Identification of Multiple Blastocystis Subtypes in Domestic Animals From Colombia Using Amplicon-Based Next Generation Sequencing.
Blastocystis is frequently reported in fecal samples from animals and humans worldwide, and a variety of subtypes (STs) have been observed in wild and domestic animals. In Colombia, few studies have focused on the transmission dynamics and epidemiological importance of Blastocystis in animals. In this study, we characterized the frequency and subtypes of Blastocystis in fecal samples of domestic animals including pigs, minipigs, cows, dogs, horses, goats, sheep, and llama from three departments of Colombia. Of the 118 fecal samples included in this study 81.4% (n = 96) were positive for Blastocystis using a PCR that amplifies a fragment of the small subunit ribosomal RNA (SSU rRNA) gene. PCR positive samples were sequenced by next generation amplicon sequencing (NGS) to determine subtypes. Eleven subtypes were detected, ten previously reported, ST5 (50.7%), ST10 (47.8%), ST25 (34.3%), ST26 (29.8%), ST21 (22.4%), ST23 (22.4%), ST1 (17.9%), ST14 (16.4%), ST24 (14.9%), ST3 (7.5%), and a novel subtype, named ST32 (3.0%). Mixed infection and/or intra -subtype variations were identified in most of the samples. Novel ST32 was observed in two samples from a goat and a cow. To support novel subtype designation, a MinION based sequencing strategy was used to generate the full-length of the SSU rRNA gene. Comparison of full-length nucleotide sequences with those from current valid subtypes supported the designation of ST32. This is the first study in Colombia using NGS to molecularly characterize subtypes of Blastocystis in farm animals. A great diversity of subtypes was observed in domestic animals including subtypes previously identified in humans. Additionally, subtype overlap between the different hosts examined in this study were observed. These findings highlight the presence of Blastocystis subtypes with zoonotic potential in farm animals indicating that farm animals could play a role in transmission to humans.


Effects of pranayam breathing on respiratory pressures and sympathovagal balance of patients with chronic airflow limitation and in control subjects.
The objective of this study was to compare the effects of Pranayam breathing on respiratory muscle strength measured as maximum expiratory and inspiratory pressures (MEP and MIP) and relevant spirometry parameters in patients with chronic obstructive pulmonary disease (COPD) and in control subjects, and on the sympatho-vagal balance in both the groups. The research was performed in the Clinical Physiology Department, Sultan Qaboos University Hospital, Oman. Eleven patients (mean age 43.91 ± 20.56 yr; mean BMI 21.9 ± 5.5 kg/m(2)) and 6 controls (43.5 ± 14.6yr; 25.4 ± 3.2 kg/m(2)) learnt and practised Pranayam. Their respiratory and cardiovascular parameters were recorded. Their respiratory "well being" was noted as a visual analogue score (VAS). The respiratory parameters were expressed as a percentage change of predicted values. Patients' respiratory parameters were significantly lower than those of controls. Patients' maximum respiratory pressures did not improve after Pranayam; however, they showed significant improvement in VAS 5.4 ± 2.4 to 7.2 ± 1.2 (P < 0.03). Controls showed significant increase in MIP after Pranayam exercises. There were no changes in other spirometry indices. Controls showed significant increase in their systolic blood pressure and stroke index after exercise. The vago-sympathetic balance shifted towards sympathetic in both patients and controls after exercise. The improvement in MIP in controls indicated the positive effect of Pranayam exercise; however, it may not be an adequately stressful exercise to produce changes in the respiratory parameters of COPD patients. The increase in VAS in patients suggested improvement in respiratory distress and quality of life.


Wavelet approximation-based affine invariant shape representation functions.
In this paper, new wavelet-based affine invariant functions for shape representation are presented. Unlike the previous representation functions, only the approximation coefficients are used to obtain the proposed functions. One of the derived functions is computed by applying a single wavelet transform; the other function is calculated by applying two different wavelet transforms with two different wavelet families. One drawback of the previously derived detail-based invariant representation functions is that they are sensitive to noise at the finer scale levels, which limits the number of scale levels that can be used. The experimental results in this paper demonstrate that the proposed functions are more stable and less sensitive to noise than the detail-based functions.


Temperature-Modulated Micromechanical Thermal Analysis with Microstring Resonators Detects Multiple Coherent Features of Small Molecule Glass Transition.
Micromechanical Thermal Analysis utilizes microstring resonators to analyze a minimum amount of sample to obtain both the thermal and mechanical responses of the sample during a heating ramp. We introduce a modulated setup by superimposing a sinusoidal heating on the linear heating and implementing a post-measurement data deconvolution process. This setup is utilized to take a closer look at the glass transition as an important fundamental feature of amorphous matter with relations to the processing and physical stability of small molecule drugs. With an additionally developed image and qualitative mode shape analysis, we are able to separate distinct features of the glass transition process and explain a previously observed two-fold change in resonance frequency. The results from this setup indicate the detection of initial relaxation to viscous flow onset as well as differences in mode responsivity and possible changes in the primary resonance mode of the string resonators. The modulated setup is helpful to distinguish these processes during the glass transition with varying responses in the frequency and quality factor domain and offers a more robust way to detect the glass transition compared to previously developed methods. Furthermore, practical and theoretical considerations are discussed when performing measurements on string resonators (and comparable emerging analytical techniques) for physicochemical characterization.


A comparison of common screening methods for predicting aberrant drug-related behavior among patients receiving opioids for chronic pain management.
The ability to predict risk for violating opioid medication policies, known as aberrant drug-related behavior, is critical for providing optimal treatment. Many pain management centers measure risk using one of several partially validated measures: the Screener and Opioid Assessment for Patients with Pain (SOAPP), the Diagnosis, Intractability, Risk, and Efficacy inventory (DIRE), and/or the Opioid Risk Tool (ORT). However, little is known about how these measures compare with each other in predicting aberrant drug-related behavior and discontinuance of opioid pain medications. The current study aimed to address this research question. Participants were 48 patients who attended a pain management center in Tennessee but were later discontinued from opioids for aberrant drug-related behavior. Patients referred for opioid medication for pain management participated in a semi-structured clinical interview with the staff psychologist and completed the aforementioned measures. Patients generally returned to the pain clinic on a monthly basis for medication management. Results. Analyses compared the sensitivity of each self-report measure and the clinical interview in predicting discontinuance for aberrant drug-related behavior. showed the highest sensitivity for the clinical interview (0.77) and the SOAPP (0.72), followed by the ORT (0.45) and the DIRE (0.17). Combining the clinical interview with the SOAPP increased sensitivity to 0.90. Among patients who were discontinued from opioids for aberrant drug-related behaviors, the clinical interview and the SOAPP were most effective at predicting risk at baseline. Implications for future research and clinical practice are discussed.


IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome.
Expansion of the polyglutamine repeat within the protein Huntingtin (Htt) causes Huntington's disease, a neurodegenerative disease associated with aging and the accumulation of mutant Htt in diseased neurons. Understanding the mechanisms that influence Htt cellular degradation may target treatments designed to activate mutant Htt clearance pathways. We find that Htt is phosphorylated by the inflammatory kinase IKK, enhancing its normal clearance by the proteasome and lysosome. Phosphorylation of Htt regulates additional post-translational modifications, including Htt ubiquitination, SUMOylation, and acetylation, and increases Htt nuclear localization, cleavage, and clearance mediated by lysosomal-associated membrane protein 2A and Hsc70. We propose that IKK activates mutant Htt clearance until an age-related loss of proteasome/lysosome function promotes accumulation of toxic post-translationally modified mutant Htt. Thus, IKK activation may modulate mutant Htt neurotoxicity depending on the cell's ability to degrade the modified species.


Beam waist measurement for terahertz time-domain spectroscopy experiments.
Classical masking aperture methods are found to be mostly inaccurate to determine the terahertz beam size in terahertz time-domain spectroscopy (TDS) experiments, owing to complex diffraction effects. Here, we present a simple and reliable method for measuring beam waists in terahertz TDS. It is based on the successive diffraction by an opaque disk followed by a small circular aperture.


Mechanistic insights on the responses of plant and ecosystem gas exchange to global environmental change: lessons from Biosphere 2.
Scaling up leaf processes to canopy/ecosystem level fluxes is critical for examining feedbacks between vegetation and climate. Collectively, studies from Biosphere 2 Laboratory have provided important insight of leaf-to-ecosystem investigations of multiple environmental parameters that were not before possible in enclosed or field studies. B2L has been a testing lab for the applicability of new technologies such as spectral approaches to detect spatial and temporal changes in photosynthesis within canopies, or for the development of cavity ring-down isotope applications for ecosystem evapotranspiration. Short and long term changes in atmospheric CO2, drought or temperature allowed for intensive investigation of the interactions between photosynthesis and leaf, soil and ecosystem respiration. Experiments conducted in the rainforest biome have provided some of the most comprehensive dataset to date on the effects of climate change variables on tropical ecosystems. Results from these studies have been later corroborated in natural rainforest ecosystems and have improved the predictive capabilities of models that now show increased resilience of tropics to climate change. Studies of temperature and CO2 effects on ecosystem respiration and its leaf and soil components have helped reconsider the use of simple first-order kinetics for characterizing respiration in models. The B2L also provided opportunities to quantify the rhizosphere priming effect, or establish the relationships between net primary productivity, atmospheric CO2 and isoprene emissions.


Can reintroduction of beavers improve insect biodiversity?
Ecosystem engineering species, such as beavers, may help the restoration of biodiversity. Through the building of dams and lodges and altering the natural hydrology, beavers change the habitat structure and create multiple habitats that facilitate a wide variety of other organisms including terrestrial invertebrate communities. Here we study the effect of beaver reintroduction in Klosterheden in Denmark on biomass of flying invertebrates and diversity of moths. Further, aerial photos were used to assess riparian structure and productivity using the normalized difference vegetation index (NDVI). Our findings show that the presence of beavers affected flying invertebrate biomass, but that this was dependent on time of the year. Further, a strong effect of presence of beavers was found on diversity of moths. The results also show an increase in vegetation productivity and structural heterogeneity at sites with presence of beavers. Overall, our results demonstrate the importance of beavers as important ecosystem engineers that affect invertebrate species composition and abundance, as well as riparian structure and productivity.


Cost-effectiveness analysis of cervical cancer screening strategies based on the Papanicolaou smear test in Korea.
Despite the increasing number of screening examinations performed for cervical cancer utilizing the Papanicolaou smear test (Pap test), few studies have examined whether this strategy is cost-effective in Korea. This study was conducted to evaluate the cost-effectiveness of cervical cancer screening strategies incorporating the Pap test based on age at the start and end of screening as well as screening interval. We designed four alternative screening strategies based on patient age when screening was started (20 or 30 years) and discontinued (lifetime, 79 years). Each strategy was assessed at screening intervals of 1, 2, 3, or 5 years. A Markov model was developed to determine the cost-effectiveness of the 16 possible cervical cancer screening strategies, and this was evaluated from a societal perspective. The main outcome measures were average lifetime cost, incremental quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Compared with various strategies comprising younger starting age, discontinuation age, and longer screening intervals, strategies employing annual screening for cervical cancer starting at a target age of 30 years and above were the most cost-effective, with an ICER of 21,012.98 dollars per QALY gained (with a Korean threshold of 30,000,000 KRW or US$27,272). We found that annual screening for cervical cancer beginning at a target age of 30 years and above is most cost-effective screening strategy. Considering the potential economic advantages, more intense screening policies for cervical cancer might be favorable among countries with high rates of cervical cancer and relatively low screening costs.


Epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children.
The precise epidemiology of childhood pneumonia remains poorly defined. Accurate and prompt etiologic diagnosis is limited by inadequate clinical, radiologic, and laboratory diagnostic methods. The objective of this study was to determine as precisely as possible the epidemiology and morbidity of community-acquired pneumonia in hospitalized children. Consecutive immunocompetent children hospitalized with radiographically confirmed lower respiratory infections (LRIs) were evaluated prospectively from January 1999 through March 2000. Positive blood or pleural fluid cultures or pneumolysin-based polymerase chain reaction assays, viral direct fluorescent antibody tests, or viral, mycoplasmal, or chlamydial serologic tests were considered indicative of infection by those organisms. Methods for diagnosis of pneumococcal pneumonia among study subjects were published by us previously. Selected clinical characteristics, indices of inflammation (white blood cell and differential counts and procalcitonin values), and clinical outcome measures (time to defervescence and duration of oxygen supplementation and hospitalization) were compared among groups of children. One hundred fifty-four hospitalized children with LRIs were enrolled. Median age was 33 months (range: 2 months to 17 years). A pathogen was identified in 79% of children. Typical respiratory bacteria were identified in 60% (of which 73% were Streptococcus pneumoniae), viruses in 45%, Mycoplasma pneumoniae in 14%, Chlamydia pneumoniae in 9%, and mixed bacterial/viral infections in 23%. Preschool-aged children had as many episodes of atypical bacterial LRIs as older children. Children with typical bacterial or mixed bacterial/viral infections had the greatest inflammation and disease severity. Multivariate logistic-regression analyses revealed that high temperature (> or = 38.4 degrees C) within 72 hours after admission (odds ratio: 2.2; 95% confidence interval: 1.4-3.5) and the presence of pleural effusion (odds ratio: 6.6; 95% confidence interval: 2.1-21.2) were significantly associated with bacterial pneumonia. This study used an expanded diagnostic armamentarium to define the broad spectrum of pathogens that cause pneumonia in hospitalized children. The data confirm the importance of S pneumoniae and the frequent occurrence of bacterial and viral coinfections in children with pneumonia. These findings will facilitate age-appropriate antibiotic selection and future evaluation of the clinical effectiveness of the pneumococcal conjugate vaccine as well as other candidate vaccines.


Levels of selected carcinogens and toxicants in vapour from electronic cigarettes.
Electronic cigarettes, also known as e-cigarettes, are devices designed to imitate regular cigarettes and deliver nicotine via inhalation without combusting tobacco. They are purported to deliver nicotine without other toxicants and to be a safer alternative to regular cigarettes. However, little toxicity testing has been performed to evaluate the chemical nature of vapour generated from e-cigarettes. The aim of this study was to screen e-cigarette vapours for content of four groups of potentially toxic and carcinogenic compounds: carbonyls, volatile organic compounds, nitrosamines and heavy metals. Vapours were generated from 12 brands of e-cigarettes and the reference product, the medicinal nicotine inhaler, in controlled conditions using a modified smoking machine. The selected toxic compounds were extracted from vapours into a solid or liquid phase and analysed with chromatographic and spectroscopy methods. We found that the e-cigarette vapours contained some toxic substances. The levels of the toxicants were 9-450 times lower than in cigarette smoke and were, in many cases, comparable with trace amounts found in the reference product. Our findings are consistent with the idea that substituting tobacco cigarettes with e-cigarettes may substantially reduce exposure to selected tobacco-specific toxicants. E-cigarettes as a harm reduction strategy among smokers unwilling to quit, warrants further study. (To view this abstract in Polish and German, please see the supplementary files online.).


Do not attempt cardiopulmonary resuscitation (DNACPR) decisions for older medical inpatients: a cohort study.
A decision not to attempt cardiopulmonary resuscitation in the event of cardiorespiratory arrest requires a discussion between the doctor and the patient and/or their relatives. We aimed to determine how many older patients admitted to acute medical wards had a pre-existing 'do not attempt cardiopulmonary resuscitation' (DNACPR) decision, how many had one recorded on the ward and how many of those who died had a DNACPR decision in place. A prospective cohort study, using data from medical records, of 481 consecutive patients aged ≥65 years admitted to the six acute medical wards of the John Radcliffe Hospital, Oxford. 105/481 (22%) had a DNACPR decision at ward admission, 30 of which had been made in the emergency unit. A further 45 decisions were recorded on the ward, mostly after discussion with relatives. Of the 37 patients who died, 36 had a DNACPR decision. For the 20 deceased patients whose DNACPR decision was recorded during their admission, the median time from documentation to death was 4 days with 7/20 (35%) recorded the day before death. Older patients with multimorbidity need the opportunity to discuss the role of CPR earlier in their care and preferably before acute hospital admission.


Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma.
Cells with deficient DNA mismatch repair develop microsatellite instability. Extensive microsatellite instability (MSI-high) is characteristic of colorectal carcinomas in hereditary nonpolyposis colorectal carcinoma (HNPCC) and in 10-% 15% of sporadic colorectal carcinomas. Microsatellite instability-high colorectal carcinomas differ from others in important clinical and pathologic features. However, MSI typing is expensive and not widely available. Microsatellite instability type may be predicted by tumor-infiltrating lymphocytes (TILs), which can be evaluated with ordinary light microscopy. The authors evaluated TILs as a pathology screen for MSI-high status in 138 colorectal carcinomas that had been evaluated for MSI in a variety of studies. This case series was systematically enriched with HNPCC and other MSI-high cases to allow accurate sensitivity and specificity estimation. Tumor-infiltrating lymphocytes were quantitated as TILs per 10 high-power microscopic fields by an observer blinded to MSI status. Of the 138 carcinomas studied, 67 (48.6%) were MSI-high, 22 (15.9%) were MSI-low, and 49 (35.5%) were MSI-stable. All 25 HNPCC colorectal carcinomas were MSI-high. Tumor-infiltrating lymphocytes counts ranged from 0 to 300, with a markedly skewed distribution (median, 11; mean, 36). Sensitivity and specificity for selected cut points of TIL count were computed. Using a TIL count of 5 as a cut point yields a sensitivity of 93% and specificity of 62%. In a population in which 12% were MSI-high, consideration of TIL could reduce the number of colorectal carcinomas referred for MSI testing by greater than one-half, and still 93% of the MSI-high carcinomas would be identified. The presence of MSI defines a subset of colorectal carcinomas with special molecular etiology and characteristic clinical, pathologic features, inclusive of increased survival. The authors conclude that quantification of TILs may provide a simple, single criterion for choosing which colorectal carcinomas are candidates for MSI testing.


A conceptual framework for understanding illegal killing of large carnivores.
The growing complexity and global nature of wildlife poaching threaten the survival of many species worldwide and are outpacing conservation efforts. Here, we reviewed proximal and distal factors, both social and ecological, driving illegal killing or poaching of large carnivores at sites where it can potentially occur. Through this review, we developed a conceptual social-ecological system framework that ties together many of the factors influencing large carnivore poaching. Unlike most conservation action models, an important attribute of our framework is the integration of multiple factors related to both human motivations and animal vulnerability into feedbacks. We apply our framework to two case studies, tigers in Laos and wolverines in northern Sweden, to demonstrate its utility in disentangling some of the complex features of carnivore poaching that may have hindered effective responses to the current poaching crisis. Our framework offers a common platform to help guide future research on wildlife poaching feedbacks, which has hitherto been lacking, in order to effectively inform policy making and enforcement.


Fetal surgery for myelomeningocele: history, research, clinical trials, and future directions.
Myelomeningocele, more commonly known as spina bifida, is the most common neural tube defect worldwide. In the United States, it is the primary cause of lifelong childhood paralysis with approximately four children born daily with this devastating disease. To minimize damage to the exposed spinal cord and prevent ascending central nervous system infections, postnatal closure of the spinal defect has been the standard of care for decades. Research into the mechanism of spinal cord injury in those with spina bifida revealed that damage continues to accrue during the gestational period. Prenatal defect closure via in utero surgery was proposed to prevent this early deterioration of the spinal cord, and early animal research demonstrated that prenatal repair was feasible and promising. This paved the way for the first human prenatal repairs in the mid-to-late 1990s. Following the promising outcomes observed during the first human cases, a randomized controlled trial, the Management of Myelomeningocele Study (MOMS), was conducted comparing postnatal repair of spina bifida to prenatal repair. The MOMS trial demonstrated that to those undergoing prenatal repair of spina bifida had a decreased need for ventriculoperitoneal shunting and improved lower extremity motor function. With the success of the MOMS trial, in utero repair is now considered the standard of care in those who meet the criteria for prenatal repair. This review will provide an overview of spina bifida and its impact, highlight the historical changes in care, describe the early research and theory that made prenatal repair an option, discuss the clinical experiences with human fetal repair and briefly touch on future research directions for those with myelomeningocele.


The entry-level occupational therapy clinical doctorate: advantages, challenges, and international issues to consider.
Internationally, occupational therapy education has gone through several paradigm shifts during the last few decades, moving from certificate to diploma to bachelors to masters and now in some instances to clinical doctorate as the entry-level professional credential to practice. In the United States there is a recommendation under consideration by the American Occupational Therapy Association (AOTA) that by 2025, all occupational therapy university programs will move to the clinical doctorate level. It should be noted, however, that the AOTA Board can only make recommendations and it is the Accreditation Council for Occupational Therapy Education (ACOTE) who has regulatory authority to approve such a change. What are the potential implications for the profession, our clients, and funders of occupational therapy services? What are the primary drivers for the move towards the clinical doctorate being the educational entry point? Is the next step in the evolution of occupational therapy education globally a shift to the entry-level clinical doctorate? This article reviews current literature and discusses issues about the occupational therapy entry-level clinical doctorate. The published evidence available about the occupational therapy entry-level clinical doctorate is summarized and the perceived or frequently cited pros and cons of moving to the clinical doctorate as the singular entry point to occupational therapy practice are considered. The potential impacts of the introduction of the clinical doctorate as the entry-to-practice qualification across the United States on the occupational therapy community internationally will be briefly discussed. If the United States moves toward the entry-level clinical doctorate as the only educational starting point for the profession, will other jurisdictions follow suit? Further discourse and investigation of this issue both inside and outside of the United States is needed so that informed decisions can be made.


Economic development and health status among the poor in squatter settlements of Karachi.
Socioeconomic status is an important determinant of health outcome measures. This study examines and presents some of the important health outcomes amongst the higher and lower socioeconomic groups within the urban poor. Data analysis is based on a Health and Demographic Survey conducted in urban squatter settlements of Karachi in 1996. A structured questionnaire was administered to all households in the catchment area. The indicator used to assess economic status is ownership of assets. Comparison between the two economic levels shows that the lower socio-economic group was more likely to experience child mortality, (CI; 1.02-1.29, p = 0.02) have lower contraceptive usage (CI; 2.11-2.64; p < 0.001) and childhood immunization rates (CI; 2.08-2.40, p < 0.001). No significant association was observed between economic levels and prevalence of diarrhea. The housing, literacy and employment status was consistently better in the higher economic stratum who were more likely to be Pushto-Punjabi speaking as compared to the Sindhi speaking population. To have sustainable improvement in the health status of the poor, those who are most vulnerable need to be identified and programs aiming to improve health should also undertake broader development initiatives like raising family income.


Interaction of ATF6 and serum response factor.
Serum response factor (SRF) is a transcription factor which binds to the serum response element (SRE) in the c-fos promoter. It is required for regulated expression of the c-fos gene as well as other immediate-early genes and some tissue-specific genes. To better understand the regulation of SRF, we used a yeast interaction assay to screen a human HeLa cell cDNA library for SRF-interacting proteins. ATF6, a basic-leucine zipper protein, was isolated by binding to SRF and in particular to its transcriptional activation domain. The binding of ATF6 to SRF was also detected in vitro. An ATF6-VP16 chimera activated expression of an SRE reporter gene in HeLa cells, suggesting that ATF6 can interact with endogenous SRF. More strikingly, an antisense ATF6 construct reduced serum induction of a c-fos reporter gene, suggesting that ATF6 is involved in activation of transcription by SRF. ATF6 was previously partially cloned as a member of the ATF family. The complete cDNA of ATF6 was isolated, and its expression pattern was described.


Wing-augmentation reduces femoral head cutting out of dynamic hip screw.
The dynamic hip screw (DHS) is commonly used in the treatment of femoral intertrochanteric fracture with high satisfactory results. However, post-operative failure does occur and result in poor prognosis. The most common failure is femoral head varus collapse, followed by lag screw cut-out through the femoral head. In this study, a novel-designed DHS with two supplemental horizontal blades was used to improve the fixation stability. In this study, nine convention DHS and 9 Orthopaedic Device Research Center (ODRC) DHSs were tested in this study. Each implant was fixed into cellular polyurethane rigid foam as a surrogate of osteoporotic femoral head. Under biaxial rocking motion, all constructs were loaded to failure point (12mm axial displacement) or up to 20,000 cycles of 1.45kN peak magnitude were achieved, whichever occurred first. The migration kinematics was continuously monitored and recorded. The final tip-to-apex distance, rotational angle and varus deformation were also recorded. The results showed that the ODRC DHS sustained significantly more loading cycles and exhibited less axial migration in comparison to the conventional DHS. The ODRC DHS showed a significantly smaller bending strain and larger torsional strain compared to the conventional DHS. The changes in tip-to-apex distance (TAD), post-study varus angle, post-study rotational angle of the ODRC DHS were all significantly less than that of the conventional DHS (p < 0.05). We concluded that the ODRC DHS augmented with two horizontal wings would increase the bone-implant interface contact surface, dissipate the load to the screw itself, which improves the migration resistance and increases the anti-rotational implant effect. In conclusion, the proposed ODRC DHS demonstrated significantly better migration resistance and anti-rotational effect in comparison to the conventional DHS construct.


Telomere length homeostasis is achieved via a switch between telomerase- extendible and -nonextendible states.
Telomerase counteracts telomere erosion that stems from incomplete chromosome end replication and nucleolytic processing. A precise understanding of telomere length homeostasis has been hampered by the lack of assays that delineate the nonuniform telomere extension events of single chromosome molecules. Here, we measure telomere elongation at nucleotide resolution in Saccharomyces cerevisiae. The number of nucleotides added to a telomere in a single cell cycle varies between a few to more than 100 nucleotides and is independent of telomere length. Telomerase does not act on every telomere in each cell cycle, however. Instead, it exhibits an increasing preference for telomeres as their lengths decline. Deletion of the telomeric proteins Rif1 or Rif2 gives rise to longer telomeres by increasing the frequency of elongation events. Thus, by taking a molecular snapshot of a single round of telomere replication, we demonstrate that telomere length homeostasis is achieved via a switch between telomerase-extendible and -nonextendible states.


Wide-field in vivo neocortical calcium dye imaging using a convection-enhanced loading technique combined with simultaneous multiwavelength imaging of voltage-sensitive dyes and hemodynamic signals.
In vivo calcium imaging is an incredibly powerful technique that provides simultaneous information on fast neuronal events, such as action potentials and subthreshold synaptic activity, as well as slower events that occur in the glia and surrounding neuropil. Bulk-loading methods that involve multiple injections can be used for single-cell as well as wide-field imaging studies. However, multiple injections result in inhomogeneous loading as well as multiple sites of potential cortical injury. We used convection-enhanced delivery to create smooth, continuous loading of a large area of the cortical surface through a solitary injection site and demonstrated the efficacy of the technique using confocal microscopy imaging of single cells and physiological responses to single-trial events of spontaneous activity, somatosensory-evoked potentials, and epileptiform events. Combinations of calcium imaging with voltage-sensitive dye and intrinsic signal imaging demonstrate the utility of this technique in neurovascular coupling investigations. Convection-enhanced loading of calcium dyes may be a useful technique to advance the study of cortical processing when widespread loading of a wide-field imaging is required.


Ictal bradycardia in a young child with focal cortical dysplasia in the right insular cortex.
We report on a three and a half year old child with episodic sinus bradycardia during habitual seizures and prolonged interictal discharges due to focal cortical dysplasia in the anterior 2/3 of the insula and the inferior frontal cortex. Seizure-induced bradycardia is rarely reported in children. Bradycardia is suspected to be related to sudden death, a rare complication of a chronic seizure disorder. Several well-documented cases in adult patients reveal a high incidence of temporal epilepsy, but MRI and PET studies in healthy subjects suggest a major role of the insular cortex, especially the right, in cardiac regulation. Our finding underlines the predominance of the right insula in cardiac control, which already seems to be present in children.


Serum levels of antioxidant vitamins and lipid peroxidation in multiple sclerosis.
We determined serum levels of ascorbic acid, betacarotene, retinol and alpha tocopherol and lipid peroxidation (as estimated by thiobarbituric acid reacting substances (TBARS) generation) in 24 multiple sclerosis (MS) patients and 24 healthy sex- and age-matched person as control. The levels of four antioxidant vitamins were significantly lower in MS patients compared to controls (p < 0.05). TBARS levels were significantly higher in the patients of MS compared to the controls (p = 0.001). In MS patients, the levels of beta-carotene, alpha tocopherol and ascorbic acid correlated significantly with each other (r2 = 0.689 - 0.779). It appeared that there was inverse correlation between the serum levels of ascorbic acid or beta-carotene, but not of alpha tocopherol or retinol, and TBARS levels in MS. The present study indicates that antioxidant vitamins (alpha tocopherol, beta-carotene, retinol and ascorbic acid) are decreased in sera of MS patients during an attack, and that this decrease may well be dependent on the increased oxidative burden as reflected by lipid peroxidation products. The role of antioxidant vitamin supplementation in prevention and/or treatment of MS remains to be explored.


Survival Impact and Clinical Predictors of Acute Gastrointestinal Bleeding in Patients With Bloodstream Infection.
The impact of gastrointestinal bleeding (GIB) on outcomes of patients with bloodstream infection (BSI) has not been studied. We aim to evaluate the risk factors and survival impact of GIB on the outcome of BSI. This study was conducted prospectively at National Taiwan University Hospital Yunlin Branch between January 1, 2015, and December 31, 2016. Patients aged ≥18 years for who BSI was confirmed by blood cultures were enrolled and followed for 90 days. Risk factors of GIB were identified by univariable and multivariable logistic regression models. The survival impact of GIB on BSI was evaluated with the Cox proportional hazards model with inverse probability of treatment weighting. Of the 1034 patients with BSI, 79 (7.64%) developed acute GIB. We identified 5 independent predictors of GIB. Patients with BSI complicated with GIB had an increased 90-day mortality compared to patients without GIB (hazard ratio 1.74, 95% confidence interval: 1.14, 2.65). Gastrointestinal bleeding had an adverse impact on the short-term survival in patients with BSI. The clinical predictors may help identify patients who may benefit from active prevention and treatment of GIB.


Barriometry - an enhanced database of accurate barrier heights for gas-phase reactions.
The kinetics of many reactions are critically dependent upon the barrier heights for which accurate determination can be difficult. From the perspective of attaining such quantities using computational quantum chemistry, it is important to appropriately validate routine and efficient methodologies such as density functional theory (DFT) procedures. In the present study, we embark on the journey of establishing diverse databases using a consistent high-level quantum chemistry procedure, against which new and existing methodologies can be assessed. Thus, we have used the composite protocol W3X-L to provide more than 100 refined reference values for existing databases [e.g., Y. Zhao and D. G. Truhlar, J. Phys. Chem. A, 2005, 109, 5656] and additionally establish benchmark data that are of interest to atmospheric and combustion chemists. While our endeavor has just begun, assessment of various DFT methods with our existing results lends support to the use of MN15 as an adequate method for general kinetics applications. We also recommend the use of less-costly W2X and WG composite protocols for obtaining adequately accurate reference thermochemical values for larger molecular systems.


Application of neurosonography to experimental physiology.
When Horsley and Clark invented the stereotaxic technique they revolutionized experimental neurobiology. For the first time it became possible to repeatably place experimental or surgical probes at precise locations within the skull. Unfortunately, variations in the position and size of neuroanatomical structures within the cranium have always limited the efficiency of this technology. Recent advances in diagnostic medical ultrasonography, however, allow for the real-time visualization of anatomical structures, in some cases with resolutions of up to 150 microm. We report here that commercially available ultrasonographs can be used in the laboratory to generate real-time in vivo images of brain structures in both anesthetized and awake-behaving animals. We found that ultrasonic imaging is compatible with many types of experimental probes including single neuron recording electrodes, microinjection pipettes, and electrodes for producing electrolytic lesions. Ultrasonic imaging can be used to place, monitor and visualize these probes in vivo. In our hands, commercially available ultrasonic probes designed for pediatric use allowed us to visualize anatomical structures with sub-millimeter resolution in primate brains. Finally, ultrasonic imaging allowed us to reduce the risk of accidentally damaging major blood vessels, greatly reducing the incidence of stroke as an unintended complication of an experimental neurosurgical procedure. Diagnostic ultrasound holds the promise of reducing the uncertainty associated with stereotaxic surgery, an improvement which would significantly improve the efficiency of many neurobiological investigations, reducing the number of animal subjects employed in this research. While this demonstration focuses on sonographic imaging in non-human primates, similar advances should also be possible for studies in other species, including rodents.


CD4 T cell immunity is critical for the control of simian varicella virus infection in a nonhuman primate model of VZV infection.
Primary infection with varicella zoster virus (VZV) results in varicella (more commonly known as chickenpox) after which VZV establishes latency in sensory ganglia. VZV can reactivate to cause herpes zoster (shingles), a debilitating disease that affects one million individuals in the US alone annually. Current vaccines against varicella (Varivax) and herpes zoster (Zostavax) are not 100% efficacious. Specifically, studies have shown that 1 dose of varivax can lead to breakthrough varicella, albeit rarely, in children and a 2-dose regimen is now recommended. Similarly, although Zostavax results in a 50% reduction in HZ cases, a significant number of recipients remain at risk. To design more efficacious vaccines, we need a better understanding of the immune response to VZV. Clinical observations suggest that T cell immunity plays a more critical role in the protection against VZV primary infection and reactivation. However, no studies to date have directly tested this hypothesis due to the scarcity of animal models that recapitulate the immune response to VZV. We have recently shown that SVV infection of rhesus macaques models the hallmarks of primary VZV infection in children. In this study, we used this model to experimentally determine the role of CD4, CD8 and B cell responses in the resolution of primary SVV infection in unvaccinated animals. Data presented in this manuscript show that while CD20 depletion leads to a significant delay and decrease in the antibody response to SVV, loss of B cells does not alter the severity of varicella or the kinetics/magnitude of the T cell response. Loss of CD8 T cells resulted in slightly higher viral loads and prolonged viremia. In contrast, CD4 depletion led to higher viral loads, prolonged viremia and disseminated varicella. CD4 depleted animals also had delayed and reduced antibody and CD8 T cell responses. These results are similar to clinical observations that children with agammaglobulinemia have uncomplicated varicella whereas children with T cell deficiencies are at increased risk of progressive varicella with significant complications. Moreover, our studies indicate that CD4 T cell responses to SVV play a more critical role than antibody or CD8 T cell responses in the control of primary SVV infection and suggest that one potential mechanism for enhancing the efficacy of VZV vaccines is by eliciting robust CD4 T cell responses.


Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer.
Despite its importance in human cancers, including colorectal cancers (CRC), oncogenic KRAS has been extremely challenging to target therapeutically. To identify potential vulnerabilities in KRAS-mutated CRC, we characterize the impact of oncogenic KRAS on the cell surface of intestinal epithelial cells. Here we show that oncogenic KRAS alters the expression of a myriad of cell-surface proteins implicated in diverse biological functions, and identify many potential surface-accessible therapeutic targets. Cell surface-based loss-of-function screens reveal that ATP7A, a copper-exporter upregulated by mutant KRAS, is essential for neoplastic growth. ATP7A is upregulated at the surface of KRAS-mutated CRC, and protects cells from excess copper-ion toxicity. We find that KRAS-mutated cells acquire copper via a non-canonical mechanism involving macropinocytosis, which appears to be required to support their growth. Together, these results indicate that copper bioavailability is a KRAS-selective vulnerability that could be exploited for the treatment of KRAS-mutated neoplasms.


The course of bone healing is influenced by the initial shear fixation stability.
Fracture healing is influenced by fixation stability and experimental evidence suggests that the initial mechanical conditions may determine the healing outcome. We hypothesised that mechanical conditions influence not only the healing outcome, but also the early phase of fracture healing. Additionally, it was hypothesised that decreased fixation stability characterised by an increased shear interfragmentary movement results in a delay in healing. Sixty-four sheep underwent a mid-shaft tibial osteotomy which was treated with either a rigid or a semi-rigid external fixator. Animals were sacrificed at 2, 3, 6 and 9 weeks postoperatively and the fracture callus was analysed using radiological, biomechanical and histological techniques. The tibia treated with semi-rigid fixation showed inferior callus stiffness and quality after 6 weeks. At 9 weeks, the calluses were no longer distinguishable in their mechanical competence. The calluses at 9 weeks produced under rigid fixation were smaller and consisted of a reduced fibrous tissue component. These results demonstrate that the callus formation over the course of healing differed both morphologically and in the rate of development. In this study, we provide evidence that the course of healing is influenced by the initial fixation stability. The semi-rigid fixator did not result in delayed healing, but a less optimal healing path was taken. An upper limit of stability required for successful healing remains unknown, however a limit by which healing is less optimal has been determined.


MK-801 can facilitate passive avoidance memory when retention is not present in control animals, and can fail to facilitate when it is present.
The results confirm that NMDA receptor blockade can result in improved retention performance of mice in step-down passive avoidance. A series of behavioural variations and analyses revealed that memory in the task depended mainly on the appearance of the grid that had been associated with shock, rather than on the execution of an instrumental response or on the spatial locus of the punishment. When the grid was made invisible during retest, retention was never found. However, MK-801 did not facilitate retention based on the appearance of the grid. In contrast, conditions were found in which, even though control animals showed no learning, MK 801 given after the learning trial facilitated retention. Thus, the dominant mode of learning and memory in the step-down task is insensitive to the drug, whereas the drug raises a weaker or alternative mode to above threshold levels.


Analgesic use in older adults with back pain: the BACE study.
Older patients with back pain are more likely to visit their general practitioner (GP) and are more likely to be prescribed analgesics. To assess analgesic use in older adults with back pain in general practice. The BACE study in the Netherlands is a prospective cohort study. Patients (aged >55 years) with back complaints were recruited when consulting their GP or shortly thereafter. Measurements took place at baseline and at 3- and 6-month follow-up. For medication use, patients were asked if they had used any medication for their back pain in the previous 3 months and, if so, to specify the medication name, dosage used, frequency of usage, and whether the medication was prescribed or purchased over the counter. Of the 1,402 patients who were approached to enter the study, 675 were included. Of these patients, 484 (72%) reported medication use at baseline. Nonsteroidal anti-inflammatory drugs (NSAIDs) (57%) were more often used than paracetamol (49%). Paracetamol was mostly obtained over the counter (69%), and NSAIDs were mostly obtained by prescription (85%). At baseline, patients with severe pain (numerical rating scale score ≥7) used more paracetamol, opioids, and muscle relaxants. Patients with chronic pain (back pain >3 months) used more paracetamol, while patients with a shorter duration of pain used more NSAIDs. During follow-up there was an overall decline in medication use; however, at 3- and 6-month follow-up, 36% and 30% of the patients, respectively, still used analgesics. In these older adults consulting their GP with back pain, 72% used analgesics at baseline. Despite a decrease in medication use during follow-up, at 3 and 6 months a considerable proportion still used analgesics.


Do Global Regulators Hold the Key to Production of Bacterial Secondary Metabolites?
The emergence of multiple antibiotic resistant bacteria has pushed the available pool of antibiotics to the brink. Bacterial secondary metabolites have long been a valuable resource in the development of antibiotics, and the genus Burkholderia has recently emerged as a source of novel compounds with antibacterial, antifungal, and anti-cancer activities. Genome mining has contributed to the identification of biosynthetic gene clusters, which encode enzymes that are responsible for synthesis of such secondary metabolites. Unfortunately, these large gene clusters generally remain silent or cryptic under normal laboratory settings, which creates a hurdle in identification and isolation of these compounds. Various strategies, such as changes in growth conditions and antibiotic stress, have been applied to elicit the expression of these cryptic gene clusters. Although a number of compounds have been isolated from different Burkholderia species, the mechanisms by which the corresponding gene clusters are regulated remain poorly understood. This review summarizes the activity of well characterized secondary metabolites from Burkholderia species and the role of local regulators in their synthesis, and it highlights recent evidence for the role of global regulators in controlling production of secondary metabolites. We suggest that targeting global regulators holds great promise for the awakening of cryptic gene clusters and for developing better strategies for discovery of novel antibiotics.


Magnetic drug targeting in a permeable microvessel.
A mathematical model is presented for predicting magnetic targeting of multifunctional carrier particles that deliver therapeutic agents to malignant tissue in vivo. These particles consist of a nonmagnetic core material that contains embedded magnetic nanoparticles and therapeutic agents such as photodynamic sensitizers. For in vivo therapy, the particles are injected into the microvascular system upstream from malignant tissue, and captured at the tumor using an applied magnetic field. In this paper, a mathematical model is developed for predicting non-invasive magnetic targeting of therapeutic carrier particles in a microvessel. The flow of blood in the microvessel is described by a two-phase Casson fluid model. The Darcy model is used to characterize the permeable nature of the inner wall of the microvessel. The fluidic force on the carrier traversing the microvessel and the magnetic force due to the external magnetic field is taken into account. We solved the system of coupled equations to obtain the capture condition for the carrier particle in the non-invasive case. The model enables rapid parametric analysis of magnetic targeting as a function of key variables including the size and shape of the carrier particle, the properties and volume fraction of the imbedded magnetic nanoparticles, the properties of the magnet, the microvessel and the permeability of the microvessel.


Screening a Resource of Recombinant Protein Fragments for Targeted Proteomics.
The availability of proteomics resources hosting protein and peptide standards, as well as the data describing their analytical performances, will continue to enhance our current capabilities to develop targeted proteomics methods for quantitative biology. This study describes the analysis of a resource of 26,840 individually purified recombinant protein fragments corresponding to more than 16,000 human protein-coding genes. The resource was screened to identify proteotypic peptides suitable for targeted proteomics efforts, and we report LC-MS/MS assay coordinates for more than 25,000 proteotypic peptides, corresponding to more than 10,000 unique proteins. Additionally, peptide formation and digestion kinetics were, for a subset of the standards, monitored using a time-course protocol involving parallel digestion of isotope-labeled recombinant protein standards and endogenous human plasma proteins. We show that the strategy by adding isotope-labeled recombinant proteins before trypsin digestion enables short digestion protocols (≤60 min) with robust quantitative precision. In a proof-of-concept study, we quantified 23 proteins in human plasma using assay parameters defined in our study and used the standards to describe distinct clusters of individuals linked to different levels of LPA, APOE, SERPINA5, and TFRC. In summary, we describe the use and utility of a resource of recombinant proteins to identify proteotypic peptides useful for targeted proteomics assay development.


Structural and functional characterization of the oxidoreductase alpha-DsbA1 from Wolbachia pipientis.
The alpha-proteobacterium Wolbachia pipientis is a highly successful intracellular endosymbiont of invertebrates that manipulates its host's reproductive biology to facilitate its own maternal transmission. The fastidious nature of Wolbachia and the lack of genetic transformation have hampered analysis of the molecular basis of these manipulations. Structure determination of key Wolbachia proteins will enable the development of inhibitors for chemical genetics studies. Wolbachia encodes a homologue (alpha-DsbA1) of the Escherichia coli dithiol oxidase enzyme EcDsbA, essential for the oxidative folding of many exported proteins. We found that the active-site cysteine pair of Wolbachia alpha-DsbA1 has the most reducing redox potential of any characterized DsbA. In addition, Wolbachia alpha-DsbA1 possesses a second disulfide that is highly conserved in alpha-proteobacterial DsbAs but not in other DsbAs. The alpha-DsbA1 structure lacks the characteristic hydrophobic features of EcDsbA, and the protein neither complements EcDsbA deletion mutants in E. coli nor interacts with EcDsbB, the redox partner of EcDsbA. The surface characteristics and redox profile of alpha-DsbA1 indicate that it probably plays a specialized oxidative folding role with a narrow substrate specificity. This first report of a Wolbachia protein structure provides the basis for future chemical genetics studies.


The diagnosis and care of transsexual children and adolescents: a pediatric endocrinologists' perspective.
The normally developed child whose gender identity and anatomic sex disagree is referred to as a transgendered child, or as used subsequently in this text, a transsexual. The ramifications of this disagreement include a high risk of psychiatric conflict and maladjustment, for both the individuals themselves and their families. Despite the efforts of researchers to systematically study this group of children, many fundamental questions remain. In many respects, those lingering questions are shared by patients with physical intersex who have been cared for by pediatric endocrinologists. In intersex and transsexual patients, the medical community, although sincerely interested, remains wary to intervene in ways that may lead to further inconsistency between anatomic sex and adult gender identity. A perspective on the problems of differentiating permanent from transient gender identity, some thoughts on the most appropriate management of the transsexual child/adolescent as well as remaining questions are discussed. Both the flexible and therefore potentially misleading gender identity in children and the medical communities' pledge to first do no harm (primum non nocere) have regrettably fostered disharmony between gender disordered patients, their families, and the practitioners who want to help them.


[Outpatient prophylaxis and treatment of arterial hypertension with application of mobile telephone systems and Internet techniques].
To compare clinical efficacy of standard outpatient follow-up of hypertensive patients with efficacy of such follow-up with application of internet techniques and mobile telephone systems (ITMTS). Two groups of hypertensive patients were examined: group 1 (n=97, 45% females, age 49 +/- 11 years) on one-year ITMTS follow-up; group 2 (n=102, 50% females, age 51 +/- 11 years) on standard one-year follow-up. Clinical efficacy was assessed by the rate of achievement and maintenance of target blood pressure, dynamics of modifiable risk factors (smoking, obesity) for a year. Withdrawal in group 1 was 36%, target blood pressure was achieved in 77% patients vs. 12% in group 2 (p < 0.001). Introduction of ITMTS technologies into outpatient clinics activity considerably raises efficacy of outpatient treatment of hypertensive patients.


Range Expansion and the Origin of USA300 North American Epidemic Methicillin-Resistant Staphylococcus aureus.
The USA300 North American epidemic (USA300-NAE) clone of methicillin-resistant Staphylococcus aureus has caused a wave of severe skin and soft tissue infections in the United States since it emerged in the early 2000s, but its geographic origin is obscure. Here we use the population genomic signatures expected from the serial founder effects of a geographic range expansion to infer the origin of USA300-NAE and identify polymorphisms associated with its spread. Genome sequences from 357 isolates from 22 U.S. states and territories and seven other countries are compared. We observe two significant signatures of range expansion, including decreases in genetic diversity and increases in derived allele frequency with geographic distance from the Pennsylvania region. These signatures account for approximately half of the core nucleotide variation of this clone, occur genome wide, and are robust to heterogeneity in temporal sampling of isolates, human population density, and recombination detection methods. The potential for positive selection of a gyrA fluoroquinolone resistance allele and several intergenic regions, along with a 2.4 times higher recombination rate in a resistant subclade, is noted. These results are the first to show a pattern of genetic variation that is consistent with a range expansion of an epidemic bacterial clone, and they highlight a rarely considered but potentially common mechanism by which genetic drift may profoundly influence bacterial genetic variation.IMPORTANCE The process of geographic spread of an origin population by a series of smaller populations can result in distinctive patterns of genetic variation. We detect these patterns for the first time with an epidemic bacterial clone and use them to uncover the clone's geographic origin and variants associated with its spread. We study the USA300 clone of methicillin-resistant Staphylococcus aureus, which was first noticed in the early 2000s and subsequently became the leading cause of skin and soft tissue infections in the United States. The eastern United States is the most likely origin of epidemic USA300. Relatively few variants, which include an antibiotic resistance mutation, have persisted during this clone's spread. Our study suggests that an early chapter in the genetic history of this epidemic bacterial clone was greatly influenced by random subsampling of isolates during the clone's geographic spread.


J-GFT NMR for precise measurement of mutually correlated nuclear spin-spin couplings.
G-matrix Fourier transform (GFT) NMR spectroscopy is presented for accurate and precise measurement of chemical shifts and nuclear spin-spin couplings correlated according to spin system. The new approach, named "J-GFT NMR", is based on a largely extended GFT NMR formalism and promises to have a broad impact on projection NMR spectroscopy. Specifically, constant-time J-GFT (6,2)D (HA-CA-CO)-N-HN was implemented for simultaneous measurement of five mutually correlated NMR parameters, that is, 15N backbone chemical shifts and the four one-bond spin-spin couplings 13Calpha-1Halpha, 13Calpha-13C', 15N-13C', and 15N-1HNu. The experiment was applied for measuring residual dipolar couplings (RDCs) in an 8 kDa protein Z-domain aligned with Pf1 phages. Comparison with RDC values extracted from conventional NMR experiments reveals that RDCs are measured with high precision and accuracy, which is attributable to the facts that (i) the use of constant time evolution ensures that signals do not broaden whenever multiple RDCs are jointly measured in a single dimension and (ii) RDCs are multiply encoded in the multiplets arising from the joint sampling. This corresponds to measuring the couplings multiple times in a statistically independent manner. A key feature of J-GFT NMR, i.e., the correlation of couplings according to spin systems without reference to sequential resonance assignments, promises to be particularly valuable for rapid identification of backbone conformation and classification of protein fold families on the basis of statistical analysis of dipolar couplings.


Voltage profile along the permeation pathway of an open channel.
For ion channels, the transmembrane potential plays a critical role by acting as a driving force for permeant ions. At the microscopic level, the transmembrane potential is thought to decay nonlinearly across the ion permeation pathway because of the irregular three-dimensional shape of the channel's pore. By taking advantage of the current structural and functional understanding of cyclic nucleotide-gated channels, in this study we experimentally explore the transmembrane potential's distribution across the open pore. As a readout for the voltage drop, we engineered cysteine residues along the selectivity filter and scanned the sensitivity of their modification rates by Ag(+) to the transmembrane potential. The experimental data, which indicate that the majority of the electric field drops across the selectivity filter, are in good agreement with continuum electrostatic calculations using a homology model of an open CNG channel. By focusing the transmembrane potential across the selectivity filter, the electromotive driving force is coupled with the movement of permeant ions in the filter, maximizing the efficiency of this process.


Proteomics Analysis to Identify and Characterize the Biomarkers and Physical Activities of Non-Frail and Frail Older Adults.
Globally, the proportion of older adults is increasing. Older people face chronic conditions such as sarcopenia and functional decline, which are often associated with disability and frailty. Proteomics assay of potential serum biomarkers of frailty in older adults. Older adults were divided into non-frail and frail groups (n = 6 each; 3 males in each group) in accordance with the Chinese-Canadian Study of Health and Aging Clinical Frailty Scale. Adults were measured for grip power and the 6-min walk test for physical activity, and venous blood was sampled after adults fasted for 8 h. Ultra-high-performance liquid chromatography-tandem mass spectrometry was used for proteomics assay. The groups were compared for levels of biomarkers by t test and Pearson correlation analysis. Non-frail and frail subjects had mean age 77.5±0.4 and 77.7±1.6 years, mean height 160.5±1.3 and 156.6±2.9 cm and mean weight 62.5±1.2 and 62.8±2.9 kg, respectively. Physical activity level was lower for frail than non-frail subjects (grip power: 13.8±0.4 vs 26.1±1.2 kg; 6-min walk test: 215.2±17.2 vs 438.3±17.2 m). Among 226 proteins detected, for 31, serum levels were significantly higher for frail than non-frail subjects; serum levels of Ig kappa chain V-III region WOL, COX7A2, and albumin were lower. The serum levels of ANGT, KG and AT were 2.05-, 1.76- and 2.22-fold lower (all p < 0.05; Figure 1A, 2A and 3A) for non-frail than frail subjects and were highly correlated with grip power (Figure 1B, 2B and 3B). Our study found that ANGT, KG and AT levels are known to increase with aging, so degenerated vascular function might be associated with frailty. In total, 226 proteins were revealed proteomics assay; levels of angiotensinogen (ANGT), kininogen-1 (KG) and antithrombin III (AT) were higher in frail than non-frail subjects (11.26±2.21 vs 5.09±0.74; 18.42±1.36 vs 11.64±1.36; 22.23±1.64 vs 9.52±0.95, respectively, p < 0.05). These 3 factors were highly correlated with grip power (p < 0.05), with higher correlations between grip power and serum levels of ANGT (r = -0.89), KG (r = -0.90), and AT (r = -0.84). In conclusion, this is the first study to demonstrate a serum proteomic profile characteristic of frailty in older adults. Serum ANGT, KG and AT levels could be potential biomarkers for monitoring the development and progression of frailty in older adults.


Efficient coarse simulation of a growing avascular tumor.
The subject of this work is the development and implementation of algorithms which accelerate the simulation of early stage tumor growth models. Among the different computational approaches used for the simulation of tumor progression, discrete stochastic models (e.g., cellular automata) have been widely used to describe processes occurring at the cell and subcell scales (e.g., cell-cell interactions and signaling processes). To describe macroscopic characteristics (e.g., morphology) of growing tumors, large numbers of interacting cells must be simulated. However, the high computational demands of stochastic models make the simulation of large-scale systems impractical. Alternatively, continuum models, which can describe behavior at the tumor scale, often rely on phenomenological assumptions in place of rigorous upscaling of microscopic models. This limits their predictive power. In this work, we circumvent the derivation of closed macroscopic equations for the growing cancer cell populations; instead, we construct, based on the so-called "equation-free" framework, a computational superstructure, which wraps around the individual-based cell-level simulator and accelerates the computations required for the study of the long-time behavior of systems involving many interacting cells. The microscopic model, e.g., a cellular automaton, which simulates the evolution of cancer cell populations, is executed for relatively short time intervals, at the end of which coarse-scale information is obtained. These coarse variables evolve on slower time scales than each individual cell in the population, enabling the application of forward projection schemes, which extrapolate their values at later times. This technique is referred to as coarse projective integration. Increasing the ratio of projection times to microscopic simulator execution times enhances the computational savings. Crucial accuracy issues arising for growing tumors with radial symmetry are addressed by applying the coarse projective integration scheme in a cotraveling (cogrowing) frame. As a proof of principle, we demonstrate that the application of this scheme yields highly accurate solutions, while preserving the computational savings of coarse projective integration.


Implementing global knowledge in local practice: a WHO lung health initiative in Nepal.
Clinical practice guidelines are used widely to improve the quality of primary health care in different health systems, including those of low-income countries. Often developed at international level and adapted to national contexts to increase the feasibility of effective uptake, guideline initiatives aim to transfer global scientific knowledge into local practice. The WHO's Practical Approach to Lung Health (PAL) is an example of such an initiative and is currently being developed to improve the quality of care for youths and adults with respiratory diseases. We assessed ex-ante the feasibility of successful implementation of PAL in a pilot programme in rural Nepal, studying three components: the quality of the innovation (i.e. the guidelines), the effectiveness of the implementation strategy (i.e. training) and the receptiveness of the social system of health staff at all levels (i.e. social and organizational characteristics). We assessed the guideline innovation with the AGREE instrument for guidelines, the intended implementation strategy by critical comparison with literature on effective strategies, and the social system with both a stakeholder analysis and a descriptive analysis of the health care system at district level. This ex-ante assessment of an adaptive local implementation of international WHO guidelines showed that in July 2002 the 'implementability' of the package was challenged on the three components studied. To increase the chances of successful implementation, the national guideline development process should be improved and the implementation strategy needs to be upgraded. In order to successfully transfer global knowledge into local practice, we need to develop additional multifactorial sustained interventions that tackle other culture-specific and health system-specific barriers as well. The primary health workers are key informants for these barriers.


New insight into quasi leaky mode approximations for unified coupled-mode analysis.
To facilitate the analysis of radiation mode couplings, quasi leaky mode approximations were utilized in coupled-mode analysis. The key to effectively and accurately apply this approach is how to well approximate radiation modes by the quasi leaky modes in an equivalent closed waveguide model. In this paper, the principle, applicability and accuracy of the approximations are demonstrated, and the detailed implementation is also suggested by applying a unified coupled-mode analysis to fiber gratings. First of all, based on a thorough study on the characteristics of the complex modes, for the first time, quasi leaky modes are classified into guided-mode-like inner-cladding and radiation-mode-like outer-cladding leaky modes so as to explicitly establish equivalence relationships between the discrete leaky modes and the continuous radiation modes. With this new insight, the whole analysis process especially for some of the practically tricky issues such as the criteria for developing the proper equivalent waveguide model and the subsequent mode expansion basis are better understood and easier to be dealt with for different problems where radiation modes come into play. Moreover, as essential preconditions to extend the conventional coupled mode analysis to the present unified one, the couplings between the guided core mode and a leaky mode are studied in a systematic and consistent manner. An intuitive and then a deep understanding on the roles of complex modes on mode coupling and power exchanging are thus gained for further simulations. Lastly, the transmission spectra of fiber gratings with different surrounding indices are simulated. The simulated results agree well with those obtained theoretically and experimentally in the literatures, which strongly validate the principle of quasi leaky mode approximations and its implementation on the unified coupled-mode analysis expounded in this paper.


Discrimination learning during the first year: stimulus and positional cues.
In four studies, 3-, 6-, and 9-month-old human infants were tested in a discrimination learning task in which visual fixation to a particular stimulus or lateral position was reinforced with an auditory stimulus. In Experiment 1, all age groups exhibited acquisition, extinction, and reinstatement of fixation to the reinforced target or position. Experiment 2 revealed that 3-month-olds retained the positional discrimination but not the stimulus discrimination after a 5-min delay between acquisition and extinction; older infants retained both types of discriminations. In Experiments 3 and 4 we investigated a possible developmental shift in the dominance of positional versus stimulus cues by training infants on displays in which stimulus and position were confounded and then by dissociating the cues on test trials. Results from both experiments indicated positional cue dominance for young infants and stimulus cue dominance for older infants. The findings are discussed in terms of differences in the attentional demands elicited by proprioceptive versus exteroceptive cues.


Identification of Alternative Splice Variants Using Unique Tryptic Peptide Sequences for Database Searches.
Alternative splicing is a mechanism in eukaryotes by which different forms of mRNAs are generated from the same gene. Identification of alternative splice variants requires the identification of peptides specific for alternative splice forms. For this purpose, we generated a human database that contains only unique tryptic peptides specific for alternative splice forms from Swiss-Prot entries. Using this database allows an easy access to splice variant-specific peptide sequences that match to MS data. Furthermore, we combined this database without alternative splice variant-1-specific peptides with human Swiss-Prot. This combined database can be used as a general database for searching of LC-MS data. LC-MS data derived from in-solution digests of two different cell lines (LNCaP, HeLa) and phosphoproteomics studies were analyzed using these two databases. Several nonalternative splice variant-1-specific peptides were found in both cell lines, and some of them seemed to be cell-line-specific. Control and apoptotic phosphoproteomes from Jurkat T cells revealed several nonalternative splice variant-1-specific peptides, and some of them showed clear quantitative differences between the two states.


Religious struggle as a predictor of mortality among medically ill elderly patients: a 2-year longitudinal study.
Although church attendance has been associated with a reduced risk of mortality, no study has examined the impact of religious struggle with an illness on mortality. To investigate longitudinally the relationship between religious struggle with an illness and mortality. A longitudinal cohort study from 1996 to 1997 was conducted to assess positive religious coping and religious struggle, and demographic, physical health, and mental health measures at baseline as control variables. Mortality during the 2-year period was the main outcome measure. Participants were 596 patients aged 55 years or older on the medical inpatient services of Duke University Medical Center or the Durham Veterans Affairs Medical Center, Durham, NC. After controlling for the demographic, physical health, and mental health variables, higher religious struggle scores at baseline were predictive of greater risk of mortality (risk ratio [RR] for death, 1.06; 95% confidence interval [CI], 1.01-1.11; chi(2) = 5.89; P =.02). Two spiritual discontent items and 1 demonic reappraisal item from the religious coping measure were predictive of increased risk for mortality: "Wondered whether God had abandoned me" (RR for death, 1.28; 95% CI, 1.07-1.50; chi(2) = 5.22; P =.02), "Questioned God's love for me" (RR for death, 1.22; 95% CI, 1.02-1.43; chi(2) = 3.69; P =.05), and "Decided the devil made this happen" (RR for death, 1.19; 95% CI, 1.05-1.33; chi(2) = 5.84; P =.02). Certain forms of religiousness may increase the risk of death. Elderly ill men and women who experience a religious struggle with their illness appear to be at increased risk of death, even after controlling for baseline health, mental health status, and demographic factors.


Cross-sectional analysis of deprivation and ideal cardiovascular health in the Paris Prospective Study 3.
We hypothesised that deprivation might represent a barrier to attain an ideal cardiovascular health (CVH) as defined by the American Heart Association (AHA). The baseline data of 8916 participants of the Paris Prospective Study 3, an observational cohort on novel markers for future cardiovascular disease, were used. The AHA 7-item tool includes four health behaviours (smoking, body weight, physical activity and optimal diet) and three biological measures (blood cholesterol, blood glucose and blood pressure). A validated 11-item score of individual material and psychosocial deprivation, the Evaluation de la Précarité et des Inégalités dans les Centres d'Examens de Santé-Evaluation of Deprivation and Inequalities in Health Examination centres (EPICES) score was used. The mean age was 59.5 years (standard deviation 6.2), 61.2% were men and 9.98% had an ideal CVH. In sex-specific multivariable polytomous logistic regression, the odds ratio (OR) for ideal behavioural CVH progressively decreased with quartile of increasing deprivation, from 0.54 (95% CI 0.41 to 0.72) to 0.49 (0.37 to 0.65) in women and from 0.61 (0.50 to 0.76) to 0.57 (0.46 to 0.71) in men. Associations with ideal biological CVH were confined to the most deprived women (OR=0.60; 95% CI 0.37 to 0.99), whereas in men, greater deprivation was related to higher OR of intermediate biological CVH (OR=1.28; 95% CI 1.05 to 1.57 for the third quartile vs the first quartile). Higher material and psychosocial deprivation may represent a barrier to reach an ideal CVH. NCT00741728.


A novel two-layer, coupled finite element approach for modeling the nonlinear elastic and viscoelastic behavior of human erythrocytes.
A novel finite element approach is presented to simulate the mechanical behavior of human red blood cells (RBC, erythrocytes). As the RBC membrane comprises a phospholipid bilayer with an intervening protein network, we propose to model the membrane with two distinct layers. The fairly complex characteristics of the very thin lipid bilayer are represented by special incompressible solid shell elements and an anisotropic viscoelastic constitutive model. Properties of the protein network are modeled with an isotropic hyperelastic third-order material. The elastic behavior of the model is validated with existing optical tweezers studies with quasi-static deformations. Employing material parameters consistent with literature, simulation results are in excellent agreement with experimental data. Available models in literature neglect either the surface area conservation of the RBC membrane or realistic loading conditions of the optical tweezers experiments. The importance of these modeling assumptions, that are both included in this study, are discussed and their influence quantified. For the simulation of the dynamic motion of RBC, the model is extended to incorporate the cytoplasm. This is realized with a monolithic fully coupled fluid-structure interaction simulation, where the fluid is described by the incompressible Navier-Stokes equations in an arbitrary Lagrangian Eulerian framework. It is shown that both membrane viscosity and cytoplasm viscosity have significant influence on simulation results. Characteristic recovery times and energy dissipation for varying strain rates in dynamic laser trap experiments are calculated for the first time and are found to be comparable with experimental data.


Clinical decision support systems.
Clinical decision support (CDS) systems link patient data with an electronic knowledge base in order to improve decision-making and computerised physician order entry (CPOE) is a requirement to set up electronic CDS. The medical informatics literature suggests categorising CDS tools into medication dosing support, order facilitators, point-of-care alerts and reminders, relevant information display, expert systems and workflow support. To date, CDS has particularly been recognised for improving processes. CDS successfully fostered prevention of deep-vein thrombosis, improved adherence to guidelines, increased the use of vaccinations, and decreased the rate of serious medication errors. However, CDS may introduce errors, and therefore the term "e-iatrogenesis" has been proposed to address unintended consequences. At least two studies reported severe treatment delays due to CPOE and CDS. In addition, the phenomenon of "alert fatigue" - arising from a high number of CDS alerts of low clinical significance - may facilitate overriding of potentially critical notifications. The implementation of CDS needs to be carefully planned, CDS interventions should be thoroughly examined in pilot wards only, and then stepwise introduced. A crucial feature of CPOE in combination with CDS is speed, since time consumption has been found to be a major factor determining failure. In the near future, the specificity of alerts will be improved, notifications will be prioritised and offer detailed advice, customisation of CDS will play an increasing role, and finally, CDS is heading for patient-centred decision support. The most important research question remains whether CDS is able to improve patient outcomes beyond processes.


Early prediction of outcome after severe traumatic brain injury: a simple and practical model.
Traumatic brain injury (TBI) is a heterogeneous syndrome with a broad range of outcome. We developed a simple model for long-term outcome prognostication after severe TBI. Secondary data analysis of a large multicenter randomized trial. Patients were grouped according to 6-month extended Glasgow outcome scale (eGOS): poor-outcome (eGOS ≤ 4; severe disability or death) and acceptable outcome (eGOS > 4; no or moderate disability). A prediction decision tree was built using binary recursive partitioning to predict poor or acceptable 6-month outcome. Comparison to two previously published and validated models was made. The decision tree included the predictors of head Abbreviated Injury Scale (AIS) severity, the Marshall computed tomography score, and pupillary reactivity. All patients with a head AIS severity of 5 were predicted to have a poor outcome. In patients with head AIS severity < 5, the model predicted an acceptable outcome for (1) those with Marshall score of 1, and (2) those with Marshall score above 1 but with reactive pupils at admission. The decision tree had a sensitivity of 72.3 % (95 % CI: 66.4-77.6 %) and specificity of 62.5 % (95 % CI: 54.9-69.6 %). The proportion correctly classified for the comparison models was similar to our model. Our model was more apt at correctly classifying those with poor outcome but more likely to misclassify those with acceptable outcome than the comparison models. Predicting long-term outcome early after TBI remains challenging and inexact. This model could be useful for research and quality improvement studies to provide an early assessment of injury severity, but is not sufficiently accurate to guide decision-making in the clinical setting.


How does initial treatment choice affect short-term and long-term costs for clinically localized prostate cancer?
Data regarding costs of prostate cancer treatment are scarce. This study investigates how initial treatment choice affects short-term and long-term costs. This retrospective, longitudinal cohort study followed prostate-cancer cases diagnosed in 2000 for 5 years using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Men age≥66 years, in Medicare fee for service, diagnosed with clinically localized prostate cancer in 2000 while residing in a SEER region, were matched to noncancer controls using age, sex, race, region, comorbidity, and survival. On the basis of treatment received during the first 9 months postdiagnosis, patients were assigned to watchful waiting, radiation, hormonal therapy, hormonal+radiation, and surgery (may have received other treatments). Incremental costs for prostate cancer were the difference in costs for prostate cancer cases versus matched controls. Costs were divided into initial treatment (months -1 to 12), long-term (each 12 months thereafter), and total (months -1 to 60). Sensitivity analyses excluded the last 12 months of life. A total of 13,769 prostate-cancer cases were matched to 13,769 noncancer controls. Watchful waiting had the lowest initial treatment ($4270) and 5-year total costs ($9130). Initial treatment costs were highest for hormonal+radiation ($17,474) and surgery ($15,197). At $26,896, 5-year total costs were highest for hormonal therapy only followed by hormonal+radiation ($25,097) and surgery ($19,214). After excluding the last 12 months of life, total costs were highest for hormonal+radiation ($23,488) and hormonal therapy ($23,199). Patterns of costs vary widely based on initial treatment. These data can inform patients and clinicians considering treatment options and policy makers interested in patterns of costs.


Community-acquired multidrug-resistant Gram-negative bacterial infective endocarditis.
We describe two cases of bacterial endocarditis secondary to multidrug-resistant Gram-negative organisms. In both cases, the diagnosis was made in accordance with the modified Duke's criteria and confirmed by histopathological analysis. Furthermore, in both instances there were no identifiable sources of bacteraemia and no history of contact with hospital or other medical services prior to the onset of symptoms. The patients were managed in similar fashion with prolonged broad-spectrum antibiotic therapy and surgical intervention and made complete recoveries. These cases highlight Gram-negative organisms as potential agents for endocarditis, as well as expose the dissemination of such multidrug-resistant bacteria into the community. The application of an integrated medical and surgical approach and therapeutic dilemmas encountered in managing these cases are described.


Tretinoin gel microsphere pump 0.04% plus 5% benzoyl peroxide wash for treatment of acne vulgaris: morning/morning regimen is as effective and safe as morning/evening regimen.
Topical tretinoin and benzoyl peroxide (BPO) are often prescribed in combination for the treatment of acne vulgaris; however, these products have not traditionally been administered simultaneously because of the potential for tretinoin degradation by BPO as well as the instability of tretinoin in daylight. The primary objective of this randomized, investigator-blinded, 12-week, phase 4 trial was to determine non-inferiority of a once-daily morning combination regimen of 5% BPO wash + tretinoin gel microsphere (TGM) 0.04% pump versus a sequential regimen (BPO in the morning/TGM in the evening) in patients > or = 12 years old with moderate facial acne vulgaris. The primary efficacy endpoint was the change from baseline in total acne lesions; the primary safety endpoint was the change in cutaneous irritation scores. The 247 participants (mean age: 18.5 years) were randomized to either the morning/morning regimen (n = 123) or the morning/evening regimen (n = 124). The morning/morning regimen was determined to be non-inferior to the morning/evening regimen in reduction of total acne lesions. The tolerability of both regimens was comparable. The morning/morning regimen is a safe and effective treatment option for patients with moderate acne vulgaris.


Dating Infidelity in Turkish Couples: The Role of Attitudes and Intentions.
Studies on dating infidelity have mostly been carried out in individualistic, Western cultures and have tended to investigate either attitudes or intentions toward infidelity in isolation from each other. The current study therefore investigated dating infidelity in a more collectivist, predominantly Muslim culture. Informed by the theory of planned behavior, it tested intentions as a potential mechanism that might account for the association between attitudes toward infidelity and reported infidelity. In doing so, the role of gender and infidelity history was also investigated in regard to attitudes and intentions toward infidelity. A sample of 420 college students (292 women) completed the Turkish versions of the Attitudes Towards Infidelity Scale and the Intentions Towards Infidelity Scale. A 2 (gender) × 2 (infidelity history: yes, no) multivariate analysis of variance (MANOVA) revealed main effects but no interaction effect. Men compared to women and cheaters compared to noncheaters reported more favorable attitudes and intentions toward infidelity. Moreover, intentions toward infidelity fully and partly mediated the association between attitudes toward infidelity and infidelity for women and men, respectively. Findings are interpreted in light of dating infidelity research, with a focus on universal and culturally specific aspects. Recommendations are made for future research.


The Carbon Switch at the Level of Pyruvate and Phosphoenolpyruvate in Sulfolobus solfataricus P2.
Sulfolobus solfataricus P2 grows on different carbohydrates as well as alcohols, peptides and amino acids. Carbohydrates such as D-glucose or D-galactose are degraded via the modified, branched Entner-Doudoroff (ED) pathway whereas growth on peptides requires the Embden-Meyerhof-Parnas (EMP) pathway for gluconeogenesis. As for most hyperthermophilic Archaea an important control point is established at the level of triosephophate conversion, however, the regulation at the level of pyruvate/phosphoenolpyruvate conversion was not tackled so far. Here we describe the cloning, expression, purification and characterization of the pyruvate kinase (PK, SSO0981) and the phosphoenolpyruvate synthetase (PEPS, SSO0883) of Sul. solfataricus. The PK showed only catabolic activity [catalytic efficiency (PEP): 627.95 mM-1s-1, 70°C] with phosphoenolpyruvate as substrate and ADP as phosphate acceptor and was allosterically inhibited by ATP and isocitrate (K i 0.8 mM). The PEPS was reversible, however, exhibited preferred activity in the gluconeogenic direction [catalytic efficiency (pyruvate): 1.04 mM-1s-1, 70°C] and showed some inhibition by AMP and α-ketoglutarate. The gene SSO2829 annotated as PEPS/pyruvate:phosphate dikinase (PPDK) revealed neither PEPS nor PPDK activity. Our studies suggest that the energy charge of the cell as well as the availability of building blocks in the citric acid cycle and the carbon/nitrogen balance plays a major role in the Sul. solfataricus carbon switch. The comparison of regulatory features of well-studied hyperthermophilic Archaea reveals a close link and sophisticated coordination between the respective sugar kinases and the kinetic and regulatory properties of the enzymes at the level of PEP-pyruvate conversion.


Quantifying bank storage of variably saturated aquifers.
Numerical simulations were conducted to quantify bank storage in a variably saturated, homogenous, and anisotropic aquifer abutting a stream during rising stream stage. Seepage faces and bank slopes ranging from 1/3 to 100/3 were simulated. The initial conditions were assumed steady-state flow with water draining toward the stream. Then, the stream level rose at a constant rate to the specified elevation of the water table given by the landward boundary condition and stayed there until the system reached a new steady state. This represents a highly simplified version of a real world hydrograph. For the specific examples considered, the following conclusions can be made. The volume of surface water entering the bank increased with the rate of stream level rise, became negligible when the rate of rise was slow, and approached a positive constant when the rate was large. Also, the volume decreased with the dimensionless parameter M (the product of the anisotropy ratio and the square of the domain's aspect ratio). When M was large (>10), bank storage was small because most pore space was initially saturated with ground water due to the presence of a significant seepage face. When M was small, the seepage face became insignificant and capillarity began to play a role. The weaker the capillary effect, the easier for surface water to enter the bank. The effect of the capillary forces on the volume of surface water entering the bank was significant and could not be neglected.


Use of data collected at cessation of lactation to predict incidence of sole ulcers and white line disease during the subsequent lactation in dairy cows.
To develop a parsimonious statistical model to predict incidence of lameness in the subsequent lactation by use of data collected at cessation of lactation in dairy cows. 574 cows. At cessation of lactation during hoof trimming, body condition score (BCS), visual locomotion score, digital cushion thickness (DCT), and digital lesions were assessed. 140 (24%) cows were treated for claw horn disruption lesions (CHDLs) at cessation of lactation (114 with sole ulcers [pododermatitis circumscripta] and 26 with white line disease). The BCS was highly associated with DCT. Cows with CHDLs at cessation of lactation had significantly lower DCT, compared with other cows. All 3 logistic regression models predicted the incidence of CHDLs in the subsequent lactation with good accuracy; the area under the receiver operating characteristic curves was 0.76, 0.76, and 0.77 for the first, second, and third logistic regression models, respectively. Evaluation of 3 logistic regression models indicated that lameness could be predicted with good accuracy by use of all 3. The ability to predict lameness will facilitate the implementation of lameness prevention strategies by targeting specific cows.


Calculation of anharmonic OH phonon dispersion curves for the Mg(OH)2 crystal.
Anharmonic OH phonon dispersion curves have been calculated for the Mg(OH)(2) crystal. A crystal Hamiltonian was set up for the vibrational problem, where the coordinates consists of the bond lengths of two hydroxide ions in the central unit cell. Its two-dimensional potential energy surface was constructed from first principle calculations within the density functional theory approximation. Dispersion curves were calculated by diagonalizing the Hamiltonian in a basis of singly excited crystal functions. The single particle functions used to construct the crystal states were taken from a Morse oscillator basis set. These well chosen functions made it possible to restrict calculations to include only very few functions, which greatly contributed to a transparent presentation of the underlying theory. All calculations could be done analytically except for the calculation of a few integrals. We have compared our results with those of a series of harmonic lattice dynamics calculations and have found that the anharmonicity shifts the IR and Raman dispersion curves downward appreciably and slightly changes the energy differences between both curves. From an analysis of the harmonic results we conclude that incorporating the coupling between OH stretching motion and the motion of their centers of mass will appreciably change the overall features of the dispersion curves. Extension of the anharmonic model along these lines will cause no problem to the theoretical approach presented in this paper.


Shame if you do--shame if you don't: women's experiences of infant feeding.
Emotions such as guilt and blame are frequently reported by non-breastfeeding mothers, and fear and humiliation are experienced by breastfeeding mothers when feeding in a public context. In this paper, we present new insights into how shame-related affects, cognitions and actions are evident within breastfeeding and non-breastfeeding women's narratives of their experiences. As part of an evaluation study of the implementation of the UNICEF UK Baby Friendly Initiative Community Award within two primary (community based) care trusts in North West England, 63 women with varied infant feeding experiences took part in either a focus group or an individual semi-structured interview to explore their experiences, opinions and perceptions of infant feeding. Using a framework analysis approach and drawing on Lazare's categories of shame, we consider how the nature of the event (infant feeding) and the vulnerability of the individual (mother) interact in the social context to create shame responses in some breastfeeding and non-breastfeeding mothers. Three key themes illustrate how shame is experienced and internalised through 'exposure of women's bodies and infant feeding methods', 'undermining and insufficient support' and 'perceptions of inadequate mothering'. The findings of this paper highlight how breastfeeding and non-breastfeeding women may experience judgement and condemnation in interactions with health professionals as well as within community contexts, leading to feelings of failure, inadequacy and isolation. There is a need for strategies and support that address personal, cultural, ideological and structural constraints of infant feeding.


The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials.
The effect of statins on risk of heart failure (HF) hospitalization and HF death remains uncertain. We aimed to establish whether statins reduce major HF events. We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized controlled endpoint statin trials from 1994 to 2014. Collaborating trialists provided unpublished data from adverse event reports. We included primary- and secondary-prevention statin trials with >1000 participants followed for >1 year. Outcomes consisted of first non-fatal HF hospitalization, HF death and a composite of first non-fatal HF hospitalization or HF death. HF events occurring <30 days after within-trial myocardial infarction (MI) were excluded. We calculated risk ratios (RR) with fixed-effects meta-analyses. In up to 17 trials with 132 538 participants conducted over 4.3 [weighted standard deviation (SD) 1.4] years, statin therapy reduced LDL-cholesterol by 0.97 mmol/L (weighted SD 0.38 mmol/L). Statins reduced the numbers of patients experiencing non-fatal HF hospitalization (1344/66 238 vs. 1498/66 330; RR 0.90, 95% confidence interval, CI 0.84-0.97) and the composite HF outcome (1234/57 734 vs. 1344/57 836; RR 0.92, 95% CI 0.85-0.99) but not HF death (213/57 734 vs. 220/57 836; RR 0.97, 95% CI 0.80-1.17). The effect of statins on first non-fatal HF hospitalization was similar whether this was preceded by MI (RR 0.87, 95% CI 0.68-1.11) or not (RR 0.91, 95% CI 0.84-0.98). In primary- and secondary-prevention trials, statins modestly reduced the risks of non-fatal HF hospitalization and a composite of non-fatal HF hospitalization and HF death with no demonstrable difference in risk reduction between those who suffered an MI or not.