean age: 52 years, range: 24-68 years) underwent surgical repair of an oro-antral fistula by means of cryoplatelet gel: in three patients, it was mixed with bioglass granules; in two, it was mixed with Bioss; in three, it was mixed with particulate bone extracted by means of a bone grafter from the oral cavity close to the operative site, with addition of demineralised bovine bone; in three, it was used together with porose hydroxyapatite, and in two patients the cryoplatelet gel was used only. No postoperative complication was reported; primary wound healing was achieved within seven to nine days. A bony orthopantoscintigraphy was performed a few months following the operative procedure, showing an active osteogenic process. In eight patients, a CT was performed after 8 to 12 months from the operation, showing a normal pneumatization with reconstruction of the floor of the maxillary sinus. Although preliminary, these findings seem to suggest that the use of bioengineered materials coupled with growth factors and osteoprogenitor cells may represent a valuable alternative to autologous bone transplantation for the reconstruction of the maxillary sinus.