Evaluating loss of visual function in multiple sclerosis as measured by low-contrast letter acuity.
Disturbances in visual function are common in patients with multiple sclerosis (MS) and are often accompanied by substantial impairments in daily functioning and quality of life. Lesions associated with these impairments frequently involve the afferent visual pathway. Because these impairments are often not readily apparent on commonly used high-contrast acuity tests, low-contrast charts (e.g., low-contrast Sloan letter charts) have gained validity in the assessment of visual dysfunction in patients with MS. Decrements in low-contrast letter acuity are associated with MS and correlate with increasing disability, MRI abnormalities, and reduced retinal nerve fiber layer (RNFL) thickness as measured by optical coherence tomography (OCT). These findings suggest that low-contrast letter acuity testing is a potentially useful addition to disability scales such as the Multiple Sclerosis Functional Composite, serving as another surrogate marker for MS disability. Assessment of RNFL thickness by OCT, which is also associated with visual impairment, also may be considered for inclusion in clinical trials evaluating treatments for MS. The effects of disease-modifying therapies on visual dysfunction in patients with MS have been evaluated only recently. Two phase 3 studies of natalizumab showed that low-contrast letter acuity testing, included as an exploratory outcome, demonstrated treatment effects. Other ongoing studies have incorporated low-contrast acuity and OCT measures of RNFL thickness. The availability and wider use of low-contrast letter acuity tests, in combination with ocular imaging techniques, may improve assessment of treatment efficacy in patients with MS.


Integral elastic, electronic-state, ionization, and total cross sections for electron scattering with furfural.
We report absolute experimental integral cross sections (ICSs) for electron impact excitation of bands of electronic-states in furfural, for incident electron energies in the range 20-250 eV. Wherever possible, those results are compared to corresponding excitation cross sections in the structurally similar species furan, as previously reported by da Costa et al. [Phys. Rev. A 85, 062706 (2012)] and Regeta and Allan [Phys. Rev. A 91, 012707 (2015)]. Generally, very good agreement is found. In addition, ICSs calculated with our independent atom model (IAM) with screening corrected additivity rule (SCAR) formalism, extended to account for interference (I) terms that arise due to the multi-centre nature of the scattering problem, are also reported. The sum of those ICSs gives the IAM-SCAR+I total cross section for electron-furfural scattering. Where possible, those calculated IAM-SCAR+I ICS results are compared against corresponding results from the present measurements with an acceptable level of accord being obtained. Similarly, but only for the band I and band II excited electronic states, we also present results from our Schwinger multichannel method with pseudopotentials calculations. Those results are found to be in good qualitative accord with the present experimental ICSs. Finally, with a view to assembling a complete cross section data base for furfural, some binary-encounter-Bethe-level total ionization cross sections for this collision system are presented.


Potential Maternal and Infant Outcomes from (Wuhan) Coronavirus 2019-nCoV Infecting Pregnant Women: Lessons from SARS, MERS, and Other Human Coronavirus Infections.
In early December 2019 a cluster of cases of pneumonia of unknown cause was identified in Wuhan, a city of 11 million persons in the People's Republic of China. Further investigation revealed these cases to result from infection with a newly identified coronavirus, termed the 2019-nCoV. The infection moved rapidly through China, spread to Thailand and Japan, extended into adjacent countries through infected persons travelling by air, eventually reaching multiple countries and continents. Similar to such other coronaviruses as those causing the Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS), the new coronavirus was reported to spread via natural aerosols from human-to-human. In the early stages of this epidemic the case fatality rate is estimated to be approximately 2%, with the majority of deaths occurring in special populations. Unfortunately, there is limited experience with coronavirus infections during pregnancy, and it now appears certain that pregnant women have become infected during the present 2019-nCoV epidemic. In order to assess the potential of the Wuhan 2019-nCoV to cause maternal, fetal and neonatal morbidity and other poor obstetrical outcomes, this communication reviews the published data addressing the epidemiological and clinical effects of SARS, MERS, and other coronavirus infections on pregnant women and their infants. Recommendations are also made for the consideration of pregnant women in the design, clinical trials, and implementation of future 2019-nCoV vaccines.


[Study of the microwave emissivity characteristics over different land cover types].
The microwave emissivity over land is very important for describing the characteristics of the lands, and it is also a key factor for retrieving the parameters of land and atmosphere. Different land covers have their emission behavior as a function of structure, water content, and surface roughness. In the present study the global land surface emissivities were calculated using six month (June, 2003-August, 2003, Dec, 2003-Feb, 2004) AMSR-E L2A brightness temperature, MODIS land surface temperature and the layered atmosphere temperature, and humidity and pressure profiles data retrieved from MODIS/Aqua under clear sky conditions. With the information of IGBP land cover types, "pure" pixels were used, which are defined when the fraction cover of each land type is larger than 85%. Then, the emissivity of sixteen land covers at different frequencies, polarization and their seasonal variation were analyzed respectively. The results show that the emissivity of vegetation including forests, grasslands and croplands is higher than that over bare soil, and the polarization difference of vegetation is smaller than that of bare soil. In summer, the emissivity of vegetation is relatively stable because it is in bloom, therefore the authors can use it as its emissivity in our microwave emissivity database over different land cover types. Furthermore, snow cover can heavily impact the change in land cover emissivity, especially in winter.


Lumican regulates corneal inflammatory responses by modulating Fas-Fas ligand signaling.
The authors have previously shown that apoptosis of stromal cells is downregulated in the lumican-null mouse and that this may be due to disruption of Fas-Fas ligand (FasL) signaling. The present study was undertaken to investigate the role of lumican in regulating Fas and its impact on inflammation and healing of corneal injuries. Apoptosis was determined by measuring caspase-3/7 activity in corneal extracts. Protein and RNA levels of Fas were estimated by immunoblot analysis and RT-PCR, respectively. Circular and incisional stromal wounds were exposed to Pseudomonas aeruginosa LPS, and healing was assessed by (1) observing wound closure with fluorescence and bright-field microscopy, (2) histology to quantify inflammatory infiltrates by immunostaining for macrophages (F4/80) and neutrophils (NIMP-R14), (3) measuring myeloperoxidase (MPO) levels by ELISA to quantify neutrophils, and (4) measuring proinflammatory cytokines by ELISA. Lum-/- -injured corneas showed significantly lower caspase-3/7 activity (apoptosis). Lum-/- -wounded corneas showed delayed healing, reduced recruitment of macrophages and neutrophils, lower MPO levels, and no induction of the proinflammatory cytokines TNFalpha and IL1beta. The Fas protein level, before and after wounding, was dramatically lower in Lum-/- - compared with Lum+/+-injured cornea. However, Fas mRNA levels were comparable in both genotypes, suggesting regulation of Fas at the protein level. Moreover, a solid-state binding assay and coimmunoprecipitation of FasL and lumican suggested binding of FasL to lumican. The data suggest that lumican binds FasL and facilitates induction of Fas. Poor signaling through Fas-FasL in lumican deficiency leads to impaired induction of inflammatory cytokines and corneal healing.


The MacKinnon Lists Technique: An efficient new method for rapidly assessing biodiversity and species abundance ranks in the marine environment.
Widespread and ever-increasing anthropogenic impacts in the marine environment are driving a need to develop more efficient survey methods for monitoring changes in marine biodiversity. There is a particular urgent need for survey methods that could more rapidly and effectively detect change in species richness, abundance and community composition. Here, test the suitability of the Mackinnon Lists Technique for use in the marine environment by testing its effectiveness for rapid assessment of fish communities. The MacKinnon Lists Technique is a time-efficient and cost-effective sampling method developed for studying avian tropical biodiversity, in which several list samples of species can be collected from a single survey. Using the well-established MaxN approach on data from deployments of a Baited Remote Underwater Video Systems for comparison, we tested the suitability of the MacKinnon Lists Technique for use in marine environments by analysing tropical reef fish communities. Using both methods for each data set, differences in community composition between depths and levels of protection were assessed. Both methods were comparable for diversity and evenness indices with similar ranks for species. Multivariate analysis showed that the MacKinnon Lists Technique and MaxN detected similar differences in community composition at different depths and protection status. However, the MacKinnon Lists Technique detected significant differences between factors when fewer videos (representing reduced survey effort) were used. We conclude that the MacKinnon Lists Technique is at least as effective as the widely used MaxN method for detecting differences between communities in the marine environment and suggest can do so with lower survey effort. The MacKinnon Lists Technique has the potential to be widely used as an effective new tool for rapid conservation monitoring in marine ecosystems.


Bone fractures from generalized convulsive seizures and status epilepticus-A systematic review.
We present a systematic review of the literature regarding types and anatomic distribution of fractures in association with generalized convulsive status epilepticus (GCSE) and convulsive seizures in adult patients accompanied by an illustrative case of a patient with GCSE and diffuse postictal pain from underlying bone fractures. The library search engines PubMed and EMBASE were screened systematically using predefined search terms. All identified articles written in English were screened for eligibility by two reviewers. The preferred reporting items for systematic reviews and meta-analyses guidelines were followed. The screening of 3145 articles revealed 39 articles meeting the inclusion criteria. Among all fractures, bilateral posterior fracture-dislocations of the shoulders were reported most frequently (33%), followed by thoracic and lumbar vertebral compression fractures (29%), skull and jaw fractures (8%), and bilateral femoral neck fractures (6%). Risk factors for seizure-related fractures are seizure severity, duration of epilepsy, the use of antiseizure drugs known to decrease bone density, and a family history of fractures. Based on these findings, a three-step screening procedure is proposed to uncover fractures in the postictal state. All studies were retrospective without standardized screening methods for seizure-associated fractures resulting in a very low level of evidence and a high risk of bias. Posterior fracture-dislocations of the shoulders, thoracic and lumbar vertebral compression, fractures of the skull and jaw, and bilateral femoral neck fractures are most frequently reported. Preventive measures including bone densitometry, calcium/vitamin D supplementation, and bisphosphonate therapy should be reinforced in epilepsy patients at risk of osteoporosis. As long as the effect of standardized screening of fractures is not investigated, it is too early to integrate such a screening into treatment guidelines. In the meantime, clinicians are urged to heighten awareness regarding seizure-associated fractures, especially in patients with postictal pain, as symptoms can be unspecific and misinterpretation may impede rehabilitation.


Deregulated cyclin D1 expression is associated with decreased efficacy of the selective epidermal growth factor receptor tyrosine kinase inhibitor gefitinib in head and neck squamous cell carcinoma cell lines.
Despite promising initial results, recent Phase III trials of the selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib ("Iressa"; AstraZeneca, Wilmington, Delaware) in advanced head and neck squamous cell carcinoma (HNSCC) have been equivocal. Cyclin D1, an EGFR target gene, is frequently overexpressed in HNSCC, has been implicated in its pathogenesis, and is strongly associated with poor prognosis in this disease. Therefore, we examined the relationship between deregulated cyclin D1 expression and sensitivity to gefitinib to determine whether this frequently occurring oncogenic change affected the cellular response to gefitinib. A panel of six EGFR-overexpressing HNSCC cell lines was used to correlate CCND1 gene copy number, cyclin D1 expression, and response to gefitinib. The effect of constitutive overexpression of cyclin D1 was assessed by establishing stably transfected clonal SCC-9 cell lines. Three of six cell lines displayed cyclin D1 amplification and/or overexpression, and these cell lines were resistant to gefitinib. SCC 9 clones overexpressing cyclin D1 continued to proliferate and maintained their S-phase fraction when treated with gefitinib, whereas empty vector control clones and the parental SCC 9 cells were profoundly inhibited and displayed marked reductions in S-phase. The resistance of cyclin D1-overexpressing clones and cyclin D1-amplified cell lines was associated with maintenance of cyclin D1 expression after gefitinib treatment. These data suggest that deregulated cyclin D1 overexpression may be associated with resistance of HNSCC to EGFR inhibitors. Therefore, the role of cyclin D1 as a marker of therapeutic response and its utility as a prognostic marker in HNSCC warrant additional analysis.


T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells.
Sle3 is an NZM2410-derived lupus susceptibility locus on murine chromosome 7. Congenic recombination has resulted in a novel mouse strain, B6.Sle3, associated with serum antinuclear autoantibodies (ANAs), T cell hyperactivity, and elevated CD4/CD8 ratios. An OVA-specific TCR transgene was used as a tool to demonstrate that Sle3 facilitated heightened T cell expansion in vitro, and in vivo, following antigen challenge. Indeed, continued T cell expansion was noted even in response to a tolerogenic signal. However, these phenotypes did not appear to be T cell intrinsic but were dictated by hyperstimulatory B6.Sle3 APCs. Importantly, B6.Sle3-derived DCs and macrophages appeared to be significantly more mature/activated, less apoptotic, and more proinflammatory and were better at costimulating T cells in vitro, compared with the B6 counterparts. Finally, the adoptive transfer of B6.Sle3-derived DCs into healthy B6 recipients elicited increased CD4/CD8 ratios and serum ANAs, 2 cardinal Sle3-associated phenotypes. We posit that their heightened expression of various costimulatory molecules, including CD80, CD106, I-A, and CD40, and their elevated production of various cytokines, including IL-12 and IL-1beta, may explain why Sle3-bearing DCs may be superior at breaching self tolerance. These studies provide mechanistic evidence indicating that intrinsic abnormalities in DCs and possibly other myeloid cells may dictate several of the phenotypes associated with systemic lupus, including ANA formation and T cell hyperactivity.


Relationship between body weight and the incidence of positive axillary nodes at mastectomy for breast cancer.
The question, whether obesity is associated with an increased incidence of positive axillary nodes at mastectomy for breast cancer, was studied in two quite different hospital populations; one from a large urban teaching hospital (Montefiore) and one from a medium-sized Air Force medical center (Malcolm Grow). In the Montefiore population, the answer was "yes"; 67% of the node-positive patients, but only 31% of the node-negative patients were obese (20% or more above ideal weight) (p less than 0.05). In the Malcolm Grow population, the answer was "no"; 20% of the node-positive and 20% of the node-negative patients were obese. The different answers, we believe, are due to the biological differences between the populations; the Montefiore population was shorter (by an average of 1.7 inches), heavier (by an average of 20 lbs), and more obese. The incidence of obesity was about three times as high in the Montefiore population (52% versus 20%; p less than 0.02) and it contained a statistically distinct subpopulation of obese patients, while the few obese patients in the Malcolm Grow population constituted merely the upper tail of a unimodal log-normal distribution of weight in that population. We propose that it is possible to demonstrate a relationship of obesity to node-positivity in the Montefiore population but not in the Malcolm Grow population because obesity was highly prevalent in the former and almost nonexistent in the latter. It seems self-evident that it is not possible to demonstrate an effect of obesity in a population if that population manifests no significant obesity, statistically speaking, but disregarding this principle, we believe, may account for the controversy in the literature about whether obesity is a risk factor in breast cancer.


Mindfulness-based stress reduction in an integrated care delivery system: one-year impacts on patient-centered outcomes and health care utilization.
Mindfulness-based stress reduction (MBSR) programs have demonstrated clinical effectiveness for both mental and physical health conditions. Less research exists on health services utilization, self-efficacy, or work productivity outcomes. To assess one-year outcomes of MBSR in patients with chronic pain, chronic illness, or stress-related problems, measuring functional status, pain, self-efficacy, depression, anxiety, somatization, psychological distress, work productivity, and changes in health services utilization. A prospective single cohort design evaluated an eight-week MBSR program for Kaiser Permanente Colorado members. Patient-reported measures were collected at baseline, eight weeks, and one year following MBSR. Differences in health services utilization were compared from six months before MBSR to six months following the one-year anniversary of MBSR. Most of the 38 participants were white (28; 74%), female (30; 79%), employed part-time (35; 92%), and average age 52.6 years, with multiple comorbidities (averaging 16.4 unique diagnoses), the most common being joint or back pain (28; 74%) and psychological disorder (20; 53%). Repeated measures analyses at 8 weeks (n = 26) and at 1 year (n = 24) showed significant improvements in self-reported mental and physical function, pain, psychological symptoms, and self-efficacy, but not work productivity. Significant decreases at 1 year were observed for visits in primary care (-50%, p < 0.0001), specialty care (-38%, p = 0.0004), and the Emergency Department (-50%, p = 0.04), and for hospital admissions (-80%, p = 0.02). The MBSR program was associated with improvements in several patient-centered outcomes over 1 year and reductions in health services utilization up to 18 months.


Selective chest imaging for blunt trauma patients: The national emergency X-ray utilization studies (NEXUS-chest algorithm).
Chest imaging plays a prominent role in blunt trauma patient evaluation, but indiscriminate imaging is expensive, may delay care, and unnecessarily exposes patients to potentially harmful ionizing radiation. To improve diagnostic chest imaging utilization, we conducted 3 prospective multicenter studies over 12years to derive and validate decision instruments (DIs) to guide the use of chest x-ray (CXR) and chest computed tomography (CT). The first DI, NEXUS Chest x-ray, consists of seven criteria (Age >60years; rapid deceleration mechanism; chest pain; intoxication; altered mental status; distracting painful injury; and chest wall tenderness) and exhibits a sensitivity of 99.0% (95% confidence interval [CI] 98.2-99.4%) and a specificity of 13.3% (95% CI, 12.6%-14.0%) for detecting clinically significant injuries. We developed two NEXUS Chest CT DIs, which are both highly reliable in detecting clinically major injuries (sensitivity of 99.2%; 95% CI 95.4-100%). Designed primarily to focus on detecting major injuries, the NEXUS Chest CT-Major DI consists of six criteria (abnormal CXR; distracting injury; chest wall tenderness; sternal tenderness; thoracic spine tenderness; and scapular tenderness) and exhibits higher specificity (37.9%; 95% CI 35.8-40.1%). Designed to reliability detect both major and minor injuries (sensitivity 95.4%; 95% CI 93.6-96.9%) with resulting lower specificity (25.5%; 95% CI 23.5-27.5%), the NEXUS CT-All rule consists of seven elements (the six NEXUS CT-Major criteria plus rapid deceleration mechanism). The purpose of this review is to synthesize the three DIs into a novel, cohesive summary algorithm with practical implementation recommendations to guide selective chest imaging in adult blunt trauma patients.


Structural and functional analysis of a new subfamily of glycosyltransferases required for glycosylation of serine-rich streptococcal adhesins.
Serine-rich repeat glycoproteins (SRRPs) are a growing family of bacterial adhesins found in many streptococci and staphylococci; they play important roles in bacterial biofilm formation and pathogenesis. Glycosylation of this family of adhesins is essential for their biogenesis. A glucosyltransferase (Gtf3) catalyzes the second step of glycosylation of a SRRP (Fap1) from an oral streptococcus, Streptococcus parasanguinis. Although Gtf3 homologs are highly conserved in SRRP-containing streptococci, they share minimal homology with functionally known glycosyltransferases. We report here the 2.3 Å crystal structure of Gtf3. The structural analysis indicates that Gtf3 forms a tetramer and shares significant structural homology with glycosyltransferases from GT4, GT5, and GT20 subfamilies. Combining crystal structural analysis with site-directed mutagenesis and in vitro glycosyltransferase assays, we identified residues that are required for UDP- or UDP-glucose binding and for oligomerization of Gtf3 and determined their contribution to the enzymatic activity of Gtf3. Further in vivo studies revealed that the critical amino acid residues identified by the structural analysis are crucial for Fap1 glycosylation in S. parasanguinis in vivo. Moreover, Gtf3 homologs from other streptococci were able to rescue the gtf3 knock-out mutant of S. parasanguinis in vivo and catalyze the sugar transfer to the modified SRRP substrate in vitro, demonstrating the importance and conservation of the Gtf3 homologs in glycosylation of SRRPs. As the Gtf3 homologs only exist in SRRP-containing streptococci, we conclude that the Gtf3 homologs represent a unique subfamily of glycosyltransferases.


Mixing of exciton and charge-transfer states in light-harvesting complex Lhca4.
Lhca4 is one of the peripheral antennae of higher plant photosystem I and it is characterized by the presence of chlorophyll a with absorption and emission bands around 30 nm red-shifted compared to those of the other chlorophylls associated with plant complexes. In this work we have investigated the origin of this red shift by using the recent structure of Lhca4 (Qin et al., Science, 2015, 348, 989) to build an exciton model that includes a charge-transfer (CT) state mixed with the excited-state manifold. A simultaneous quantitative fit of absorption, linear dichroism, fluorescence, and Stark absorption spectra of the wild-type Lhca4 and NH mutant (where the sites involved in CT are affected) enables us to determine the origin of the CT state and explore its spectral signatures. A huge borrowing of dipole strength by the CT, accompanied by anomalous broadening and red-shifting of the fluorescence as well as dramatic changes in the Stark spectrum, can be accounted for by a model implying an exciton-type mixing between excited states and CT states.


Cancer data quality and harmonization in Europe: the experience of the BENCHISTA Project - international benchmarking of childhood cancer survival by stage.
Variation in stage at diagnosis of childhood cancers (CC) may explain differences in survival rates observed across geographical regions. The BENCHISTA project aims to understand these differences and to encourage the application of the Toronto Staging Guidelines (TG) by Population-Based Cancer Registries (PBCRs) to the most common solid paediatric cancers. PBCRs within and outside Europe were invited to participate and identify all cases of Neuroblastoma, Wilms Tumour, Medulloblastoma, Ewing Sarcoma, Rhabdomyosarcoma and Osteosarcoma diagnosed in a consecutive three-year period (2014-2017) and apply TG at diagnosis. Other non-stage prognostic factors, treatment, progression/recurrence, and cause of death information were collected as optional variables. A minimum of three-year follow-up was required. To standardise TG application by PBCRs, on-line workshops led by six tumour-specific clinical experts were held. To understand the role of data availability and quality, a survey focused on data collection/sharing processes and a quality assurance exercise were generated. To support data harmonization and query resolution a dedicated email and a question-and-answers bank were created. 67 PBCRs from 28 countries participated and provided a maximally de-personalized, patient-level dataset. For 26 PBCRs, data format and ethical approval obtained by the two sponsoring institutions (UCL and INT) was sufficient for data sharing. 41 participating PBCRs required a Data Transfer Agreement (DTA) to comply with data protection regulations. Due to heterogeneity found in legal aspects, 18 months were spent on finalizing the DTA. The data collection survey was answered by 68 respondents from 63 PBCRs; 44% of them confirmed the ability to re-consult a clinician in cases where stage ascertainment was difficult/uncertain. Of the total participating PBCRs, 75% completed the staging quality assurance exercise, with a median correct answer proportion of 92% [range: 70% (rhabdomyosarcoma) to 100% (Wilms tumour)]. Differences in interpretation and processes required to harmonize general data protection regulations across countries were encountered causing delays in data transfer. Despite challenges, the BENCHISTA Project has established a large collaboration between PBCRs and clinicians to collect detailed and standardised TG at a population-level enhancing the understanding of the reasons for variation in overall survival rates for CC, stimulate research and improve national/regional child health plans.


Lifelong memory responses perpetuate humoral TH2 immunity and anaphylaxis in food allergy.
A number of food allergies (eg, fish, shellfish, and nuts) are lifelong, without any disease-transforming therapies, and unclear in their underlying immunology. Clinical manifestations of food allergy are largely mediated by IgE. Although persistent IgE titers have been attributed conventionally to long-lived IgE+ plasma cells (PCs), this has not been directly and comprehensively tested. We sought to evaluate mechanisms underlying persistent IgE and allergic responses to food allergens. We used a model of peanut allergy and anaphylaxis, various knockout mice, adoptive transfer experiments, and in vitro assays to identify mechanisms underlying persistent IgE humoral immunity over almost the entire lifespan of the mouse (18-20 months). Contrary to conventional paradigms, our data show that clinically relevant lifelong IgE titers are not sustained by long-lived IgE+ PCs. Instead, lifelong reactivity is conferred by allergen-specific long-lived memory B cells that replenish the IgE+ PC compartment. B-cell reactivation requires allergen re-exposure and IL-4 production by CD4 T cells. We define the half-lives of antigen-specific germinal centers (23.3 days), IgE+ and IgG1+ PCs (60 and 234.4 days, respectively), and clinically relevant cell-bound IgE (67.3 days). These findings can explain lifelong food allergies observed in human subjects as the consequence of allergen exposures that recurrently activate memory B cells and identify these as a therapeutic target with disease-transforming potential.


Endoscopic repair of full-thickness gluteus medius tears.
Tears in the gluteus medius and minimus tendons recently have emerged as an important cause of chronic greater trochanteric pain syndrome. Increasing recognition of the gluteal insertion as a cause of chronic pain and weakness, as well as technologic advances in endoscopic hip surgery, has made gluteal insertional repair a rapidly emerging technique in minimally invasive surgery of the hip. We present an endoscopic double-row technique for gluteal insertional repair that allows for visualization, debridement, and repair, re-creating the normal footprint.


Conformation of a coarse-grained protein chain (an aspartic acid protease) model in effective solvent by a bond-fluctuating Monte Carlo simulation.
In a coarse-grained description of a protein chain, all of the 20 amino acid residues can be broadly divided into three groups: Hydrophobic (H) , polar (P) , and electrostatic (E) . A protein can be described by nodes tethered in a chain with a node representing an amino acid group. Aspartic acid protease consists of 99 residues in a well-defined sequence of H , P , and E nodes tethered together by fluctuating bonds. The protein chain is placed on a cubic lattice where empty lattice sites constitute an effective solvent medium. The amino groups (nodes) interact with the solvent (S) sites with appropriate attractive (PS) and repulsive (HS) interactions with the solvent and execute their stochastic movement with the Metropolis algorithm. Variations of the root mean square displacements of the center of mass and that of its center node of the protease chain and its gyration radius with the time steps are examined for different solvent strength. The structure of the protease swells on increasing the solvent interaction strength which tends to enhance the relaxation time to reach the diffusive behavior of the chain. Equilibrium radius of gyration increases linearly on increasing the solvent strength: A slow rate of increase in weak solvent regime is followed by a faster swelling in stronger solvent. Variation of the gyration radius with the time steps suggests that the protein chain moves via contraction and expansion in a somewhat quasiperiodic pattern particularly in strong solvent.


Application of posterior pelvic tilt taping for the treatment of chronic low back pain with sacroiliac joint dysfunction and increased sacral horizontal angle.
Kinesio Taping (KT) is a therapeutic method used by physical therapists and athletic trainers in combination with other treatment techniques for various musculoskeletal and neuromuscular problems. However, no research has evaluated the effect of KT in patients with low back pain (LBP). The purpose of this case was to describe the application of posterior pelvic tilt taping (PPTT) with Kinesio tape as a treatment for chronic LBP and to reduce the anterior pelvic tilt angle. Case report. The patien was a 20-year-old female amateur swimmer with a Cobb's angle (L1-S1) of 68°, a sacral horizontal angle of 45°, and pain in both medial buttock areas and sacroiliac joints. We performed PPTT with Kinesio tape for 2 weeks (six times per week for an average of 9 h each time). The patient's radiographs showed that the Cobb's angle (L1-S1) had decreased from 68° to 47° and that the sacral horizontal angle had decreased from 45° to 31°. Reductions in hypomobility or motion asymmetry, as assessed by the motion palpation test, and in pain, as measured by the pain-provocation tests, were observed. On palpation for both medial buttock areas in the prone position, the patient felt no pain. The patient experienced no pain or stiffness in the low back area while performing forward flexion in the standing position with knees fully extended when washing dishes in the sink. The case study demonstrated that PPTT intervention favourably affected the pelvic inclination and sacral horizontal angle, leading to beneficial effects on sacroiliac joint dysfunction (SIJD) and medial buttock pain. Additional research on the clinical effects of this taping procedure requires greater numbers of athletes with SIJD or LBP who have inappropriate anterior pelvic tilt angles and hyperlordosis.


Dysregulated Expression of Glycolipids in Tumor Cells: From Negative Modulator of Anti-tumor Immunity to Promising Targets for Developing Therapeutic Agents.
Glycolipids are complex molecules consisting of a ceramide lipid moiety linked to a glycan chain of variable length and structure. Among these are found the gangliosides, which are sialylated glycolipids ubiquitously distributed on the outer layer of vertebrate plasma membranes. Changes in the expression of certain species of gangliosides have been described to occur during cell proliferation, differentiation, and ontogenesis. However, the aberrant and elevated expression of gangliosides has been also observed in different types of cancer cells, thereby promoting tumor survival. Moreover, gangliosides are actively released from the membrane of tumor cells, having a strong impact on impairing anti-tumor immunity. Beyond the undesirable effects of gangliosides in cancer cells, a substantial number of cancer immunotherapies have been developed in recent years that have used gangliosides as the main target. This has resulted in successful immune cell- or antibody-responses against glycolipids, with promising results having been obtained in clinical trials. In this review, we provide a general overview on the metabolism of glycolipids, both in normal and tumor cells, as well as examining glycolipid-mediated immune modulation and the main successes achieved in immunotherapies using gangliosides as molecular targets.


Long-term cerebral white and gray matter changes after preeclampsia.
To determine whether changes in cerebral structure are present after preeclampsia that may explain increased cerebrovascular risk in these women. We conducted a case control study in women between 5 and 15 years after either a preeclamptic or normotensive pregnancy. Brain MRI was performed. Analysis of white matter structure was undertaken using voxel-based segmentation of fluid-attenuation inversion recovery sequences to assess white matter lesion volume and diffusion tensor imaging to measure microstructural integrity. Voxel-based analysis of gray matter volumes was performed with adjustment for skull size. Thirty-four previously preeclamptic women (aged 42.8 ± 5.1 years) and 49 controls were included. Previously preeclamptic women had reduced cortical gray matter volume (523.2 ± 30.1 vs 544.4 ± 44.7 mL, p < 0.05) and, although both groups displayed white matter lesions, changes were more extensive in previously preeclamptic women. They displayed increased temporal lobe white matter disease (lesion volume: 23.2 ± 24.9 vs 10.9 ± 15.0 μL, p < 0.05) and altered microstructural integrity (radial diffusivity: 538 ± 19 vs 526 ± 18 × 10-6 mm2/s, p < 0.01), which also extended to occipital and parietal lobes. The degree of temporal lobe white matter change in previously preeclamptic women was independent of their current cardiovascular risk profile (p < 0.05) and increased with time from index pregnancy (p < 0.05). A history of preeclampsia is associated with temporal lobe white matter changes and reduced cortical volume in young women, which is out of proportion to their classic cardiovascular risk profile. The severity of changes is proportional to time since pregnancy, which would be consistent with continued accumulation of damage after pregnancy.


Early growth of Mexican-American children: lagging in preliteracy skills but not social development.
Latino toddlers fall behind White peers at 24 months of age in oral language and interactive skills with their mothers in English or Spanish. But Latino children enter kindergarten with social skills that rival White peers, despite social-class disparities. We ask whether cognitive trajectories widen during the 24-48 month period, how these patterns differ for Latinos, especially Mexican-Americans, and whether similar gaps in social-emotional growth appear. We analyzed growth patterns for a nationally representative birth sample (n = 4,690) drawn in 2001, estimating levels of change in development from 24 to 48 months of age, focusing on Latino subgroups. The mean gap in cognitive processing for Mexican-American children, already wide at 24-months of age relative to Whites (three-fourths of a standard deviation), remained constant at 48 months. But differences in social-emotional status were statistically insignificant at both 24 and 48 months. Mexican-American mothers were observed to be equally warm and supportive relative to White peers during interaction tasks. Yet the former group engaged less frequently in cognitive facilitation, oral language, and preliteracy activities in the home. Growth in both cognitive and social domains was considerably lower in larger families, placing children raised in poor or Spanish-speaking homes within a large household at greater risk of delays. Pediatricians and practitioners must carefully gauge the social-emotional well-being of Latino children, in developmental surveillance activities. Growth in cognitive and social domains unfolds independently for children of Mexican heritage, even when raised in economically poor families.


Packing confined hard spheres denser with adaptive prism phases.
We show that hard spheres confined between two parallel hard plates pack denser with periodic adaptive prismatic structures which are composed of alternating prisms of spheres. The internal structure of the prisms adapts to the slit height which results in close packings for a range of plate separations, just above the distance where three intersecting square layers fit exactly between the plates. The adaptive prism phases are also observed in real-space experiments on confined sterically stabilized colloids and in Monte Carlo simulations at finite pressure.


Accumulation of attenuating mutations in varying proportions within a high passage very virulent plus strain of Gallid herpesvirus type 2.
Marek's disease (MD) is controlled through mass vaccination. Although these vaccines reduce or delay tumor formation they fail to induce sterilizing immunity and prevent virus shedding. Relatively little is known about the genetic changes that lead to attenuation. It has been established that serial passage of virulent strains in avian cell lines results in the generation of attenuated progeny at some undefined passage level. A detailed cataloging of the mutations needed for attenuation will be important for advancing our understanding of MD biology and should facilitate the development of better vaccines. Using deep sequencing, the complete nucleotide sequence of the very virulent plus (vv+) strain 648A representing the 101 st passage was determined. Pathotyping studies have indicated that 648Ap101 is indeed attenuated. Comparative sequence analysis with the 648A strain at passage 11 has identified numerous gross genetic changes and subtle single nucleotide polymorphisms scattered throughout the genome. Relative to the strain (648Ap11), deletions were identified in MD-specific genes located in the repeat long (R(L)), unique long (U(L)) and repeat short (R(S)) regions. A deletion in the R(L) region, present in 33% of the p101 sequences, mapped to the genes encoding viral interleukin 8 (vIL8), RLORF4 and RLORF5. An R(S) deletion was mapped to the Meq oncoprotein binding site within the ICP4 promoter and was present in 97.8% of the p101 sequences. A short deletion in the U(L) region mapped to the 3' terminus of the gene encoding vLipase and was present in 54% of the p101 sequences. The cis-acting sites involved in DNA replication and packaging also contained deletions in varying proportions (64% and 100%, respectively). Three mutations, present in 100% of p101 sequences, were identified in the overlapping genes encoding the Arg-rich protein (MDV002/079) and the virus-encoding telomerase (vTR). Varying proportions of 12 single nucleotide polymorphisms (SNPs) were identified within 11 open reading frames (ORFs) and 3 noncoding regions. This comparative sequencing study has provided a wealth of information regarding genetic changes which have occurred during the attenuation process and has indicated that serial passage results in the generation of mixed populations.


The CI MuMuFe - A New MMN Paradigm for Measuring Music Discrimination in Electric Hearing.
Cochlear implants (CIs) allow good perception of speech while music listening is unsatisfactory, leading to reduced music enjoyment. Hence, a number of ongoing efforts aim to improve music perception with a CI. Regardless of the nature of these efforts, effect measurements must be valid and reliable. While auditory skills are typically examined by behavioral methods, recording of the mismatch negativity (MMN) response, using electroencephalography (EEG), has recently been applied successfully as a supplementary objective measure. Eleven adult CI users and 14 normally hearing (NH) controls took part in the present study. To measure their detailed discrimination of fundamental features of music we applied a new multifeature MMN-paradigm which presented four music deviants at four levels of magnitude, incorporating a novel "no-standard" approach to be tested with CI users for the first time. A supplementary test measured behavioral discrimination of the same deviants and levels. The MMN-paradigm elicited significant MMN responses to all levels of deviants in both groups. Furthermore, the CI-users' MMN amplitudes and latencies were not significantly different from those of NH controls. Both groups showed MMN strength that was in overall alignment with the deviation magnitude. In CI users, however, discrimination of pitch levels remained undifferentiated. On average, CI users' behavioral performance was significantly below that of the NH group, mainly due to poor pitch discrimination. Although no significant effects were found, CI users' behavioral results tended to be in accordance with deviation magnitude, most prominently manifested in discrimination of the rhythm deviant. In summary, the study indicates that CI users may be able to discriminate subtle changes in basic musical features both in terms of automatic neural responses and of attended behavioral detection. Despite high complexity, the new CI MuMuFe paradigm and the "no-standard" approach provided reliable results, suggesting that it may serve as a relevant tool in future CI research. For clinical use, future studies should investigate the possibility of applying the paradigm with the purpose of assessing discrimination skills not only at the group level but also at the individual level.


What is the impact of a research publication?
An increasing number of metrics are used to measure the impact of research papers. Despite being the most commonly used, the 2-year impact factor is limited by a lack of generalisability and comparability, in part due to substantial variation within and between fields. Similar limitations apply to metrics such as citations per paper. New approaches compare a paper's citation count to others in the research area, while others measure social and traditional media impact. However, none of these measures take into account an individual author's contribution to the paper or the number of authors, which we argue are key limitations. The UK's 2014 Research Exercise Framework included a detailed bibliometric analysis comparing 15 selected metrics to a 'gold standard' evaluation of almost 150 000 papers by expert panels. We outline the main correlations between the most highly regarded papers by the expert panel in the Psychiatry, Clinical Psychology and Neurology unit and these metrics, most of which were weak to moderate. The strongest correlation was with the SCImago Journal Rank, a variant of the journal impact factor, while the amount of Twitter activity showed no correlation. We suggest that an aggregate measure combining journal metrics, field-standardised citation data and alternative metrics, including weighting or colour-coding of individual papers to account for author contribution, could provide more clarity.


OX40 is required for regulatory T cell-mediated control of colitis.
The immune response in the gastrointestinal tract is a tightly controlled balance between effector and regulatory cell responses. Here, we have investigated the role of OX40 in influencing the balance between conventional T cells and Foxp3+ regulatory T (T reg) cells. Under steady-state conditions, OX40 was required by T reg cells for their accumulation in the colon, but not peripheral lymphoid organs. Strikingly, under inflammatory conditions OX40 played an essential role in T reg cell-mediated suppression of colitis. OX40(-/-) T reg cells showed reduced accumulation in the colon and peripheral lymphoid organs, resulting in their inability to keep pace with the effector response. In the absence of OX40 signaling, T reg cells underwent enhanced activation-induced cell death, indicating that OX40 delivers an important survival signal to T reg cells after activation. As OX40 also promoted the colitogenic Th1 response, its expression on T reg cells may be required for effective competition with OX40-dependent effector responses. These results newly identify a key role for OX40 in the homeostasis of intestinal Foxp3+ T reg cells and in suppression of colitis. These fi ndings should be taken into account when considering OX40 blockade for treatment of IBD.


Association of child care burden and household composition with adherence to highly active antiretroviral therapy in the Women's Interagency HIV Study.
Our objective was to describe the association that childcare burden, household composition, and health care utilization have with adherence to highly active antiretroviral therapy (HAART) among women in the United States. The primary outcome was 95% or more adherence to HAART evaluated at 10,916 semiannual visits between October 1998 and March 2006 among 1419 HIV-infected participants enrolled in the Women's Interagency HIV Study. HAART adherence levels of 95% or more were reported at 76% of the semiannual visits. At only 4% of the person-visits did women report either quite a bit or extreme difficulty in caring for child; at 52% of the person-visits women reported at least one child 18 years of age or older living in the household. We found a one-unit increase in the difficulty in caring for children (childcare burden was assessed on a 5-point scale: not difficult [1] to extremely difficult [5]) was associated with a 6% decreased odds of 95% or more HAART adherence (adjusted odds ratio [OR] = 0.94; p = 0.07). Each additional child 18 years of age or less living in the household was associated with an 8% decreased odds of 95% or more adherence (adjusted OR = 0.92, p = 0.03). Both the number and type of adult living in the household, as well as health care utilization were not associated with HAART adherence. Greater child care burden and number of children 18 years old or younger living in household were both inversely associated with HAART adherence. Assessing patients' difficulties in caring for children and household composition are important factors to consider when addressing adherence to HAART.


Watt-level passively Q-switched double-cladding fiber laser based on graphene oxide saturable absorber.
A watt-level passively Q-switched ytterbium-doped double-cladding fiber laser with a graphene oxide (GO) absorber was demonstrated. The structure of the GO saturable absorber mirror (GO-SAM) was of the sandwich type. A maximum output power of 1.8 W was obtained around a wavelength of 1044 nm. To the best of our knowledge, this is the highest output power in Q-switched fiber lasers based on a GO saturable absorber. The pure GO was protected from the oxygen in the air so that the damage threshold of the GO-SAM was effectively raised. The gain fiber was a D-shaped ytterbium-doped double-cladding fiber. The pulse repetition rates were tuned from 120 to 215 kHz with pump powers from 3.89 to 7.8 W. The maximum pulse energy was 8.37 μJ at a pulse width of 1.7 μs.


Elevated plasma matrix metalloproteinase-9 protein and its gene polymorphism in patients with community-acquired pneumonia.
The purpose here was to detect the association among plasma matrix metalloproteinase-9 (MMP-9) concentration, single nucleotide polymorphisms (SNPs) of MMP-9 gene and community-acquired pneumonia (CAP). The enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were, respectively used to measure the plasma MMP-9 level and its gene polymorphisms. The level of plasma of MMP-9 was elevated in patients with CAP as compared to that of normal controls and decreased significantly after treatment. Plasma MMP-9 concentration was significantly correlated with white blood cell (WBC) and neutrophil counts in patients with CAP. No significant difference was found in the genotypes distribution of MMP-9 SNPs, rs3918242, rs17576 or rs2274756, between patients with CAP and normal controls. Plasma MMP-9 concentration was not associated with MMP-9 polymorphism. When the cut-off level of the plasma MMP-9 concentration was set to be 105.02 ng/mL, the odds ratio of plasma MMP-9 for CAP risk was 9.86 (95% confident interval: 4.27-22.75). Plasma MMP-9 level may act as a prediction marker for CAP. Elevated plasma MMP-9 could be a biological marker for the diagnosis and be a new strategy for target therapy of community-acquired pneumonia.


Ligand-induced conformational changes and a reaction intermediate in branched-chain 2-oxo acid dehydrogenase (E1) from Thermus thermophilus HB8, as revealed by X-ray crystallography.
The alpha(2)beta(2) tetrameric E1 component of the branched-chain 2-oxo acid (BCOA) dehydrogenase multienzyme complex is a thiamin diphosphate (ThDP)-dependent enzyme. E1 catalyzes the decarboxylation of a BCOA concomitant with the formation of the alpha-carbanion/enamine intermediate, 2-(1-hydroxyalkyl)-ThDP, followed by transfer of the 1-hydroxyalkyl group to the distal sulfur atom on the lipoamide of the E2 component. In order to elucidate the catalytic mechanism of E1, the alpha- and beta-subunits of E1 from Thermus thermophilus HB8 have been co-expressed in Escherichia coli, purified and crystallized as a stable complex, and the following crystal structures have been analyzed: the apoenzyme (E1(apo)), the holoenzyme (E1(holo)), E1(holo) in complex with the substrate analogue 4-methylpentanoate (MPA) as an ES complex model, and E1(holo) in complex with 4-methyl-2-oxopentanoate (MOPA) as the alpha-carbanion/enamine intermediate (E1(ceim)). Binding of cofactors to E1(apo) induces a disorder-order transition in two loops adjacent to the active site. Furthermore, upon binding of MPA to E1(holo), the loop comprised of Gly121beta-Gln131beta moves close to the active site and interacts with MPA. The carboxylate group of MPA is recognized mainly by Tyr86beta and N4' of ThDP. The hydrophobic moiety of MPA is recognized by Phe66alpha, Tyr95alpha, Met128alpha and His131alpha. As an intermediate, MOPA is decarboxylated and covalently linked to ThDP, and the conformation of the protein loop is almost the same as in the substrate-free (holoenzyme) form. These results suggest that E1 undergoes an open-closed conformational change upon formation of the ES complex with a BCOA, and the mobile region participates in the recognition of the carboxylate group of the BCOA. ES complex models of E1(holo).MOPA and of E1(ceim).lipoamide built from the above structures suggest that His273alpha and His129beta' are potential proton donors to the carbonyl group of a BCOA and to the proximal sulfur atom on the lipoamide, respectively.


Genetic susceptibility for C19 androgen induction of ovarian granulosa cell tumorigenesis in SWXJ strains of mice.
Susceptibility to pubertal onset, malignant granulosa cell (GC) tumors of the ovary is inherited in SWR/Bm and certain SWR-related SWXJ recombinant inbred strains of mice. In some SWXJ strains, GC tumors occur spontaneously (spontaneous strains), and in others GC tumors can only be induced by treatment with dehydroepiandrosterone (DHEA-dependent strains). A gene controlling susceptibility to both spontaneous and DHEA-induced GC tumorigenesis, Gct, has been assigned to Chromosome 4. Additional research on the role of steroids in GC tumorigenesis has revealed a second gene controlling response to C19 androgenic steroids. Spontaneous strains showed increased tumor frequency after treatment with testosterone (T), whereas DHEA-dependent strains showed no GC tumors following T treatment. Within treatment groups, serum steroid data from DHEA, T, and control treated mice showed no consistent differences between spontaneous and DHEA-dependent strains with respect to progesterone, DHEA, androstenedione, dihydrotestosterone, T, estrone, or estradiol. Thus, observed differences in GC tumor responsiveness to exogenous steroids were not due to different patterns of steroid metabolism among spontaneous and DHEA-dependent strains. Further studies on the range of effective C19 steroids were conducted using one spontaneous and one DHEA-dependent strain. The spontaneous strain showed increased GC tumor frequency in response to dihydrotestosterone and androsterone treatment, whereas the DHEA-dependent strain showed no response. This result suggests that spontaneous strains may be sensitive to a broad range of C19 steroids. To determine whether genetic differences in endogenous steroid levels have a role in spontaneous GC tumorigenesis, serum steroid levels were measured in SWR/Bm and SJL/Bm progenitor strains during the developmental period of risk between 22 and 38 days of age. With the exception of transiently increased DHEA at 22 days, there were no consistent differences in steroid levels analyzed. Thus, serum steroid profiles were not reliably prognostic for GC tumorigenesis. In conclusion, GC tumor induction in response to T treatment has co-segregated with susceptibility to spontaneous GC tumors in the SWXJ recombinant inbred strains. Thus, the second gene in our ovarian granulosa cell tumor model regulates responsiveness to T. We propose to name this gene spontaneous ovarian tumorigenesis (Sot), with alleles for susceptibility (s) carried by spontaneous strains and resistance (r) carried by DHEA-dependent strains.


Effectiveness of mRNA Covid-19 Vaccine among U.S. Health Care Personnel.
The prioritization of U.S. health care personnel for early receipt of messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), allowed for the evaluation of the effectiveness of these new vaccines in a real-world setting. We conducted a test-negative case-control study involving health care personnel across 25 U.S. states. Cases were defined on the basis of a positive polymerase-chain-reaction (PCR) or antigen-based test for SARS-CoV-2 and at least one Covid-19-like symptom. Controls were defined on the basis of a negative PCR test for SARS-CoV-2, regardless of symptoms, and were matched to cases according to the week of the test date and site. Using conditional logistic regression with adjustment for age, race and ethnic group, underlying conditions, and exposures to persons with Covid-19, we estimated vaccine effectiveness for partial vaccination (assessed 14 days after receipt of the first dose through 6 days after receipt of the second dose) and complete vaccination (assessed ≥7 days after receipt of the second dose). The study included 1482 case participants and 3449 control participants. Vaccine effectiveness for partial vaccination was 77.6% (95% confidence interval [CI], 70.9 to 82.7) with the BNT162b2 vaccine (Pfizer-BioNTech) and 88.9% (95% CI, 78.7 to 94.2) with the mRNA-1273 vaccine (Moderna); for complete vaccination, vaccine effectiveness was 88.8% (95% CI, 84.6 to 91.8) and 96.3% (95% CI, 91.3 to 98.4), respectively. Vaccine effectiveness was similar in subgroups defined according to age (<50 years or ≥50 years), race and ethnic group, presence of underlying conditions, and level of patient contact. Estimates of vaccine effectiveness were lower during weeks 9 through 14 than during weeks 3 through 8 after receipt of the second dose, but confidence intervals overlapped widely. The BNT162b2 and mRNA-1273 vaccines were highly effective under real-world conditions in preventing symptomatic Covid-19 in health care personnel, including those at risk for severe Covid-19 and those in racial and ethnic groups that have been disproportionately affected by the pandemic. (Funded by the Centers for Disease Control and Prevention.).


Cognitive behavioural therapy versus supportive therapy for persistent positive symptoms in psychotic disorders: the POSITIVE Study, a multicenter, prospective, single-blind, randomised controlled clinical trial.
It has been demonstrated that cognitive behavioural therapy (CBT) has a moderate effect on symptom reduction and on general well being of patients suffering from psychosis. However, questions regarding the specific efficacy of CBT, the treatment safety, the cost-effectiveness, and the moderators and mediators of treatment effects are still a major issue. The major objective of this trial is to investigate whether CBT is specifically efficacious in reducing positive symptoms when compared with non-specific supportive therapy (ST) which does not implement CBT-techniques but provides comparable therapeutic attention. The POSITIVE study is a multicenter, prospective, single-blind, parallel group, randomised clinical trial, comparing CBT and ST with respect to the efficacy in reducing positive symptoms in psychotic disorders. CBT as well as ST consist of 20 sessions altogether, 165 participants receiving CBT and 165 participants receiving ST. Major methodological aspects of the study are systematic recruitment, explicit inclusion criteria, reliability checks of assessments with control for rater shift, analysis by intention to treat, data management using remote data entry, measures of quality assurance (e.g. on-site monitoring with source data verification, regular query process), advanced statistical analysis, manualized treatment, checks of adherence and competence of therapists. Research relating the psychotherapy process with outcome, neurobiological research addressing basic questions of delusion formation using fMRI and neuropsychological assessment and treatment research investigating adaptations of CBT for adolescents is combined in this network. Problems of transfer into routine clinical care will be identified and addressed by a project focusing on cost efficiency. This clinical trial is part of efforts to intensify psychotherapy research in the field of psychosis in Germany, to contribute to the international discussion on psychotherapy in psychotic disorders, and to help implement psychotherapy in routine care. Furthermore, the study will allow drawing conclusions about the mediators of treatment effects of CBT of psychotic disorders.


Coffee, tea, and caffeine consumption and incidence of colon and rectal cancer.
Frequent coffee consumption has been associated with a reduced risk of colorectal cancer in a number of case-control studies. Cohort studies have not revealed such an association but were limited in size. We explored the association between consumption of coffee and tea and the incidence of colorectal cancer in two large prospective cohorts of women and men. We used data from the Nurses' Health Study (women) and the Health Professionals' Follow-up Study (men). Consumption of coffee and tea and total caffeine intake were assessed and updated in 1980, 1984, 1986, 1990, and 1994 among women and in 1986, 1990, and 1994 among men. The incidence of cancer of the colon or rectum was ascertained through 1998. Hazard ratios were calculated using Cox proportional hazards models that adjusted for potential confounders. All tests of statistical significance were two-sided. During almost 2 million person-years of follow-up, 1438 cases of colorectal cancer were observed. Consumption of caffeinated coffee or tea with caffeine or caffeine intake was not associated with the incidence of colon or rectal cancer in either cohort. For both cohorts combined, the covariate-adjusted hazard ratio for colorectal cancer associated with consumption of each additional cup of caffeinated coffee was 0.99 (95% confidence interval [CI] = 0.96 to 1.03). However, participants who regularly consumed two or more cups of decaffeinated coffee per day had a 52% (95% CI = 19% to 71%) lower incidence of rectal cancer than those who never consumed decaffeinated coffee. Consumption of caffeinated coffee, tea with caffeine, or caffeine was not associated with incidence of colon of rectal cancer, whereas regular consumption of decaffeinated coffee was associated with a reduced incidence of rectal cancer.


International Analysis of LVAD Point-of-Care Versus Plasma INR: A Multicenter Study.
International normalized ratio (INR) measurements manage risks of bleeding and clotting sequelae in the population with left ventricular assist device (LVAD). Studies suggest that point-of-care (POC) INR does not significantly differ from plasma INR (P-INR) values in other patient populations, although this has not been validated in a multicenter LVAD study. We sought to determine whether POC-INR and P-INR values differ significantly in the LVAD population and reviewed patients with permanent LVAD implantation at seven institutions internationally. Our cohort comprised of 279 paired POC-INR and P-INR checks in patients supported on average 630 ± 598 days postimplant with predominately HeartWare, HeartMate II, and HeartMate III devices. The population averaged 57.9 years of age, and there were 86.7% male. We found no statistically significant difference between POC-INR and P-INR values. International normalized ratio accuracy correlated weakly with the time between INR measurements (p < 0.001). When the time difference was less than 4 hours, the difference between INR pairs was significantly lower than measurements greater than 8 hours (p = 0.006). There was no statistically significant difference when comparing paired INR values and time after implant to INR check (p = 0.43), age (p = 0.12), known coagulopathy (p = 0.12), bleeding history (p = 0.22), or thrombosis history (p = 0.34). This is the first large multicenter international study comparing POC-INR and P-INR measurements in patients with LVAD and found no statistically significant difference between either methods, particularly when measured within less than 4 hours of each other.


Carbocation Stability in H-ZSM5 at High Temperature.
Zeolites are common catalysts for multiple industrial applications, including alcohol dehydration to produce olefins, and given their commercial importance, reaction mechanisms in zeolites have long been proposed and studied. Some proposed reaction mechanisms for alcohol dehydration exhibit noncyclic carbocation intermediates or transition states that resemble carbocations, and several previous studies suggest that the tert-butyl cation is the only noncyclic cation more stable than the corresponding chemisorbed species with the hydrocarbon bound to the framework oxygen (i.e., an alkoxide). To determine if carbocations can exist at high temperatures in zeolites, where these catalysts are finding new applications for biomass vapor-phase upgrading (∼500 °C), the stability of carbocations and the corresponding alkoxides were calculated with two ONIOM embedding methods (M06-2X/6-311G(d,p):M06-2X/3-21G) and (PBE-D3/6-311G(d,p):PBE-D3/3-21G) and plane-wave density functional theory (DFT) using the PBE functional corrected with entropic and Tkatchenko-Scheffler van der Waals corrections. The embedding methods tested are unreliable at finding minima for primary carbocations, and only secondary or higher carbocations can be described with embedding methods consistent with the periodic DFT results. The relative energy between the carbocations and alkoxides differs significantly between the embedding and the periodic DFT methods. The difference is between ∼0.23 and 14.30 kcal/mol depending on the molecule, the model, and the functional chosen for the embedding method. At high temperatures, the pw-DFT calculations predict that the allyl, isopropyl, and sec-butyl cations exhibit negligible populations while acetyl and tert-butyl cations exhibit significant populations (>10%). Moreover, the periodic DFT results indicate that mechanisms including secondary and tertiary carbocations intermediates or carbocations stabilized by adjacent oxygen or double bonds are possible at high temperatures relevant to some industrial uses of zeolite catalysts, although as the minority species in most cases.


Effect of transcatheter closure by AmplatzerTM Duct Occluder II in patients with small ventricular septal defect.
Transcatheter closure of ventricular septal defect (VSD) is an alternative treatment of surgery. However, because of the potential risk of the complete atrioventricular block (AVB) and the lack of available dedicated devices for VSD, this procedure rarely used most centers. Recently in Thailand, with distinct device design that may cause less clamp force and radial force, the AmplatzerTMDuct Occluder (ADO) II has become available for the closure of small VSDs. This is a retrospective review of 49 patients who underwent transcatheter VSD closure using ADO II at Songklanagarind hospital and Queen Sirikit National Institute of Child Health between January 2014 and December 2016 with an intention to report procedural success rate and 12-months-outcomes. Twenty-six cases were female. The median age and weight at treatment were 7.8 year (ranged from 1.9 to 25 year) and 25.1 kg (ranged from 11 and 57 kg). The majority (65.3%) of the VSD was a perimembranous defect. The mean diameter of LV entry was 5.2 ± 2.5 mm and the mean RV exit was 3.2 ± 0.8 mm. Four patients had more than 1 exit at RV orifice. The mean length of the VSD was 5.3 ± 1.8 mm. The mean aortic valve-VSD distance was 3.9 ± 2.0 mm. The mean tricuspid valve-VSD distance was 3.8 ± 2.5 mm. The procedural success achieved in all patients (100%), most of the implantations were performed in a retrograde approach (53.1%). The ADO II was successfully implanted in 2 cases (5%) who failed other devices in the first attempts. There were no major complications. There were no changes in the severity of tricuspid and aortic valve regurgitation immediate after implantation and at 12 months' follow-up. Three patients (6%) had tiny to small residual shunt at 12 months' follow-up. None of the patients had a complete heart block. However, new-onset of left bundle branch block and right bundle branch block occurred in 2 (5%) cases and 5 (10%) cases, respectively. With symmetrical double-disc design and softness of the device, the ADO II can be safely and effectively used for closure of the VSDs with the defect size less than 6 mm.


Combining proteomics and transcriptome sequencing to identify active plant-cell-wall-degrading enzymes in a leaf beetle.
The primary plant cell wall is a complex mixture of polysaccharides and proteins encasing living plant cells. Among these polysaccharides, cellulose is the most abundant and useful biopolymer present on earth. These polysaccharides also represent a rich source of energy for organisms which have evolved the ability to degrade them. A growing body of evidence suggests that phytophagous beetles, mainly species from the superfamilies Chrysomeloidea and Curculionoidea, possess endogenous genes encoding complex and diverse families of so-called plant cell wall degrading enzymes (PCWDEs). The presence of these genes in phytophagous beetles may have been a key element in their success as herbivores. Here, we combined a proteomics approach and transcriptome sequencing to identify PCWDEs present in larval gut contents of the mustard leaf beetle, Phaedon cochleariae. Using a two-dimensional proteomics approach, we recovered 11 protein bands, isolated using activity assays targeting cellulose-, pectin- and xylan-degrading enzymes. After mass spectrometry analyses, a total of 13 proteins putatively responsible for degrading plant cell wall polysaccharides were identified; these proteins belong to three glycoside hydrolase (GH) families: GH11 (xylanases), GH28 (polygalacturonases or pectinases), and GH45 (β-1,4-glucanases or cellulases). Additionally, highly stable and proteolysis-resistant host plant-derived proteins from various pathogenesis-related protein (PRs) families as well as polygalacturonase-inhibiting proteins (PGIPs) were also identified from the gut contents proteome. In parallel, transcriptome sequencing revealed the presence of at least 19 putative PCWDE transcripts encoded by the P. cochleariae genome. All of these were specifically expressed in the insect gut rather than the rest of the body, and in adults as well as larvae. The discrepancy observed in the number of putative PCWDEs between transcriptome and proteome analyses could be partially explained by differences in transcriptional level. Combining proteome and transcriptome sequencing analyses proved to be a powerful tool for the discovery of active PCWDEs in a non-model species. Our data represent the starting point of an in-depth functional and evolutionary characterization of PCWDE gene families in phytophagous beetles and their contribution to the adaptation of these highly successful herbivores to their host plants.


Higher-order cycling skills among 11- to 13-year-old cyclists and relationships with cycling experience, risky behavior, crashes and self-assessed skill.
In the Netherlands, young cyclists are extremely vulnerable in traffic, which may partly be due to their still underdeveloped higher-order cycling skill. So far, knowledge on their actual level of skill is lacking. Using a computerized test battery mimicking real-life risky traffic conditions, this study assessed the level of higher-order cycling skill in children 11 and 12 years of age and tested the hypothesis that these skills show caveats. Furthermore, factors potentially influencing the development and impact of these skills were studied, such as cycling experience, risky road behavior, crash involvement, and self-assessed skill. A total of 335 students (49% female) completed computerized tests on hazard perception, gap acceptance, blind spot strategies, and priority decisions in traffic, and completed questionnaires on cycling experience, risky cycling behavior, crashes, and self-assessment of cycling skill. On the hazard perception test, one-third of the participants missed at least half of the number of hazards. They made errors in about 50% of the priority decisions, accepted critical gaps when crossing the road, and conversely rejected safe gaps; only 1% of the participants identified all blind spots of a truck correctly, while 69% made unsafe decisions when interacting with trucks in traffic scenarios. Overall, in complex traffic situations performance was worse than in simple ones. The hypothesis of lack of skills was therefore accepted. However, the study failed to demonstrate consistent relationships between subtest performance and cycling experience, risky behavior, crashes, and self-assessed skill, which weakens the theoretical assumptions concerning the subtests. The results suggest that children at the end of primary school are still lacking elementary skills for safe cycling, calling for measures to accelerate skill development. Test batteries are essential tools for systematically monitoring skill development in cyclists, evaluating education programs, and for guiding the development of effective road safety education. The next step is the validation of such batteries.


A critical review of epidemiological studies in inflammatory bowel disease.
This review addresses the difficulty in interpreting the results of epidemiological studies in IBD and in making meaningful comparisons between studies. Both ulcerative colitis and Crohn disease appear to be more common in some industrialized countries such as Scandinavia, United Kingdom, North America and less common in Central and Southern Europe, Asia and Africa. Given data showing an increased incidence of ulcerative colitis in the United Kingdom, it is crucial that more studies be conducted in developing countries. While the incidence of Crohn disease has increased strikingly in many areas, the incidence of ulcerative colitis has remained fairly stable in most. This could be due to the rising number of community-based studies, as well as the improved accuracy in diagnosing Crohn disease. Although, the incidence of IBD among Blacks in Africa is low, infection rates are high, life expectancy is lower than in developed countries. Data from the USA suggest that rates are similar in Afro-American and Caucasian populations. Rates for Jewish populations may be slightly higher than in non-Jewish populations but this also varies geographically. Careful attention to genetic, environmental, and socioeconomic factors must be accounted for in these studies. There is no strong evidence to support that IBD is more common in urban than in rural settings and migration towards more accessible health care has not been adequately addressed. Recent epidemiological studies suggest that mortality rates for IBD are similar to that of the general population for the majority of patients. However, older patients with IBD and newly diagnosed cases with severe diseases are at increased risk of dying. Epidemiological studies remain important in assisting with health policy planning and in hypothesis testing of etiological factors. As better diagnostic techniques become widely available and public health registries are increasingly used, it is possible that geographic differences will diminish. International collaborative studies will be better equipped to answer research questions addressing risk factors and disease natural history. We have summarized in Table V the essential criteria to conduct a sound epidemiological study, which would permit future testing of hypotheses among different populations.


Bmp4 is essential for the formation of the vestibular apparatus that detects angular head movements.
Angular head movements in vertebrates are detected by the three semicircular canals of the inner ear and their associated sensory tissues, the cristae. Bone morphogenetic protein 4 (Bmp4), a member of the Transforming growth factor family (TGF-beta), is conservatively expressed in the developing cristae in several species, including zebrafish, frog, chicken, and mouse. Using mouse models in which Bmp4 is conditionally deleted within the inner ear, as well as chicken models in which Bmp signaling is knocked down specifically in the cristae, we show that Bmp4 is essential for the formation of all three cristae and their associated canals. Our results indicate that Bmp4 does not mediate the formation of sensory hair and supporting cells within the cristae by directly regulating genes required for prosensory development in the inner ear such as Serrate1 (Jagged1 in mouse), Fgf10, and Sox2. Instead, Bmp4 most likely mediates crista formation by regulating Lmo4 and Msx1 in the sensory region and Gata3, p75Ngfr, and Lmo4 in the non-sensory region of the crista, the septum cruciatum. In the canals, Bmp2 and Dlx5 are regulated by Bmp4, either directly or indirectly. Mechanisms involved in the formation of sensory organs of the vertebrate inner ear are thought to be analogous to those regulating sensory bristle formation in Drosophila. Our results suggest that, in comparison to sensory bristles, crista formation within the inner ear requires an additional step of sensory and non-sensory fate specification.


Gene expression profiles in normal and Otx2-/- early gastrulating mouse embryos.
The mouse Otx2 gene is a homeobox transcription factor required as early as gastrulation for the proper development of the head. We compared gene expression profiles in wild-type and Otx2(-/-) 6.5 days postcoitum embryos by using a serial analysis of gene expression assay adapted to microdissected structures. Among a broader list, the study of six genes found to be differentially expressed allows defining a role for Otx2 in the orchestration of cell movements leading to the adequate organization of the embryo before gastrulation.


Aplastic anemia during pregnancy: a review of obstetric and anesthetic considerations.
Aplastic anemia is a hematologic condition occasionally presenting during pregnancy. This pathological process is associated with significant maternal and neonatal morbidity and mortality. Obstetric and anesthetic management is challenging, and treatment requires a coordinated effort by an interdisciplinary team, in order to provide safe care to these patients. In this review, we describe the current state of the literature as it applies to the complexity of aplastic anemia in pregnancy, focusing on pathophysiologic aspects of the disease in pregnancy, as well as relevant obstetric and anesthetic considerations necessary to treat this challenging problem. A multidisciplinary-team approach to the management of aplastic anemia in pregnancy is necessary to coordinate prenatal care, optimize maternofetal outcomes, and plan peripartum interventions. Conservative transfusion management is critical to prevent alloimmunization. Although a safe threshold-platelet count for neuraxial anesthesia has not been established, selection of anesthetic technique must be evaluated on a case-to-case basis.


Birth order effects on nonverbal IQ scores in autism multiplex families.
Lord (1992) published a brief report showing a trend for decreasing nonverbal IQ scores with increasing birth order in a sample of 16 autism multiplex families, and urged replication in a larger sample. In this report, analyses of nonverbal IQ scores for a sample of 144 autism multiplex families indicated that nonverbal IQ scores were significantly lower in secondborn compared with firstborn siblings with autism. This birth order effect was independent of gender as well as the age differences within sib pairs. No such birth order effects were found for social or communicative deficits as measured by the Autism Diagnostic Interview-Revised (ADI-R), but there was a modest tendency for increased scores for ritualistic behaviors for the firstborn sibs. Further, there were no gender differences on nonverbal IQ scores in this sample. Results are discussed in terms of implications for genetic studies of autism.


Laparoscopic distal pancreatectomy for neuroendocrine tumors of the pancreas.
The incidence of incidentally discovered nonfunctioning pancreatic neuroendocrine tumors (PNETs) is increasing because of the widespread use of radiologic imaging studies. Due to their mostly small size, PNETs in the body and tail of the pancreas are suited for laparoscopic surgery. This video described our technique of laparoscopic distal pancreatectomy with and without preservation of spleen and splenic vessels for PNET. The decision on preservation of spleen and splenic vessels was made according to the relative location of tumors to the splenic vessels.


Laboratory Evaluation of the Properties of Asphalt Mixture with Wood Ash Filler.
Today, the road construction profession is more than ever facing limited and increasingly expensive resources for component materials of asphalt mixtures, which has also led to the need for continuous research on the use of waste materials. One such potentially usable waste material is ash obtained by the combustion of wood biomass that is used to produce heat and electricity. The goal of this paper is to ascertain the possibility of using wood ash (WA) as the filler in asphalt concrete mixtures for the base-wearing layers of a pavement. The properties of Marshall stability (MS), quotient (MQ) and deformations, and the indirect tensile strength of water-conditioned samples and dry samples were tested on asphalt samples of an AC16 surf mixture with different contents of wood ash as the filler. The obtained values of MS and MQ indicate that a 50% content of bio ash in the filler results in an increase in asphalt's resistance to the appearance of plastic deformations and greater tensile strength and in good asphalt resistance to the action of water.


Disfiguring annular sarcoidosis improved by adalimumab.
Depending on the location, dermatoses can produce blemishes that severely impair quality of life and require highly effective treatment that is otherwise used for extensive skin involvement. We report the case of a 39-year-old, otherwise healthy male disfigured by an 8 × 7-cm hypopigmented and centrally atrophic annular plaque with erythematous indurated borders in an area of scar tissue on his forehead. Skin biopsies revealed non-caseating granulomas, and hilar involvement was identified, leading to the diagnosis of systemic sarcoidosis stage II with cutaneous involvement. The lesions proved resistant to multiple therapies, but responded within 4 months to adalimumab with regression of the lesion and inflammatory infiltrate. The visual analogue scale of disease activity decreased from 7/10 to 3.5/10, and the Dermatology Life Quality Index from 16/30 to 3/30 points. In conclusion, TNF-α inhibition can control inflammation and disfigurement by cutaneous sarcoidosis and restore quality of life.


Gene expression of single articular chondrocytes.
Although previous studies in the field of tissue engineering have provided important information about articular cartilage, their conclusions are based on population averages and do not account for variations in cell subpopulations. To obtain a precise understanding of chondrocytes, we investigated the effects of cartilage zone and seeding duration on single chondrocyte gene expression to select an optimal zone for tissue engineering (Phase I), followed by an evaluation of growth factor exposure on the zone selected in Phase I (Phase II). In Phase I, superficial and middle/deep bovine articular chondrocytes were seeded in monolayers for 3 or 18 h. In Phase II, middle/deep chondrocytes (selected in Phase I) received 100 ng/ml insulin-like growth factor-I (IGF-I) for 3 h. Real-time reverse transcription/polymerase chain reaction was used to quantify the abundance of D-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the relative abundances of aggrecan, collagens I and II, cartilage oligomeric matrix protein (COMP), matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1). GAPDH varied zonally, but neither time nor IGF-I had an effect on it, suggesting that GAPDH is a suitable housekeeping gene for comparisons within each zone, but not across zones. IGF-I increased the expression of aggrecan and collagen II in middle/deep chondrocytes seeded for 18 h. TIMP-1 expression increased with time in control cells, suggesting that chondrocytes enter a matrix protective state after seeding. IGF-I diminished this effect, suggesting that treatment with IGF-I refocuses chondrocytes on matrix production rather than on protection from metalloproteinases. Concomitant to increasing TIMP-1, MMP-1 was detectable by 18 h in superficial cells, providing further evidence of a trend toward matrix degradation with time. Collagen I was undetected in all cells, and no differences were observed for COMP, confirming that no dedifferentiation or osteoarthritic changes occurred. Taken together, these results establish a unique understanding of individual chondrocyte behavior.


Three days after a single exposure to ozone, the mechanism of airway hyperreactivity is dependent on substance P and nerve growth factor.
Ozone causes persistent airway hyperreactivity in humans and animals. One day after ozone exposure, airway hyperreactivity is mediated by release of eosinophil major basic protein that inhibits neuronal M(2) muscarinic receptors, resulting in increased acetylcholine release and increased smooth muscle contraction in guinea pigs. Three days after ozone, IL-1β, not eosinophils, mediates ozone-induced airway hyperreactivity, but the mechanism at this time point is largely unknown. IL-1β increases NGF and the tachykinin substance P, both of which are involved in neural plasticity. These experiments were designed to test whether there is a role for NGF and tachykinins in sustained airway hyperreactivity following a single ozone exposure. Guinea pigs were exposed to filtered air or ozone (2 parts per million, 4 h). In anesthetized and vagotomized animals, ozone potentiated vagally mediated airway hyperreactivity 24 h later, an effect that was sustained over 3 days. Pretreatment with antibody to NGF completely prevented ozone-induced airway hyperreactivity 3 days, but not 1 day, after ozone and significantly reduced the number of substance P-positive airway nerve bundles. Three days after ozone, NK(1) and NK(2) receptor antagonists also blocked this sustained hyperreactivity. Although the effect of inhibiting NK(2) receptors was independent of ozone, the NK(1) receptor antagonist selectively blocked vagal hyperreactivity 3 days after ozone. These data confirm mechanisms of ozone-induced airway hyperreactivity change over time and demonstrate 3 days after ozone that there is an NGF-mediated role for substance P, or another NK(1) receptor agonist, that enhances acetylcholine release and was not present 1 day after ozone.


A one-year survey on the use of a powder from Rosa canina lito in acute exacerbations of chronic pain.
This pilot surveillance included 152 patients with acute exacerbations of chronic pain, 124 (Back group) with non-specific low back pain (NSLBP), 20 with NSLBP overridden by osteoarthritic pain (Knee-Hip group), and eight with specific LBP (included in the safety analysis). Patients were recommended the rose hip and seed powder Litozin at a dose providing up to 3 mg of galactolipid/day for up to 54 weeks. Clinical symptoms and well-being were assessed every 6 weeks. The patients also kept a diary of their pain and the requirement for rescue medication. Data were analysed by intention to treat with last observation carried forward. Only 77 patients completed the year of surveillance. Multivariate analysis suggested an appreciable overall improvement during the surveillance, irrespective of group, and this was reflected for most of the individual measures in repeated measures ANOVA. The degree and time-course of improvement echoed that seen in similar surveillances of patients receiving an aqueous extract of Harpagophytum. Multiple regression analyses indicated that percentage changes from baseline tended to be greater in patients with greater degrees of pain and disability, but were otherwise largely unrelated to the patients' characteristics. There were no serious adverse events. The rose hip and seed powder, Litozin, seems to deserve further, more definitive studies as a possible option in long-term management of NSLBP with or without osteoarthritic pain.


Structure of human phytanoyl-CoA 2-hydroxylase identifies molecular mechanisms of Refsum disease.
Refsum disease (RD), a neurological syndrome characterized by adult onset retinitis pigmentosa, anosmia, sensory neuropathy, and phytanic acidaemia, is caused by elevated levels of phytanic acid. Many cases of RD are associated with mutations in phytanoyl-CoA 2-hydroxylase (PAHX), an Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase that catalyzes the initial alpha-oxidation step in the degradation of phytenic acid in peroxisomes. We describe the x-ray crystallographic structure of PAHX to 2.5 A resolution complexed with Fe(II) and 2OG and predict the molecular consequences of mutations causing RD. Like other 2OG oxygenases, PAHX possesses a double-stranded beta-helix core, which supports three iron binding ligands (His(175), Asp(177), and His(264)); the 2-oxoacid group of 2OG binds to the Fe(II) in a bidentate manner. The manner in which PAHX binds to Fe(II) and 2OG together with the presence of a cysteine residue (Cys(191)) 6.7 A from the Fe(II) and two further histidine residues (His(155) and His(281)) at its active site distinguishes it from that of the other human 2OG oxygenase for which structures are available, factor inhibiting hypoxia-inducible factor. Of the 15 PAHX residues observed to be mutated in RD patients, 11 cluster in two distinct groups around the Fe(II) (Pro(173), His(175), Gln(176), Asp(177), and His(220)) and 2OG binding sites (Trp(193), Glu(197), Ile(199), Gly(204), Asn(269), and Arg(275)). PAHX may be the first of a new subfamily of coenzyme A-binding 2OG oxygenases.


Relation of beta2-adrenoceptor polymorphisms at codons 16 and 27 to persistence of asthma symptoms after the onset of puberty.
It has long been recognized that many children with asthma outgrow the disease after the onset of puberty, but little is known about genetic factors influencing this outcome. The aim of the present study was to determine whether the polymorphisms at codons 16 and 27 of the beta2-adrenoceptor are significant predictors of the persistence of asthma during adolescence. We used data from the prospective Tucson Children's Respiratory Study. Children were genotyped for the polymorphisms at codons 16 and 27. The presence of wheezing/asthma was assessed by questionnaire from age 6 years up to the reported onset of puberty (prepubertal period) and after the onset of puberty up to age 16 years (adolescence). Among children who wheezed in the prepubertal period (n = 168), subjects homozygous for Gly at codon 16 were at significantly increased risk for persistent wheezing after puberty, as compared with carriers of the other genotypes (relative risk [RR], 1.43; 95% confidence interval [CI], 1.06 to 1.92; p = 0.019). This relation was present among boys (RR, 2.17; 95% CI, 1.41 to 3.36) but not girls (RR, 0.85; 95% CI, 0.55 to 1.30), and increased linearly according to the frequency of wheezing episodes after the onset of puberty. These findings persisted after adjusting for ethnicity and other potential confounders and after selecting only white children. The polymorphism at codon 27 showed no relation with risk for persistent wheezing. This study provides evidence for a strong gender-specific effect of the Gly16 polymorphism on the persistence of asthma after the onset of puberty.


Contrast-based fully automatic segmentation of white matter hyperintensities: method and validation.
White matter hyperintensities (WMH) on T2 or FLAIR sequences have been commonly observed on MR images of elderly people. They have been associated with various disorders and have been shown to be a strong risk factor for stroke and dementia. WMH studies usually required visual evaluation of WMH load or time-consuming manual delineation. This paper introduced WHASA (White matter Hyperintensities Automated Segmentation Algorithm), a new method for automatically segmenting WMH from FLAIR and T1 images in multicentre studies. Contrary to previous approaches that were based on intensities, this method relied on contrast: non linear diffusion filtering alternated with watershed segmentation to obtain piecewise constant images with increased contrast between WMH and surroundings tissues. WMH were then selected based on subject dependant automatically computed threshold and anatomical information. WHASA was evaluated on 67 patients from two studies, acquired on six different MRI scanners and displaying a wide range of lesion load. Accuracy of the segmentation was assessed through volume and spatial agreement measures with respect to manual segmentation; an intraclass correlation coefficient (ICC) of 0.96 and a mean similarity index (SI) of 0.72 were obtained. WHASA was compared to four other approaches: Freesurfer and a thresholding approach as unsupervised methods; k-nearest neighbours (kNN) and support vector machines (SVM) as supervised ones. For these latter, influence of the training set was also investigated. WHASA clearly outperformed both unsupervised methods, while performing at least as good as supervised approaches (ICC range: 0.87-0.91 for kNN; 0.89-0.94 for SVM. Mean SI: 0.63-0.71 for kNN, 0.67-0.72 for SVM), and did not need any training set.


The Patient-Reported Outcomes Measurement Information System (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005-2008.
Patient-reported outcomes (PROs) are essential when evaluating many new treatments in health care; yet, current measures have been limited by a lack of precision, standardization, and comparability of scores across studies and diseases. The Patient-Reported Outcomes Measurement Information System (PROMIS) provides item banks that offer the potential for efficient (minimizes item number without compromising reliability), flexible (enables optional use of interchangeable items), and precise (has minimal error in estimate) measurement of commonly studied PROs. We report results from the first large-scale testing of PROMIS items. Fourteen item pools were tested in the U.S. general population and clinical groups using an online panel and clinic recruitment. A scale-setting subsample was created reflecting demographics proportional to the 2000 U.S. census. Using item-response theory (graded response model), 11 item banks were calibrated on a sample of 21,133, measuring components of self-reported physical, mental, and social health, along with a 10-item Global Health Scale. Short forms from each bank were developed and compared with the overall bank and with other well-validated and widely accepted ("legacy") measures. All item banks demonstrated good reliability across most of the score distributions. Construct validity was supported by moderate to strong correlations with legacy measures. PROMIS item banks and their short forms provide evidence that they are reliable and precise measures of generic symptoms and functional reports comparable to legacy instruments. Further testing will continue to validate and test PROMIS items and banks in diverse clinical populations.


Cyclophilin A is required for the replication of group M human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus SIV(CPZ)GAB but not group O HIV-1 or other primate immunodeficiency viruses.
The human immunodeficiency virus type 1 (HIV-1) Gag polyprotein binds to cyclophilin A and incorporates this cellular peptidyl prolyl-isomerase into virions. Disruption of cyclophilin A incorporation, either by gag mutations or by cyclosporine A, inhibits virion infectivity, indicating that cyclophilin A plays an essential role in the HIV-1 life cycle. Using assays for packaging of cyclophilin A into virions and for viral replication sensitivity to cyclosporine A, as well as information gleaned from the alignment of Gag residues encoded by representative viral isolates, we demonstrate that of the five lineages of primate immunodeficiency viruses, only HIV-1 requires cyclophilin A for replication. Cloned viral isolates from clades A, B, and D of HIV-1 group M, as well as a phylogenetically related isolate from chimpanzee, all require cyclophilin A for replication. In contrast, the replication of two outlier (group O) HIV-1 isolates is unaffected by concentrations of cyclosporine A which disrupt cyclophilin A incorporation into virions, indicating that these viruses are capable of replicating independently of cyclophilin A. These studies identify the first phenotypic difference between HIV-1 group M and group O and are consistent with phylogenetic studies suggesting that the two HIV-1 groups were introduced into human populations via separate zoonotic transmission events.


Ways of understanding the encounter with head and neck cancer patients in the hospital dental team--a phenomenographic study.
Head and neck cancer is the sixth most common malignancy in the world. Fifty percent of the patients can be cured by surgery, radiotherapy or a combination approach. Head and neck cancer is life-threatening, and treatment may leave the patient with visible facial disfigurements and impairment of functions such as speech and eating. This affects not only the patient, but may arouse difficult feelings in the treatment staff. Dental personnel are involved in all facets of treatment, yet they have no specific training in cancer care. The aim of this study was to describe the variation in ways dental personnel understand and experience the encounter with head and neck cancer patients, as the way of understanding a certain phenomenon is judged to be fundamental to the way we act and form our beliefs. Twenty members of hospital dental teams were interviewed. The interviews focused on experiences of the encounter with head and neck cancer patients. A qualitative research approach, phenomenography, was used in analysing the interviews. The encounter was perceived in three qualitatively different ways: as an act of caring, as a serious and responsible task and as an overwhelming emotional situation. The results indicate that hospital dental personnel are not able to lean on education and professional training in finding ways of dealing with situations with strong emotional impact. This has implications for the treatment of patients with head and neck cancer, as well as education of dental personnel.