Women's Pathways to Abortion Care in South Carolina: A Qualitative Study of Obstacles and Supports.
Women seeking timely and affordable abortion care may face myriad challenges, including high out-of-pocket costs, transportation demands, scheduling difficulties and stigma. State-level regulations may exacerbate these burdens and impede women's access to a full range of care. Women's reports of their experiences can inform efforts to improve pathways to abortion care. In 2014, semistructured qualitative interviews were conducted with 45 women obtaining abortions in South Carolina, which has a restrictive abortion environment. Interviews elicited information about women's pathways to abortion, including how they learned about and obtained care, whether they received professional referrals, and the supports and obstacles they experienced. Transcripts were examined using thematic analysis to identify key themes along the pathways, and a process map was constructed to depict women's experiences. Twenty participants reported having had contact with a health professional or crisis pregnancy center staff for pregnancy confirmation, and seven of them received an abortion referral. Women located abortion clinics through online searches, previous experience, and friends or family. Financial strain was the most frequently cited obstacle, followed by transportation challenges. Women reported experiencing emotional strain, stress and stigma, and described the value of receiving social support. Because of financial pressures, the regulation with the greatest impact was the one prohibiting most insurance plans from covering abortion care. Further research on experiences of women seeking abortion services, and how these individuals are affected by evolving state policy environments, will help shape initiatives to support timely, affordable and safe abortion care in a climate of increasing restrictions.


The reliability and clinical utility of ICD-11 schizoaffective disorder: A field trial.
A major goal for the revision of the International Classification of Diseases and Related Health Problems, Tenth Edition (ICD-10) is to increase the clinical utility of the diagnostic system. Schizoaffective disorder has a history of poor diagnostic reliability due to the similarities and overlap in symptoms that it shares with other disorders, especially primary psychotic and mood disorders. The present study was part of the case-controlled field trials for ICD-11 and examines how the proposed changes for schizoaffective disorder may improve differential diagnosis and diagnostic accuracy. Clinicians from around the globe (n = 873) were provided with either ICD-10 or ICD-11 diagnostic guidelines and asked to apply them to case vignettes comparing schizoaffective disorder to schizophrenia and mood disorders with psychotic symptoms. Participants were asked to respond to follow-up diagnostic questions to determine which components of the diagnostic guidelines affected diagnostic accuracy. Overall, clinicians showed small improvements in accurately diagnosing vignettes using ICD-11 over ICD-10. Results suggest the discrepancy in diagnosing schizoaffective disorder is related primarily to the presence of mood symptoms and discrepancies about whether those symptoms are more consistent with schizoaffective disorder or a mood disorder diagnosis. Continuing to identify ways to more accurately capture this symptom picture will be important in the future as well as systematic efforts to educate clinicians about differential diagnosis.


Modification of type IV pilus-associated epithelial cell adherence and multicellular behavior by the PilU protein of Neisseria gonorrhoeae.
Expression of type IV pili (Tfp) correlates with the ability of Neisseria gonorrhoeae to colonize the human host, as well as with adherence to human epithelial tissue, twitching motility, competence for natural transformation, and autoagglutination. N. gonorrhoeae PilF (required for Tfp biogenesis) and PilT (required for twitching motility and transformation) share significant identities with members of a family of putative ATPases involved in membrane trafficking of macromolecules. An open reading frame downstream of the pilT locus encoding a 408-amino-acid protein with 33% identity with the gonococcal PilT protein and 45% identity with the PilU protein in Pseudomonas aeruginosa was characterized, and the corresponding gene was designated pilU. Unlike N. gonorrhoeae pilT mutants, pilU mutants express twitching motility and are competent for DNA transformation. However, loss-of-function mutations in pilU increased bacterial adherence to ME-180 human epithelial cells eightfold and disrupted in vitro Tfp-associated autoagglutination. Comparative alignment of N. gonorrhoeae PilU with other members of the TrbB-like family of traffic ATPases revealed a conserved carboxy-terminal domain unique to family members which are not essential for Tfp biogenesis but which specifically modify Tfp-associated phenotypes. Studies of the pilT-pilU locus by using Northern blotting, transcriptional fusions, and reverse transcription-PCR showed that the two genes encoding closely related proteins with dissimilar effects on Tfp phenotypes are transcribed from a single promoter.


When Genome-Based Approach Meets the "Old but Good": Revealing Genes Involved in the Antibacterial Activity of Pseudomonas sp. P482 against Soft Rot Pathogens.
Dickeya solani and Pectobacterium carotovorum subsp. brasiliense are recently established species of bacterial plant pathogens causing black leg and soft rot of many vegetables and ornamental plants. Pseudomonas sp. strain P482 inhibits the growth of these pathogens, a desired trait considering the limited measures to combat these diseases. In this study, we determined the genetic background of the antibacterial activity of P482, and established the phylogenetic position of this strain. Pseudomonas sp. P482 was classified as Pseudomonas donghuensis. Genome mining revealed that the P482 genome does not contain genes determining the synthesis of known antimicrobials. However, the ClusterFinder algorithm, designed to detect atypical or novel classes of secondary metabolite gene clusters, predicted 18 such clusters in the genome. Screening of a Tn5 mutant library yielded an antimicrobial negative transposon mutant. The transposon insertion was located in a gene encoding an HpcH/HpaI aldolase/citrate lyase family protein. This gene is located in a hypothetical cluster predicted by the ClusterFinder, together with the downstream homologs of four nfs genes, that confer production of a non-fluorescent siderophore by P. donghuensis HYS(T). Site-directed inactivation of the HpcH/HpaI aldolase gene, the adjacent short chain dehydrogenase gene, as well as a homolog of an essential nfs cluster gene, all abolished the antimicrobial activity of the P482, suggesting their involvement in a common biosynthesis pathway. However, none of the mutants showed a decreased siderophore yield, neither was the antimicrobial activity of the wild type P482 compromised by high iron bioavailability. A genomic region comprising the nfs cluster and three upstream genes is involved in the antibacterial activity of P. donghuensis P482 against D. solani and P. carotovorum subsp. brasiliense. The genes studied are unique to the two known P. donghuensis strains. This study illustrates that mining of microbial genomes is a powerful approach for predictingthe presence of novel secondary-metabolite encoding genes especially when coupled with transposon mutagenesis.


Reviewing an Original Research Manuscript for the International Journal of Exercise Science: A Guide for Students and Professionals.
Considerations for the review process of manuscripts submitted to the International Journal of Exercise Science are presented. Initial steps to evaluation include reading the abstract to determine your ability as a reviewer, becoming familiar with the journal requirements, and formulating an initial impression of the manuscript. At this point an assessment is made to determine how the reviewer should treat the manuscript. If it is determined that the manuscript is acceptable with minor revisions, or may be acceptable with major changes, a full review should be performed. A full review of the manuscript requires a thorough examination of the major headings including the Introduction, Methods, Results, and Discussion. The written review is composed of two parts, a section with the decision that is composed of comments only for the editor, and a section that provides feedback to the authors. Specific comments to the authors should include an honest critique that aids in improving the manuscript.


Endovascular treatment of Angio-Seal-related limb ischemia--primary results and long-term follow-up.
To investigate primary success rates and long term follow-up of endovascular treatment of AngioSeal-related limb ischemia. Current knowledge on optimal therapy of ischemic complications following application of AngioSeal is limited. A single-center prospectively maintained database was retrospectively interrogated and AngioSeal-related complications requiring endovascular treatment over an 8-year-time period was identified. Fifteen patients fulfilling the inclusion criteria were identified, resulting in an approximated incidence of 0.26% of all devices implanted at our institution. In all cases, the complication was managed successfully in the absence of complications. Eleven patients were treated with balloon angioplasty (PTA) and four with stent implantation because of suboptimal PTA results. Twelve patients were available for noninvasive vascular follow-up examination for a median time of 40 months postinterventionally. Only two patients needed a second intervention consisting of balloon angioplasty due to symptomatic restenosis. At final follow-up all patients were asymptomatic with no relevant restenosis. Endovascular treatment for AngioSeal-related limb ischemia with or without stent implantation results in an excellent immediate and long-term clinical and hemodynamic outcome.


Identifying wildlife reservoirs of neglected taeniid tapeworms: Non-invasive diagnosis of endemic Taenia serialis infection in a wild primate population.
Despite the global distribution and public health consequences of Taenia tapeworms, the life cycles of taeniids infecting wildlife hosts remain largely undescribed. The larval stage of Taenia serialis commonly parasitizes rodents and lagomorphs, but has been reported in a wide range of hosts that includes geladas (Theropithecus gelada), primates endemic to Ethiopia. Geladas exhibit protuberant larval cysts indicative of advanced T. serialis infection that are associated with high mortality. However, non-protuberant larvae can develop in deep tissue or the abdominal cavity, leading to underestimates of prevalence based solely on observable cysts. We adapted a non-invasive monoclonal antibody-based enzyme-linked immunosorbent assay (ELISA) to detect circulating Taenia spp. antigen in dried gelada urine. Analysis revealed that this assay was highly accurate in detecting Taenia antigen, with 98.4% specificity, 98.5% sensitivity, and an area under the curve of 0.99. We used this assay to investigate the prevalence of T. serialis infection in a wild gelada population, finding that infection is substantially more widespread than the occurrence of visible T. serialis cysts (16.4% tested positive at least once, while only 6% of the same population exhibited cysts). We examined whether age or sex predicted T. serialis infection as indicated by external cysts and antigen presence. Contrary to the female-bias observed in many Taenia-host systems, we found no significant sex bias in either cyst presence or antigen presence. Age, on the other hand, predicted cyst presence (older individuals were more likely to show cysts) but not antigen presence. We interpret this finding to indicate that T. serialis may infect individuals early in life but only result in visible disease later in life. This is the first application of an antigen ELISA to the study of larval Taenia infection in wildlife, opening the doors to the identification and description of infection dynamics in reservoir populations.


A therapeutic trial of amniotic epithelial cell implantation in patients with lysosomal storage diseases.
To determine whether allografts of normal amniotic epithelium might provide a nonimmunogenic cellular source of exogenous lysosomal enzymes, subcutaneous implants of amniotic epithelium were performed in six children with clinically advanced storage diseases. The clinical and the biochemical status of each patient was observed for several weeks after amniotic epithelial cell implantation (AECI). Serial studies of blood samples from each patient in the post-AECI period did not demonstrate any increase in levels of deficient lysosomal hydrolase. In two patients, quantitative urinary excretion of substrate was also studied and did not show consistent alterations after AECI. No patient had objective improvement in clinical or neurodevelopmental status following AECI. Two patients died with progressive disease at 2 1/2 and 3 1/2 mo after AECI; no residual amniotic epithelium was found at postmortem examination. Four patients are alive with progressive disease at 6-14 mo after AECI. We conclude that allografts of normal human amnion do not provide sufficient replacement hydrolases for clinical or biochemical improvement in lysosomal storage diseases.


Traumatic experiences and post-traumatic stress disorder among elderly Germans: results of a representative population-based survey.
Only a few population-based studies on the epidemiology of post-traumatic stress disorders (PTSDs) are available to date. Most of the existing studies are from the U.S.A. Against the background of World War II, the extent and long-term effects of war-related traumatic experiences in the German elderly population are of special interest. Nevertheless, population-based data on this topic are lacking to date. This study examines the occurrence of traumatic experiences and the prevalence rates of PTSD according to DSM-IV and of partial PTSD in a randomly selected sample of the German general population aged 60 years and over (N = 814) using self-rating instruments. PTSD is apparent in 3.4%; when partial post-traumatic stress syndromes are included, a total of 7.2% of the aged population are involved. The most common individual symptoms resulting from war-induced trauma are avoidance of thoughts and feelings, sleep disturbances, distressing dreams and intrusive thoughts. The most frequently mentioned traumatic experiences of the generation examined in this study were war-related trauma experienced as children or in early adulthood during World War II. As a person's age increases, so does the prevalence of war-related traumatic experiences. There are some gender differences in traumatic experiences, but not in post-traumatic symptoms. The results emphasize the importance of war-related traumatic experiences from World War II in the German elderly population and their impact on the prevalence of PTSD more than 60 years later.


Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy.
The genomic revolution has identified therapeutic targets for a plethora of diseases, creating a need to develop robust technologies for combination drug therapy. In the present work, we describe a self-assembled polymeric nanoparticle (NP) platform to target and control precisely the codelivery of drugs with varying physicochemical properties to cancer cells. As proof of concept, we codelivered cisplatin and docetaxel (Dtxl) to prostate cancer cells with synergistic cytotoxicity. A polylactide (PLA) derivative with pendant hydroxyl groups was prepared and conjugated to a platinum(IV) [Pt(IV)] prodrug, c,t,c-[Pt(NH(3))(2)(O(2)CCH(2)CH(2)COOH)(OH)Cl(2)] [PLA-Pt(IV)]. A blend of PLA-Pt(IV) functionalized polymer and carboxyl-terminated poly(D,L-lactic-co-glycolic acid)-block-poly(ethylene glycol) copolymer in the presence or absence of Dtxl, was converted, in microfluidic channels, to NPs with a diameter of ∼100 nm. This process resulted in excellent encapsulation efficiency (EE) and high loading of both hydrophilic platinum prodrug and hydrophobic Dtxl with reproducible EEs and loadings. The surface of the NPs was derivatized with the A10 aptamer, which binds to the prostate-specific membrane antigen (PSMA) on prostate cancer cells. These NPs undergo controlled release of both drugs over a period of 48-72 h. Targeted NPs were internalized by the PSMA-expressing LNCaP cells via endocytosis, and formation of cisplatin 1,2-d(GpG) intrastrand cross-links on nuclear DNA was verified. In vitro toxicities demonstrated superiority of the targeted dual-drug combination NPs over NPs with single drug or nontargeted NPs. This work reveals the potential of a single, programmable nanoparticle to blend and deliver a combination of drugs for cancer treatment.


B cells are associated with survival and immunotherapy response in sarcoma.
Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes1,2. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely3,4. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8+ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.


Vision from the right stem.
Cultures of limbal cells are a safe and effective treatment for the destruction of the human cornea owing to chemical burns. The essential feature of the graft is the presence of an adequate number of stem cells, which can be determined by the expression of the p63 transcription factor. Here, we will discuss the general principles defining the rigorous criteria for graftable limbal cultures in light of their clinical performances. Such criteria might prove relevant to the future therapeutic use of any cultured cell type.


Dietary advice for reducing cardiovascular risk.
Changes in population diet are likely to reduce cardiovascular disease and cancer, but the effect of dietary advice is uncertain. This review is an update of a previous review published in 2007. To assess the effects of providing dietary advice to achieve sustained dietary changes or improved cardiovascular risk profile among healthy adults. We searched the Cochrane Central Register of Controlled Trials, the Database of Abstracts of Reviews of Effects (DARE) and the HTA database on The Cochrane Library (Issue 4, 2010). We searched MEDLINE (Ovid) (1950 to week 2 October 2010) and EMBASE (Ovid) (1980 to Week 42 2010). Additional searches were done on CAB Health (1972 to December 1999), CVRCT registry (2000), CCT (2000) and SIGLE (1980 to 2000). Dissertation abstracts and reference lists of articles were checked and researchers were contacted. Randomised studies with no more than 20% loss to follow-up, lasting at least three months and involving healthy adults comparing dietary advice with no advice or minimal advice. Trials involving children, trials to reduce weight or those involving supplementation were excluded. Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. Forty-four trials with 52 intervention arms (comparisons) comparing dietary advice with no advice were included in the review; 18,175 participants or clusters were randomised. Twenty-nine of the 44 included trials were conducted in the USA. Dietary advice reduced total serum cholesterol by 0.15 mmol/L (95% CI 0.06 to 0.23) and LDL cholesterol by 0.16 mmol/L (95% CI 0.08 to 0.24) after 3 to 24 months. Mean HDL cholesterol levels and triglyceride levels were unchanged. Dietary advice reduced blood pressure by 2.61 mm Hg systolic (95% CI 1.31 to 3.91) and 1.45 mm Hg diastolic (95% CI 0.68 to 2.22) and 24-hour urinary sodium excretion by 40.9 mmol (95% CI 25.3 to 56.5) after 3 to 36 months but there was heterogeneity between trials for the latter outcome. Three trials reported plasma antioxidants, where small increases were seen in lutein and β-cryptoxanthin, but there was heterogeneity in the trial effects. Self-reported dietary intake may be subject to reporting bias, and there was significant heterogeneity in all the following analyses. Compared to no advice, dietary advice increased fruit and vegetable intake by 1.18 servings/day (95% CI 0.65 to 1.71). Dietary fibre intake increased with advice by 6.5 g/day (95% CI 2.2 to 10.82), while total dietary fat as a percentage of total energy intake fell by 4.48% (95% CI 2.47 to 6.48) with dietary advice, and saturated fat intake fell by 2.39% (95% CI 1.4 to 3.37).Two trials analysed incident cardiovascular disease (CVD) events (TOHP I/II). Follow-up was 77% complete at 10 to 15 years after the end of the intervention period and estimates of event rates lacked precision but suggested that sodium restriction advice probably led to a reduction in cardiovascular events (combined fatal plus non-fatal events) plus revascularisation (TOHP I hazards ratio (HR) 0.59, 95% CI 0.33 to 1.08; TOHP II HR 0.81, 95% CI 0.59 to 1.12). Dietary advice appears to be effective in bringing about modest beneficial changes in diet and cardiovascular risk factors over approximately 12 months, but longer-term effects are not known.


OSO-5 Dim Light Monitor.
The design, calibration, and operation of the University of Minnesota's experiment on board the satellite OS0-5 are described. The instrument was designed to measure zodiacal light, airglow, and lightning. The orientation and stability of the spacecraft is also discussed as it pertains to the experiment.


Solution structure of toxin 2 from centruroides noxius Hoffmann, a beta-scorpion neurotoxin acting on sodium channels.
We have determined the solution structure of Cn2, a beta-toxin extracted from the venom of the New World scorpion Centruroides noxius Hoffmann. Cn2 belongs to the family of scorpion toxins that affect the sodium channel activity, and is very toxic to mammals (LD50=0.4 microg/20 g mouse mass). The three-dimensional structure was determined using 1H-1H two-dimensional NMR spectroscopy, torsion angle dynamics, and restrained energy minimization. The final set of 15 structures was calculated from 876 experimental distance constraints and 58 angle constraints. The structures have a global r. m.s.d. of 1.38 A for backbone atoms and 2.21 A for all heavy atoms. The overall fold is similar to that found in the other scorpion toxins acting on sodium channels. It is made of a triple-stranded antiparallel beta-sheet and an alpha-helix, and is stabilized by four disulfide bridges. A cis-proline residue at position 59 induces a kink of the polypeptide chain in the C-terminal region. The hydrophobic core of the protein is made up of residues L5, V6, L51, A55, and by the eight cysteine residues. A hydrophobic patch is defined by the aromatic residues Y4, Y40, Y42, W47 and by V57 on the side of the beta-sheet facing the solvent. A positively charged patch is formed by K8 and K63 on one edge of the molecule in the C-terminal region. Another positively charged spot is represented by the highly exposed K35. The structure of Cn2 is compared with those of other scorpion toxins acting on sodium channels, in particular Aah II and CsE-v3. This is the first structural report of an anti-mammal beta-scorpion toxin and it provides the necessary information for the design of recombinant mutants that can be used to probe structure-function relationships in scorpion toxins affecting sodium channel activity.


Turning Regenerative Medicine Breakthrough Ideas and Innovations into Commercial Products.
The TERMIS-Europe (EU) Industry committee intended to address the two main critical issues in the clinical/commercial translation of Advanced Therapeutic Medicine Products (ATMP): (1) entrepreneurial exploitation of breakthrough ideas and innovations, and (2) regulatory market approval. Since January 2012, more than 12,000 publications related to regenerative medicine and tissue engineering have been accepted for publications, reflecting the intense academic research activity in this field. The TERMIS-EU 2014 Industry Symposium provided a reflection on the management of innovation and technological breakthroughs in biotechnology first proposed to contextualize the key development milestones and constraints of allocation of financial resources, in the development life-cycle of radical innovation projects. This was illustrated with the biofuels story, sharing similarities with regenerative medicine. The transition was then ensured by an overview of the key identified challenges facing the commercialization of cell therapy products as ATMP examples. Real cases and testimonies were then provided by a palette of medical technologies and regenerative medicine companies from their commercial development of cell and gene therapy products. Although the commercial development of ATMP is still at the proof-of-concept stage due to technology risks, changing policies, changing markets, and management changes, the sector is highly dynamic with a number of explored therapeutic approaches, developed by using a large diversity of business models, both proposed by the experience, pitfalls, and successes of regenerative medicine pioneers, and adapted to the constraint resource allocation and environment in radical innovation projects.


Heritable Phytohormone Profiles of Poplar Genotypes Vary in Resistance to a Galling Aphid.
Insect galls are highly specialized structures arising from atypical development of plant tissue induced by insects. Galls provide the insect enhanced nutrition and protection against natural enemies and environmental stresses. Galls are essentially plant organs formed by an intimate biochemical interaction between the gall-inducing insect and its host plant. Because galls are plant organs, their development is likely to be governed by phytohormones involved in normal organogenesis. We characterized concentrations of both growth and defensive phytohormones in ungalled control leaves and galls induced by the aphid Pemphigus betae on narrowleaf cottonwood Populus angustifolia that differ genotypically in resistance to this insect. We found that susceptible trees differed from resistant trees in constitutive concentrations of both growth and defense phytohormones. Susceptible trees were characterized by significantly higher constitutive cytokinin concentrations in leaves, significantly greater ability of aphids to elicit cytokinin increases, and significantly lower constitutive defense phytohormone concentrations than observed in resistant trees. Phytohormone concentrations in both constitutive and induced responses in galled leaves exhibited high broad-sense heritability that, respectively, ranged from 0.39 to 0.93 and from 0.28 to 0.66, suggesting that selection can act upon these traits and that they might vary across the landscape. Increased cytokinin concentrations may facilitate forming strong photosynthate sinks in the galls, a requirement for galling insect success. By characterizing for the first time the changes in 15 phytohormones belonging to five different classes, this study offers a better overview of the signaling alteration occurring in galls that has likely been important for their ecology and evolution. Copyright © 2019 The Author(s). This is an open-access article distributed under the CC BY-NC-ND 4.0 International license .


Predation, individual variability and vertebrate population dynamics.
Both predation and individual variation in life history traits influence population dynamics. Recent results from laboratory predator-prey systems suggest that differences between individuals can also influence predator-prey dynamics when different genotypes experience different predation-associated mortalities. Despite the growing number of studies in this field, there is no synthesis identifying the overall importance of the interactions between predation and individual heterogeneity and their role in shaping the dynamics of free-ranging populations of vertebrates. We aim to fill this gap with a review that examines how individual variability in prey susceptibility, in predation costs, in predator selectivity, and in predatory performance, might influence prey population dynamics. Based on this review, it is clear that (1) predation risk and costs experienced by free-ranging prey are associated with their phenotypic attributes, (2) many generalist predator populations consist of individual specialists with part of the specialization associated with their phenotypes, and (3) a complete understanding of the population dynamic consequences of predation may require information on individual variability in prey selection and prey vulnerability. Altogether, this work (1) highlights the importance of maintaining long-term, detailed studies of individuals of both predators and prey in contrasting ecological conditions, and (2) advocates for a better use of available information to account for interactive effects between predators and their prey when modelling prey population dynamics.


Transcription factor IRF8 directs a silencing programme for TH17 cell differentiation.
T(H)17 cells are recognized as a unique subset of T helper cells that have critical roles in the pathogenesis of autoimmunity and tissue inflammation. Although RORγt is necessary for the generation of T(H)17 cells, the molecular mechanisms underlying the functional diversity of T(H)17 cells are not fully understood. Here we show that a member of interferon regulatory factor (IRF) family of transcription factors, IRF8, has a critical role in silencing T(H)17-cell differentiation. Mice with a conventional knockout, as well as a T cell-specific deletion, of the Irf8 gene exhibited more efficient T(H)17 cells. Indeed, studies of an experimental model of colitis showed that IRF8 deficiency resulted in more severe inflammation with an enhanced T(H)17 phenotype. IRF8 was induced steadily and inhibited T(H)17-cell differentiation during T(H)17 lineage commitment at least in part through its physical interaction with RORγt. These findings define IRF8 as a novel intrinsic transcriptional inhibitor of T(H)17-cell differentiation.


Applying Psychiatry and Psychology Principles to Lifestyle Approaches for Mental and Behavioral Health.
Research suggests that mental health symptoms and disorders are historically underdiagnosed and undertreated, in part due to the siloed nature of medicine. Yet, approximately 50 million American adults experience a mental health disorder. As the field of lifestyle medicine continues to emerge and grow, there is an important opportunity to address mental health from a lifestyle medicine perspective, as well as to ensure that lifestyle medicine can be utilized for all patients, including those with mental health conditions. To effectively address mental health, the field of lifestyle medicine would benefit from understanding and leveraging the decades of science and practice from the fields of psychiatry and psychology, as well as the expertise of psychiatrists and psychologists who are familiar with the science and trained in lifestyle medicine. Incorporating empirical literature from other areas, utilizing well-established conceptual frameworks, and addressing the overlap between lifestyle medicine and mental health early in, and throughout, training and education, are important steps to move toward addressing mental and behavioral health with a lifestyle medicine approach.


Incidence and prevalence of uveitis in South Korea: a nationwide cohort study.
To evaluate the incidence and prevalence of uveitis and associated risk factors in South Korea. For this retrospective national cohort study, approximately 1 000 000 Korean residents were randomly selected from the Korean National Health Insurance Service database. Uveitis was defined according to the Korean Classification of Diseases. The uveitis incidence and prevalence were calculated. Sociodemographic factors and comorbidities associated with uveitis were evaluated via Cox proportional regression models. A total of 1 094 440 subjects were evaluated over 7 051 346 person-years (mean follow-up: 6.44 years). Overall, 7447 newly developed uveitis cases were identified during the period of 2007-2013; the average incidence of uveitis was 10.6 per 10 000 person-years (95% CI 10.3 to 10.8). The average incidences of anterior and non-anterior uveitis were 9.0 and 1.5 per 10 000 person-years, respectively. The prevalence rates of uveitis, anterior uveitis and non-anterior uveitis were 17.3, 15.0 and 2.3 per 10 000 persons, respectively, during the period of 2007-2013. Increasing age, male sex, residing in a relatively rural area and high income were associated with uveitis, along with Behçet's disease, juvenile idiopathic arthritis, ankylosing spondylitis, systemic lupus erythematous, ulcerative colitis and tuberculosis. The overall incidence of uveitis in Korea was similar to those reported in Taiwan and the USA. Despite a potentially inaccurate disease definition, claims data may be useful for monitoring the substantial uveitis burden in South Korea.


Data-Driven Differential Diagnosis of Dementia Using Multiclass Disease State Index Classifier.
Clinical decision support systems (CDSSs) hold potential for the differential diagnosis of neurodegenerative diseases. We developed a novel CDSS, the PredictND tool, designed for differential diagnosis of different types of dementia. It combines information obtained from multiple diagnostic tests such as neuropsychological tests, MRI and cerebrospinal fluid samples. Here we evaluated how the classifier used in it performs in differentiating between controls with subjective cognitive decline, dementia due to Alzheimer's disease, vascular dementia, frontotemporal lobar degeneration and dementia with Lewy bodies. We used the multiclass Disease State Index classifier, which is the classifier used by the PredictND tool, to differentiate between controls and patients with the four different types of dementia. The multiclass Disease State Index classifier is an extension of a previously developed two-class Disease State Index classifier. As the two-class Disease State Index classifier, the multiclass Disease State Index classifier also offers a visualization of its decision making process, which makes it especially suitable for medical decision support where interpretability of the results is highly important. A subset of the Amsterdam Dementia cohort, consisting of 504 patients (age 65 ± 8 years, 44% females) with data from neuropsychological tests, cerebrospinal fluid samples and both automatic and visual MRI quantifications, was used for the evaluation. The Disease State Index classifier was highly accurate in separating the five classes from each other (balanced accuracy 82.3%). Accuracy was highest for vascular dementia and lowest for dementia with Lewy bodies. For the 50% of patients for which the classifier was most confident on the classification the balanced accuracy was 93.6%. Data-driven CDSSs can be of aid in differential diagnosis in clinical practice. The decision support system tested in this study was highly accurate in separating the different dementias and controls from each other. In addition to the predicted class, it also provides a confidence measure for the classification.


Sleep and daytime sleepiness in upper airway resistance syndrome compared to obstructive sleep apnoea syndrome.
This study has investigated differences in the nocturnal sleep and daytime sleepiness among patients with obstructive sleep apnoea syndrome (OSAS), upper airway resistance (UARS), sleep hypopnoea syndrome, and normal control subjects, using sleep scoring and spectral activity analysis of the electroencephalogram (EEG). Twelve nonobese males with UARS aged 30-60 yrs were recruited. These subjects were strictly matched for age and body mass index with twelve OSAS patients, 12 sleep hypopnoea syndrome patients, and 12 normal controls, all male. Daytime sleepiness was evaluated using the Epworth Sleepiness Scale (ESS) and the Multiple Sleep Latency Test (MSLT). The macrostructure of sleep was determined using international criteria and spectral analysis of the sleep EEG was obtained from a central lead. The sleep macrostructure of OSAS and UARS patients was significantly different from that of controls. These patients were also sleepier during the daytime than controls. Complaints of tiredness and daytime sleepiness, ESS and MSLT scores were similar in the different patient groups. Mild dysmorphia was present in all three patient groups. However, nocturnal sleep was significantly different among the different groups. OSAS patients had significantly more awake time during sleep than the UARS patients. The spectral activity of the total sleep time of the patient groups also differed significantly from that of controls. When the sleep spectral activity of UARS and OSAS patients were compared, OSAS patients had less slow wave sleep activity than UARS patients. UARS patients had a significantly higher absolute power in the 7-9 Hz bandwidth than OSAS patients. The absolute delta power over the different sleep cycles was also different between controls and patients, and between UARS and OSAS patients. There are clear differences in the macrostructure and spectral activity of sleep between upper airway resistance and obstructive sleep apnoea syndrome patients, demonstrated by differences in the cortical activity recorded in the central lead during sleep. Despite these nocturnal sleep differences, the tests of subjective daytime sleepiness are not significantly different.


What do preschool-aged children do when they wake at night: toward an understanding of night-waking behaviors among community children.
Little is known about behaviors displayed by preschoolers during night-waking. Mothers (N = 203) of community preschoolers completed the Children's Night-waking Behavior Scale and measures of night-waking, co-sleeping, and daytime behavior. Approximately 1/2 of wakings involved calling out, getting out of bed, and requests for comfort; 1/4 involved activity, fear, or instrumental requests. Specific associations between night-waking behaviors, night-waking, and bedtime and daytime behaviors were observed; associations were not consistent across child gender and age. For example, comfort requests were associated with mothers' perceptions of sleep as problematic in 4- and 5-year-old children only (ρ = .42); activity requests were associated with hyperactivity for boys only (r = .36). Understanding night-waking requires consideration of factors beyond parenting, such as children's behavior, age, and gender.


Human sex differentiation: from transcription factors to gender.
Over the past decade, knowledge of the genetic control of human sex differentiation has greatly expanded our understanding of the developmental processes needed to form a male or female. The purpose of this review is to discuss how transcription factors are relevant to such processes. Additionally, an attempt is made to relate current knowledge of these factors with gender development of subjects with intersex conditions. Finally, we discuss how information about the genetic control of sex differentiation may contribute to decisions about medical treatment of individuals with conditions of abnormal sex differentiation.


Effective topical combination therapy for treatment of lichen striatus in children: a case series and review.
Lichen striatus (LS) is an uncommon linear dermatosis that is primarily seen in children from 4 months to 15 years of age. While some of these eruptions are asymptomatic, others can be quite pruritic. In darker-skinned individuals, post-inflammatory hypopigmentation can be significant and may provide a cause for concern for the patients and/or their parents. In our case series of 4 patients, we observed rapid resolution of LS by combining a topical retinoid with a topical steroid. To our knowledge, this is the first report of successful treatment with this kind of combination therapy in the English literature. The patients not only achieved satisfying cosmesis, but also complete resolution of their pruritus. The most common side effect of topical tazarotene is localized irritation at treatment sites, but the patients in this particular series tolerated the treatment well.


Factors affecting ambulance utilization for asthma attack treatment: understanding where to target interventions.
Asthma is a serious, sometimes fatal condition, in which attacks vary in severity, potentially requiring emergency medical services (EMS) ambulance treatment. A portion of asthma attacks requiring EMS ambulance treatment may be prevented with improved education and access to care. The aim of this study was to identify areas of the city with high rates of utilization of EMS ambulance for treatment, and the demographics, socio-economic status, and time of day associated with these rates, to better target future interventions to prevent emergencies and reduce cost. A cross-sectional study was conducted on individuals in Houston, TX (USA) requiring ambulance treatment for asthma attacks from 2004 to 2011. 12,155 EMS ambulance-treated asthma attack cases were linked to census tracts. High rate treatment areas were identified with geospatial mapping. Census tract demographic characteristics of these high rate areas were compared with the remainder of the city using logistic regression. The association between case level demographics and the time of day of asthma attack within the high rate area was also assessed with logistic regression. EMS ambulance-treated high rate areas were identified and found to have a utilization incidence rate over six times higher per 100,000 people than the remainder of the city. There is an increased risk of location in this high rate area with a census tract level increase of percent of population: earning less than $10,000 yearly income (RR 1.21, 1.16-1.26), which is black (RR 1.08, 1.07-1.10), which is female (RR 1.34, 1.20-1.49) and have obtained less than a high school degree (RR 1.02, 1.01-1.03). Within the high rate area, case level data indicates an increased risk of requiring an ambulance after normal doctor office hours for men compared with women (RR 1.13, 1.03-1.22), for black compared with Hispanic ethnicity (RR 1.31, 1.08-1.59), or for adults (less than 41 and greater than 60) compared with children. Interventions to prevent asthma emergencies should be targeted in the high rate area and towards groups identified most at risk. Consideration should be given to improved access to care after normal doctor office hours in these locations. While ambulance treatment reflects the most urgent care needs, these interventions are also expected to reduce the need for emergency room visits.


Engineering of porcine pepsin. Alteration of S1 substrate specificity of pepsin to those of fungal aspartic proteinases by site-directed mutagenesis.
The S1 substrate specificity of porcine pepsin has been altered to resemble that of fungal aspartic proteinase with preference for a basic amino acid residue in P1 by site directed mutagenesis. On the basis of primary and tertiary structures of aspartic proteinases, the active site-flap mutants of porcine pepsin were constructed, which involved the replacement of Thr-77 by Asp (T77D), the insertion of Ser between Gly-78 and Ser-79 (G78(S)S79), and the double mutation (T77D/G78(S)S79). The specificities of the mutants were determined using p-nitrophenylalanine-based substrates containing a Phe or Lys residue at the P1 position. The double mutant cleaved the Lys-Phe(4-NO2) bonds, while wild-type enzyme digested other bonds. In addition, the pH dependence of hydrolysis of Lys-containing substrates by the double mutant indicates that the interactions between Asp-77 of the mutant and P1 Lys contribute to the transition state stabilization. The double mutant was also able to activate bovine trypsinogen to trypsin by the selective cleavage of the Lys6-Ile7 bond of trypsinogen. Results of this study suggest that the structure of the active site flap contributes to the S1 substrate specificity for basic amino acid residues in aspartic proteinases.


Measurement properties of adult quality-of-life measurement instruments for eczema: protocol for a systematic review.
Eczema is a common chronic or chronically relapsing skin disease that has a substantial impact on quality of life (QoL). By means of a consensus-based process, the Harmonising Outcome Measures in Eczema (HOME) initiative has identified QoL as one of the four core outcome domains to be assessed in all eczema trials (Allergy 67(9):1111-7, 2012). Various measurement instruments exist to measure QoL in adults with eczema, but there is a great variability in both content and quality (for example, reliability and validity) of the instruments used, and it is not always clear if the best instrument is being used. Therefore, the aim of the proposed research is a comprehensive systematic assessment of the measurement properties of the existing measurement instruments that were developed and/or validated for the measurement of patient-reported QoL in adults with eczema. This study is a systematic review of the measurement properties of patient-reported measures of QoL developed and/or validated for adults with eczema. Medline via PubMed and EMBASE will be searched using a selection of relevant search terms. Eligible studies will be primary empirical studies evaluating, describing, or comparing measurement properties of QoL instruments for adult patients with eczema. Eligibility assessment and data abstraction will be performed independently by two reviewers. Evidence tables will be generated for study characteristics, instrument characteristics, measurement properties, and interpretability. The quality of the measurement properties will be assessed using predefined criteria. Methodological quality of studies will be assessed using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. A best evidence synthesis will be undertaken if more than one study has investigated a particular measurement property. The proposed systematic review will produce a comprehensive assessment of measurement properties of existing QoL instruments in adult patients with eczema. We aim to identify one best currently available instrument to measure QoL in eczema patients. PROSPERO CRD42015017138.


Pain Prevention Using Head and Neck Cancer as a Model.
Pain is a common and often debilitating consequence of cancer and its treatment. Efforts to improve pain management for patients diagnosed with cancer have not resulted in widespread patient reports of acceptable management of pain. Patients and providers alike remain opiophobic due to a number of issues, resulting in suboptimal management of pain. Recent literature has revealed that it may be possible to prevent pain related to cancer and its treatment and therefore avoid or decrease the amount of opioids used to treat pain. This may result in better quality of life for patients. Several newer antiepileptic drugs (AEDs) have been found to decrease the perception of pain in a number of patient populations, including those with head and neck cancer. The side-effect profile for the newer AEDs is mild and well tolerated. Future efforts should focus on the use of newer AEDs to prevent pain in other cancer populations, with a focus on ideal dose and scheduling. Once established, recommendations regarding the prevention of pain in patients with cancer can be incorporated into national guidelines.


Exopolysaccharide from Lactobacillus plantarum LRCC5310 offers protection against rotavirus-induced diarrhea and regulates inflammatory response.
We aimed to determine the effects of Lactobacillus strains against rotaviral infections. Rotaviruses are the major causative agent of acute gastroenteritis in infants and children worldwide. However, to date, no specific antiviral drugs for the treatment of rotavirus infection have been developed. We identified 263 Lactobacillus strains from 35 samples of the traditional Korean fermented vegetable food kimchi. Among them, Lactobacillus plantarum LRCC5310, more specifically the exopolysaccharides produced by these cells, were shown to have an antiviral effect against human rotavirus Wa strain in vitro. In vivo, the oral administration of exopolysaccharides for 2 d before and 5 d after mouse infection with the murine rotavirus epidemic diarrhea of infant mice strain led to a decrease in the duration of diarrhea and viral shedding and prevented the destruction of enteric epithelium integrity in the infected mice. We demonstrated here that the exopolysaccharides extracted from L. plantarum LRCC5310 can be used for the effective control of rotavirus infection.


Intrinsic temperature sensitivity of tilted fiber Bragg grating based surface plasmon resonance sensors.
A miniature surface plasmon resonance sensor is fabricated from a gold-coated standard optical fiber with an in-core tilted fiber Bragg grating fabricated by UV exposure. The sensor has a measured refractive index sensitivity of 571.5 nm/RIU (refractive index unit) at constant temperature. We show here that the intrinsic temperature sensitivity of this device is reduced to less than 6.3 pm/degrees C (between 23 degrees C and 59 degrees C) when measurements are referenced to a core mode reflection resonance of the grating. This residual sensitivity is essentially that of the 50 nm thick deposited gold layer but it is bigger by one order of magnitude than the expected value (0.51 pm/degrees C) for a gold-water interface.


Cardiovascular characteristics of chronic fatigue syndrome.
Patients with chronic fatigue syndrome (CFS) commonly exhibit orthostatic intolerance. Abnormal sympathetic predominance in the autonomic cardiovascular response to gravitational stimuli was previously described in numerous studies. The aim of the current study was to describe cardiological and clinical characteristics of Italian patients with CFS. All of the patients were of Caucasian ethnicity and had been referred to our center, the Cardiology Department of the University Hospital of Pavia (Pavia, Italy) with suspected CFS. A total of 44 patients with suspected CFS were included in the present study and the diagnosis was confirmed in 19 patients according to recent clinical guidelines. The characteristics at baseline of the population confirm findings from various previous reports regarding the prevalence in females with a female to male ratio of 4:1, the age of onset of the pathology and the presence of previous infection by the Epstein-Barr virus, cytomegalovirus and other human herpesviruses. Despite the current data indicating that the majority of the cardiological parameters investigated are not significantly different in patients with and without CFS, a significant association between the disease and low levels of blood pressure was identified. Other pilot studies revealed a higher prevalence of hypotension and orthostatic intolerance in patients with CFS. Furthermore, many of the CFS symptoms, including fatigue, vertigo, decreased concentration, tremors and nausea, may be explained by hypotension.


Gene expression profiling of pediatric acute myelogenous leukemia.
Contemporary treatment of pediatric acute myeloid leukemia (AML) requires the assignment of patients to specific risk groups. To explore whether expression profiling of leukemic blasts could accurately distinguish between the known risk groups of AML, we analyzed 130 pediatric and 20 adult AML diagnostic bone marrow or peripheral blood samples using the Affymetrix U133A microarray. Class discriminating genes were identified for each of the major prognostic subtypes of pediatric AML, including t(15;17)[PML-RARalpha], t(8;21)[AML1-ETO], inv(16) [CBFbeta-MYH11], MLL chimeric fusion genes, and cases classified as FAB-M7. When subsets of these genes were used in supervised learning algorithms, an overall classification accuracy of more than 93% was achieved. Moreover, we were able to use the expression signatures generated from the pediatric samples to accurately classify adult de novo AMLs with the same genetic lesions. The class discriminating genes also provided novel insights into the molecular pathobiology of these leukemias. Finally, using a combined pediatric data set of 130 AMLs and 137 acute lymphoblastic leukemias, we identified an expression signature for cases with MLL chimeric fusion genes irrespective of lineage. Surprisingly, AMLs containing partial tandem duplications of MLL failed to cluster with MLL chimeric fusion gene cases, suggesting a significant difference in their underlying mechanism of transformation.


Advanced pancreatic cancer: a meta-analysis of clinical trials over thirty years.
In contrast to other cancers, survival rates for pancreatic ductal adenocarcinoma (PDAC) patients have improved but minimally over the past thirty years. The aim of this study was to perform a meta-analysis of clinical trials published since 1986 to determine trends in median overall survival in primarily metastatic PDAC. All Phase 2-4 clinical trials published during or after 1986 investigating first-line systemic chemotherapy in metastatic PDAC were included in the meta-analysis. Publications obtained through PubMed and www.ClinicalTrials.gov were cross-referenced to identify additional trials. Trials enrolling fewer than 50% of study participants with metastatic disease were excluded. Of 19,488 patients enrolled in 151 clinical trials, 84% had metastatic disease and 16% had locally advanced pancreatic cancer. In clinical trials published from 1986 to 2016, the weighted median overall survival (wMOS) increased by 3.0 months. The median wMOS was higher in combination therapy (7.31 months, IQR 5.4 to 8.5) compared to non-gemcitabine, single-agent therapy (4.76 months, IQR 3.5 to 6.0), gemcitabine monotherapy (6.48 months, IQR 5.9 to 7.2), and gemcitabine plus single-agent therapy (7.09 months, IQR 6.3 to 8.2). Of all regimens used in more than one study arm, FOLFIRINOX had the highest wMOS (10.9 months). Regardless of treatment regimen, survival rates in PDAC have minimally improved over time. Of drugs used in two or more study arms, only FOLFIRINOX has a wMOS greater than ten months. Emphasis should, therefore, be placed on identification of novel targets that promote early diagnosis and intervention. The authors on this manuscript are in parts, supported by grants from the National Institutes of Health (EDRN U01 CA200466, SPORE P50 CA127297, R01 CA183459, R21 AA026428 and R01 CA 195586).


Quantum tunneling injection of hot electrons in Au/TiO2 plasmonic photocatalysts.
Visible light absorption of plasmonic Au nanoparticles supported on semiconductor TiO2 leads to injection of their photoactivated "hot electrons (ehot-)" into the TiO2 conduction band. This charge separation facilitates several oxidation and reduction reactions. These plasmonic systems, however, suffer from low quantum yields because the Schottky barrier created at the Au-TiO2 interface suppresses ehot- injection. Here we report that Au nanoparticles supported on the anatase particles isolated from Degussa (Evonik) P25 TiO2 promote ehot- injection with much higher efficiency than those supported on other commercially-available TiO2 and catalyze aerobic oxidation with very high quantum yield (7.7% at 550 nm). Photoelectrochemical and spectroscopic analysis revealed that the number of Ti4+ atoms located at the Au-TiO2 interface is the crucial factor. These Ti4+ atoms neutralize the negative charge of the Au particles and create a Schottky barrier with narrower depletion layer. This facilitates efficient ehot- injection by "quantum tunneling" through the Schottky barrier without overbarrier energy. The ehot- injection depends on several factors, and loading of 2 wt% Au particles with 3.5-4 nm diameters at around room temperature exhibits the highest activity of plasmonic photocatalysis.


Biological fitness and the Price Equation in class-structured populations.
Price׳s extended covariance selection mathematics is applied to class-structured populations with additional assumptions, to derive the 'genetic Price Equation with class structure'. Each individual belongs to a class, and there may be overlapping generations; the equation is genetic because the trait is restricted to an arbitrary weighted sum of allele frequencies. Two special cases are then considered, a demography-like case corresponding to Fisher's fundamental theorem of natural selection, and a sex-ratio-like case corresponding to Fisher's sex ratio argument: these differ in whether it is natural to assume that the per-capita or the total reproductive values of each class are maintained from the parental to the descendant population. These cases also match the two existing attempts to eliminate from the effects of natural selection those passive changes in allele frequencies that are caused by the class structure, and suggest improvements in one of them. In each case a more specialised Price Equation, and a 'fundamental theorem of natural selection', are proved, which hold out of class-structure equilibrium, showing that passive changes can be eliminated in more than one way, and hinting at the possibility of a more general formulation. Previous class-structured Price Equations and a 'fundamental theorem' are linked to these results. The power of Price's formal approach is vividly illustrated by this lucid conspectus of otherwise self-standing theories with confusing interconnections.


Bend, stretch, and touch: Locating a finger on an actively deformed transparent sensor array.
The development of bendable, stretchable, and transparent touch sensors is an emerging technological goal in a variety of fields, including electronic skin, wearables, and flexible handheld devices. Although transparent tactile sensors based on metal mesh, carbon nanotubes, and silver nanowires demonstrate operation in bent configurations, we present a technology that extends the operation modes to the sensing of finger proximity including light touch during active bending and even stretching. This is accomplished using stretchable and ionically conductive hydrogel electrodes, which project electric field above the sensor to couple with and sense a finger. The polyacrylamide electrodes are embedded in silicone. These two widely available, low-cost, transparent materials are combined in a three-step manufacturing technique that is amenable to large-area fabrication. The approach is demonstrated using a proof-of-concept 4 × 4 cross-grid sensor array with a 5-mm pitch. The approach of a finger hovering a few centimeters above the array is readily detectable. Light touch produces a localized decrease in capacitance of 15%. The movement of a finger can be followed across the array, and the location of multiple fingers can be detected. Touch is detectable during bending and stretch, an important feature of any wearable device. The capacitive sensor design can be made more or less sensitive to bending by shifting it relative to the neutral axis. Ultimately, the approach is adaptable to the detection of proximity, touch, pressure, and even the conformation of the sensor surface.


A New Taxon of Basal Ceratopsian from China and the Early Evolution of Ceratopsia.
Ceratopsia is one of the best studied herbivorous ornithischian clades, but the early evolution of Ceratopsia, including the placement of Psittacosaurus, is still controversial and unclear. Here, we report a second basal ceratopsian, Hualianceratops wucaiwanensis gen. et sp. nov., from the Upper Jurassic (Oxfordian) Shishugou Formation of the Junggar Basin, northwestern China. This new taxon is characterized by a prominent caudodorsal process on the subtemporal ramus of the jugal, a robust quadrate with an expansive quadratojugal facet, a prominent notch near the ventral region of the quadrate, a deep and short dentary, and strongly rugose texturing on the lateral surface of the dentary. Hualianceratops shares several derived characters with both Psittacosaurus and the basal ceratopsians Yinlong, Chaoyangsaurus, and Xuanhuaceratops. A new comprehensive phylogeny of ceratopsians weakly supports both Yinlong and Hualianceratops as chaoyangsaurids (along with Chaoyangsaurus and Xuanhuaceratops), as well as the monophyly of Chaoyangosauridae + Psittacosaurus. This analysis also weakly supports the novel hypothesis that Chaoyangsauridae + Psittacosaurus is the sister group to the rest of Neoceratopsia, suggesting a basal split between these clades before the Late Jurassic. This phylogeny and the earliest Late Jurassic age of Yinlong and Hualianceratops imply that at least five ceratopsian lineages (Yinlong, Hualianceratops, Chaoyangsaurus + Xuanhuaceratops, Psittacosaurus, Neoceratopsia) were present at the beginning of the Late Jurassic.


Genome-wide RNA-seq analysis indicates that the DAG1 transcription factor promotes hypocotyl elongation acting on ABA, ethylene and auxin signaling.
Hypocotyl elongation is influenced by light and hormones, but the molecular mechanisms underlying this process are not yet fully elucidated. We had previously suggested that the Arabidopsis DOF transcription factor DAG1 may be a negative component of the mechanism of light-mediated inhibition of hypocotyl elongation, as light-grown dag1 knock-out mutant seedlings show significant shorter hypocotyls than the wild type. By using high-throughput RNA-seq, we compared the transcriptome profile of dag1 and wild type hypocotyls and seedlings. We identified more than 250 genes differentially expressed in dag1 hypocotyls, and their analysis suggests that DAG1 is involved in the promotion of hypocotyl elongation through the control of ABA, ethylene and auxin signaling. Consistently, ChIP-qPCR results show that DAG1 directly binds to the promoters of WRKY18 encoding a transcription factor involved in ABA signaling, of the ethylene- induced gene ETHYLENE RESPONSE FACTOR (ERF2), and of the SMALL AUXIN UP RNA 67 (SAUR67), an auxin-responding gene encoding a protein promoting hypocotyl cell expansion.


Traumatic Brain Injury and Risk of Long-Term Brain Changes, Accumulation of Pathological Markers, and Developing Dementia: A Review.
Traumatic brain injuries (TBI) have received widespread media attention in recent years as being a risk factor for the development of dementia and chronic traumatic encephalopathy (CTE). This has sparked fears about the potential long-term effects of TBI of any severity on cognitive aging, leading to a public health concern. This article reviews the evidence surrounding TBI as a risk factor for the later development of changes in brain structure and function, and an increased risk of neurodegenerative disorders. A number of studies have shown evidence of long-term brain changes and accumulation of pathological biomarkers (e.g., amyloid and tau proteins) related to a history of moderate-to-severe TBI, and research has also demonstrated that individuals with moderate-to-severe injuries have an increased risk of dementia. While milder injuries have been found to be associated with an increased risk for dementia in some recent studies, reports on long-term brain changes have been mixed and often are complicated by factors related to injury exposure (i.e., number of injuries) and severity/complications, psychiatric conditions, and opioid use disorder. CTE, although often described as a neurodegenerative disorder, remains a neuropathological condition that is poorly understood. Future research is needed to clarify the significance of CTE pathology and determine whether that can explain any clinical symptoms. Overall, it is clear that most individuals who sustain a TBI (particularly milder injuries) do not experience worse outcomes with aging, as the incidence for dementia is found to be less than 7% across the literature.


The complete chloroplast genome sequence of Coix lacryma-jobi L. (Poaceae), a cereal and medicinal crop.
Coix lacryma-jobi is a cereal and medicinal crop belonging to the Poaceae family. This study characterized complete chloroplast genome sequence of a Korean cultivar Johyun of C. lacryma-jobi var. ma-yuen through the de novo hybrid assembly with Illumina and PacBio genomic reads. The chloroplast genome is 140,863 bp long and composed of large single copy (82,827 bp), small single copy (12,522 bp), and a pair of inverted repeats (each 22,757 bp). A total of 123 genes including 87 protein-coding genes, 32 tRNA genes, and four rRNA genes were predicted in the genome. Phylogenetic analysis confirmed a close relationship of C. lacryma-jobi with species in the Panicoideae subfamily of the Poaceae family.


Maternal Attachment Inventory: psychometric evaluation of the Korean version.
This paper is a report of an assessment of the validity and reliability of the Korean language version of the Maternal Attachment Inventory. Although the Maternal Attachment Inventory has been widely used to measure mother-infant attachment, no psychometric evaluation of the measure with a Korean population has been reported. Data from 196 mothers within 6 weeks postpartum were collected during July to November 2003 and used to evaluate the validity and reliability of the Korean version of the Maternal Attachment Inventory. Validity was examined using exploratory factor analysis, item-to-subscale correlations, and correlations with other theoretically relevant variables (maternal foetal attachment and maternal sensitivity). For reliability testing, Cronbach's alpha coefficients, item analyses, and subscale-to-total correlations were examined. Factor analysis showed that the Korean version had three factors explaining 62.9% of the variance. Item-to-subscale correlation coefficients ranged from 0.49 to 0.91. Correlation coefficients between the Maternal Attachment Inventory and both maternal foetal attachment and maternal sensitivity ranged from 0.10 to 0.64. However, correlations between the third factor scores and both maternal foetal attachment scores and maternal sensitivity scores were not statistically significant. Cronbach's alpha coefficients ranged from 0.65 to 0.94. Correlation coefficients of the inter-item analysis ranged from -0.01 to 0.87. Corrected item-total correlation coefficients were 0.31-0.82. Subscale-to-total correlation coefficients of the Maternal Attachment Inventory ranged from 0.52 to 0.92. Most items of the Korean version of the Maternal Attachment Inventory were adequate for measuring mothers' affectionate attachment. The instrument, however, exhibited weaknesses in the psychometric properties related to validity and reliability, particularly regarding the three items included in the third factor. More studies using factor analysis of the Maternal Attachment Inventory are needed.


Differential regulation of the two principal Runx2/Cbfa1 n-terminal isoforms in response to bone morphogenetic protein-2 during development of the osteoblast phenotype.
Cbfa1/Runx2 is a transcription factor essential for bone formation and osteoblast differentiation. Two major N-terminal isoforms of Cbfa1, designated type I/p56 (PEBP2aA1, starting with the sequence MRIPV) and type II/p57 (til-1, starting with the sequence MASNS), each regulated by distinct promoters, are known. Here, we show that the type I transcript is constitutively expressed in nonosseous mesenchymal tissues and in osteoblast progenitor cells. Cbfa1 type I isoform expression does not change with the differentiation status of the cells. In contrast, the type II transcript is increased during differentiation of primary osteoblasts and is induced in osteoprogenitors and in premyoblast C2C12 cells in response to bone morphogenetic protein-2. The functional equivalence of the two isoforms in activation and repression of bone-specific genes indicates overlapping functional roles. The presence of the ubiquitous type I isoform in nonosseous cells and before bone morphogenetic protein-2 induced expression of the type II isoform suggests a regulatory role for Cbfa1 type I in early stages of mesenchymal cell development, whereas type II is necessary for osteogenesis and maintenance of the osteoblast phenotype. Our data indicate that Cbfa1 function is regulated by transcription, cellular protein levels, and DNA binding activity during osteoblast differentiation. Taken together, our studies suggest that developmental timing and cell type- specific expression of type I and type II Cbfa isoforms, and not necessarily molecular properties or sequences that reside in the N-terminus of Cbfa1, are the principal determinants of the osteogenic activity of Cbfa1.


Co-activation of tongue protrudor and retractor muscles during chemoreceptor stimulation in the rat.
1. Our primary purpose was to test the hypothesis that the tongue protrudor (genioglossus, GG) and retractor (styloglossus, SG and hyoglossus, HG) muscles are co-activated when respiratory drive increases, and that co-activation will cause retraction of the tongue. This was addressed by performing two series of experiments using a supine, anaesthetized, tracheotomized rat in which tongue muscle force and the neural drive to the protrudor and retractor muscles could be measured during spontaneous breathing. In the first series of experiments, respiratory drive was increased progressively by occluding the tracheal cannula for thirty respiratory cycles; in the second series of experiments, the animals were subjected to hyperoxic hypercapnia and poikilocapnic hypoxia. 2. Airway occlusion for thirty breaths caused progressive, quantitatively similar increases in efferent motor nerve activity to protrudor and retractor tongue muscles. Net tongue muscle force was always consistent with tongue retraction during occlusion, and peak force rose in parallel with the neural activites. When airway occlusion was repeated following section of the lateral XIIth nerve branch (denervation of retractor muscles) the tongue either protruded (15/21 animals; 10 +/- 2 mN at the 30th occluded breath) or retracted weakly (6/21 animals; 6 +/- 2 mN at 30th occluded breath). 3. To ensure that our findings were not the result of damage to the muscle nerves, occlusion experiments were also done in eight animals in which GG EMG activity was recorded instead of nerve activities. Changes in peak integrated GG electryomyogram (EMG) activity and peak retraction force during occlusion were highly correlated (r2 = 0.86, slope = 1.05). 4. In separate experiments in fourteen rats, we found that hyperoxic hypercapnia and poikilocapnic hypoxia also result in parallel increases in the respiratory-related EMG activity of the GG and HG muscles. Also, as in the occlusion experiments, augmentations of protrudor and retractor muscle EMG activities were associated with parallel changes in tongue retraction force. 5. These studies in anaesthetized rats demonstrate that tracheal occlusion and independent stimulation of central or peripheral chemoreceptors results in inspiratory-related co-activation of the protrudor and retractor muscles, and proportional changes in tongue retraction force. These observations also demonstrate that recording GG EMG activity in isolation could lead to erroneous conclusions about respiratory-related movements of the tongue.


Economic analysis of delivering primary health care services through community health workers in 3 North Indian states.
We assessed overall annual and unit cost of delivering package of services and specific services at sub-centre level by CHWs and cost effectiveness of Government of India's policy of introducing a second auxiliary nurse midwife (ANM) at the sub-centre compared to scenario of single ANM sub-centre. We undertook an economic costing of health services delivered by CHWs, from a health system perspective. Bottom-up costing method was used to collect data on resources spent in 50 randomly selected sub-centres selected from 4 districts. Mean unit cost along with its 95% confidence intervals were estimated using bootstrap method. Multiple linear regression model was used to standardize cost and assess its determinants. Annually it costs INR 1.03 million (USD 19,381), or INR 187 (USD 3.5) per capita per year, to provide a package of preventive, curative and promotive services through community health workers. Unit costs for antenatal care, postnatal care, DOTS treatment and immunization were INR 525 (USD 10) per full ANC care, INR 767 (USD 14) per PNC case registered, INR 974 (USD 18) per DOTS treatment completed and INR 97 (USD 1.8) per child immunized in routine immunization respectively. A 10% increase in human resource costs results in 6% rise in per capita cost. Similarly, 10% increment in the ANC case registered per provider through-put results in a decline in unit cost ranging from 2% in the event of current capacity utilization to 3% reduction in case of full capacity utilization. Incremental cost of introducing 2nd ANM at sub-centre level per unit percent increase ANC coverage was INR 23,058 (USD 432). Our estimates would be useful in undertaking full economic evaluations or equity analysis of CHW programs. Government of India's policy of hiring 2nd ANM at sub-centre level is very cost effective from Indian health system perspective.


Automatic fitting of spiking neuron models to electrophysiological recordings.
Spiking models can accurately predict the spike trains produced by cortical neurons in response to somatically injected currents. Since the specific characteristics of the model depend on the neuron, a computational method is required to fit models to electrophysiological recordings. The fitting procedure can be very time consuming both in terms of computer simulations and in terms of code writing. We present algorithms to fit spiking models to electrophysiological data (time-varying input and spike trains) that can run in parallel on graphics processing units (GPUs). The model fitting library is interfaced with Brian, a neural network simulator in Python. If a GPU is present it uses just-in-time compilation to translate model equations into optimized code. Arbitrary models can then be defined at script level and run on the graphics card. This tool can be used to obtain empirically validated spiking models of neurons in various systems. We demonstrate its use on public data from the INCF Quantitative Single-Neuron Modeling 2009 competition by comparing the performance of a number of neuron spiking models.


Early severe vasomotor menopausal symptoms are associated with diabetes.
The purpose of this study was to investigate associations between profiles of vasomotor menopausal symptoms (VMS) during the menopausal transition with the prevalence of diabetes. VMS and diabetes were measured at baseline and 3-year intervals for 15 years in 4,895 women in the Australian Longitudinal Study on Women's Health who were aged 45 to 50 years at baseline in 1996. Latent class analysis and generalized estimating equation models for binary repeated measures were performed. The VMS profiles were labeled as mild, moderate, early severe, and late severe. The prevalence of diabetes in the total group was 9.0%. Compared with mild VMS, the odds of diabetes were higher in those with a late severe profile (though not statistically significant; adjusted odds ratio, 1.28; 95% CI, 0.97-1.68) and in those with an early severe profile (adjusted odds ratio, 1.67; 95% CI, 1.20-2.32). Adjustment for body mass index attenuated this association, but the odds of diabetes were still significantly higher in women with an early severe profile than in women with mild VMS (odds ratio, 1.55; 95% CI, 1.11-2.17). The moderate profile was not associated with diabetes. Women with an early severe VMS profile are more likely to have diabetes across a period of 15 years. This association is not explained by body mass index or other potential confounders. Our findings imply that the predictive value of VMS for diabetes may vary with the timing of VMS relative to menopause.


Feasibility and Value of Establishing a Community-Based Virtual Multidisciplinary Sarcoma Case Conference.
Management of soft tissue and bone sarcoma presents many challenges, both diagnostically and therapeutically, and requires multidisciplinary collaboration; however, such collaboration is often challenging to establish, especially in the community setting. We share our experiences of a virtual multidisciplinary sarcoma case conference (VMSCC). We conducted retrospective review of the VMSCC data-initially via Webex, now Microsoft Teams-and the surveys of referring physicians to understand the feasibility and value of the VMSCC. The VMSCC was established in March 2013 in Kaiser Permanente Northern California with consistent participation of the Departments of Musculoskeletal Oncology (orthopedic oncology), Musculoskeletal Radiology, Pathology, Medical Oncology, Radiation Oncology, Nuclear Medicine, Surgical Oncology, and Genetics. Pediatric Oncology participated ad hoc when pediatric sarcoma cases were presented. Referrals were from multiple specialties and regions, including the Kaiser Permanente Mid-Atlantic and Hawaii regions. From March 2013 to December 2019, 1,585 cases were reviewed encompassing 36 histologic types. More than 300 cases were reviewed per year from 2017 to 2019. Survey results of referring physicians demonstrate that the VMSCC enhanced the confidence of treating physicians, and its recommendations frequently led to treatment changes. Establishing a valuable community-based VMSCC is feasible. VMSCC recommendations frequently led to treatment changes and improved the confidence of treating physicians.


Memory CD4+ T cells protect against influenza through multiple synergizing mechanisms.
Memory CD4+ T cells combat viral infection and contribute to protective immune responses through multiple mechanisms, but how these pathways interact is unclear. We found that several pathways involving memory CD4+ T cells act together to effectively clear influenza A virus (IAV) in otherwise unprimed mice. Memory CD4+ T cell protection was enhanced through synergy with naive B cells or CD8+ T cells and maximized when both were present. However, memory CD4+ T cells protected against lower viral doses independently of other lymphocytes through production of IFN-γ. Moreover, memory CD4+ T cells selected for epitope-specific viral escape mutants via a perforin-dependent pathway. By deconstructing protective immunity mediated by memory CD4+ T cells, we demonstrated that this population simultaneously acts through multiple pathways to provide a high level of protection that ensures eradication of rapidly mutating pathogens such as IAV. This redundancy indicates the need for reductionist approaches for delineating the individual mechanisms of protection mediated by memory CD4+ T cells responding to pathogens.


Empathic fear responses in mice are triggered by recognition of a shared experience.
Empathy is an important psychological capacity that involves the ability to recognize and share emotions with others. In humans, empathy for others is facilitated by having had a similar prior experience. It increases with the intensity of distress that observers believe is occurring to others, and is associated with acute emotional responses to witnessing others' distress. We sought to develop a relatively simple and fast mouse model of human empathy that resembled these characteristics. We modeled empathy by measuring the freezing of observer mice to observing the footshock of a subject mouse. Observer mice froze to subject footshocks only when they had a similar shock experience 24 hours earlier. Moreover, this freezing increased with the number of footshocks given to the subject and it was accentuated within seconds after footshock delivery. Freezing was not seen in naïve observers or in experienced observers that observed a subject who was spared footshock. Observers did not freeze to a subject's footshock when they had experienced a swim stress 24 hours prior, demonstrating a specific effect for shared experience, as opposed to a generalized stressor in eliciting observer mouse freezing. We propose that this two-day experimental protocol resembles many aspects of human empathy in a mouse model that is amenable to transgenic analysis of neural substrates for empathy and its impairment in certain clinical disorders.


Topology of the CD2-CD48 cell-adhesion molecule complex: implications for antigen recognition by T cells.
The T-lymphocyte cell-surface molecule, CD2, was the first heterophilic cell-adhesion molecule to be discovered and has become an important paradigm for understanding the structural basis of cell adhesion. Interaction of CD2 with its ligands. CD58 (in humans) and CD48 (in mice and rats), contributes to antigen recognition by T cells. CD2, CD48 and CD58 are closely related members of the immunoglobulin superfamily and their extracellular regions are predicted to have very similar structures. The three-dimensional crystal structure of this region of CD2 has been determined, revealing two immunoglobulin domains with the ligand-binding site situated on an exposed beta sheet in the membrane-distal domain. This GFCC'C" beta sheet is also involved in a homophilic 'head-to-head' interaction in the CD2 crystal lattice, which has been proposed to be a model for the interactions of CD2 with its ligands. We show that the CD2-binding site on rat CD48 lies on the equivalent beta-sheet of its membrane-distal immunoglobulin domain. By making complementary mutations, we have shown that two charged residues in the CD48 ligand-binding site interact directly with two oppositely charged residues in CD2's ligand-binding site. These results indicate that the amino-terminal immunoglobulin domains of CD2 and CD48 bind each other in the same orientation as the CD2-CD2 crystal lattice interaction, strongly supporting the suggestion that CD2 interacts head-to-head with its ligand. Modelling CD48 onto the CD2 structure reveals that the CD2-CD48 complex spans approximately the same distance (134 A) as predicted for the complex between the T-cell receptor and the peptide-bound major histocompatibility complex (MHC) molecule. Our results, together with recent structural studies of CD2, provide the first indication of the specific topology of a cell-adhesion molecule complex. The similar dimensions predicted for the CD2-CD48 complex and the complex between the T-cell receptor and the peptide-bound MHC molecule suggest that one of the functions of CD2 may be to position the plasma membranes of the T cell and the antigen-presenting (or target) cell at the optimal distance for the low-affinity interaction between the T-cell receptor and the peptide-bound MHC molecule.


Ceftaroline fosamil for community-acquired bacterial pneumonia and acute bacterial skin and skin structure infection.
Bacterial resistance is increasing on a global basis, making treatment options more limited. The development of new agents to meet this threat is a matter of urgency. Ceftaroline fosamil , a member of an advanced cephalosporin class of antimicrobials, is currently approved by the US Food and Drug Administration for use in for acute bacterial skin and skin structure infection (ABSSSI) and community-acquired bacterial pneumonia. Ceftaroline displays activity against Gram-positive and Gram-negative bacteria, including both methicillin-susceptible and resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae (including penicillin- and ceftriaxone-resistant strains), respiratory pathogens (such as Moraxella catarrhalis and Haemophilus influenzae, including beta-lactamase-producing strains) and limited coverage against Enterobacteriaceae. Chemistry, mechanism of action, spectrum of activity, resistance, pharmacokinetics/pharmacodynamics, indications for use, safety and special populations are covered in this review. Ceftaroline's unique activity against MRSA and penicillin- and ceftriaxone-resistant S. pneumoniae strains is due to its high affinity for penicillin binding protein (PBP)-2a and PBP-2x, respectively. In randomized, double-blinded, clinical trials, ceftaroline fosamil was found to be non-inferior to ceftriaxone for the treatment CABP and to vancomycin plus aztreonam for ABSSSI. Substantial differences between the cephalosporins exist. Ceftaroline has unique characteristics that may make it useful in specific clinical circumstances, especially against multi-drug-resistant Gram-positive organisms.


Establishing a clinical service for the management of sports-related concussions.
The clinical management of sports-related concussions is a specialized area of interest with a lack of empirical findings regarding best practice approaches. The University of Pittsburgh Medical Center Sports Concussion Program was the first of its kind; 13 years after its inception, it remains a leader in the clinical management and research of sports-related concussions. This article outlines the essential components of a successful clinical service for the management of sports-related concussions, using the University of Pittsburgh Medical Center Sports Concussion Program as a case example. Drawing on both empirical evidence and anecdotal conclusions from this high-volume clinical practice, this article provides a detailed account of the inner workings of a multidisciplinary concussion clinic with a comprehensive approach to the management of sports-related concussions. A detailed description of the evaluation process and an in-depth analysis of targeted clinical pathways and subtypes of sports-related concussions effectively set the stage for a comprehensive understanding of the assessment, treatment, and rehabilitation model used in Pittsburgh today.


Conformational control of the bacterial Clp protease by natural product antibiotics.
Covering: up to 2017The bacterial Clp protease is a highly conserved and structurally versatile machine. It has gained a lot of recognition during the last decade as a novel antibacterial drug target with an unprecedented mechanism of action. Due to its complexity, there are distinct means of interfering with its natural functions and several compounds targeting this machine have been identified. In this review, we summarize the current state of knowledge about natural products deregulating Clp proteolysis, a crucial and delicate process within the cell. Among those, acyldepsipeptide antibiotics of the ADEP class (ADEPs) are characterized best. The molecular mechanism of ADEP-mediated deregulation sheds light on the inner workings of the Clp protease.


Reconstructing recent human evolution.
The two most distinct models of recent human evolution, the multiregional and the recent African origin models, have different retrodictions concerning specific archaic-recent population relationships. The former model infers multiple regional archaic-modern connections and the ancient establishment of regional characteristics, whereas the latter model implies only an African archaic-all modern relationship, with recent (late Pleistocene) development of regionality. In this paper, four late archaic groups from Europe, southwest Asia, Africa and East Asia are compared with various fossil and recent Homo sapiens crania or cranial samples. The results of Penrose shape comparisons narrowly favour a late archaic African-modern special relationship over an East Asian-modern one, with European and southwest Asian Neanderthal groups much more distant. No specific archaic-recent regional relationships are indicated in the shape analyses, nor in separate examinations of patterns of regionality, which indicate a recent origin for present day regionality. The Skhul-Qafzeh sample provides an excellent shape intermediate between the archaic and recent samples.


Cellular and molecular mechanisms in chronic obstructive pulmonary disease: an overview.
In the last decade, the analysis of bronchial biopsies and lung parenchyma obtained from chronic obstructive pulmonary disease (COPD) patients compared with those from smokers with normal lung function and non-smokers has provided new insights on the role of the different inflammatory and structural cells, their signalling pathways and mediators, contributing to a better knowledge of the pathogenesis of COPD. This review summarizes and discusses the lung pathology of COPD patients with emphasis on inflammatory cell phenotypes that predominate in different clinical conditions. In bronchial biopsies, a cascade of events takes place during progression from mild-to-severe disease. T lymphocytes, particularly CD8+ cells and macrophages are the prevalent inflammatory cells in the lung of healthy smokers and patients with mild COPD, while total and activated neutrophils predominate in severe COPD. The number of CD4+, CD8+ cells and macrophages expressing nuclear factor-kappa B (NF-kappaB), STAT-4 and IFN-gamma proteins as well as endothelial adhesion molecule-1 in endothelium is increased in mild/moderate disease. In contrast, activated neutrophils (MPO+ cells) and increased nitrotyrosine immunoreactivity develops in severe COPD. In bronchial biopsies obtained during COPD exacerbations, some studies have shown an increased T cell and granulocyte infiltration. Regular treatment with high doses of inhaled glucocorticoids does not significantly change the number of inflammatory cells in bronchial biopsies from patients with moderate COPD. The profile in lung parenchyma is similar to bronchial biopsies. 'Healthy' smokers and mild/moderate diseased patients show increased T lymphocyte infiltration in the peripheral airways. Pulmonary emphysema is associated with a general increase of inflammatory cells in the alveolar septa. The molecular mechanisms driving the lymphocyte and neutrophilic prevalence in mild and severe disease, respectively, needs to be extensively studied. Up-regulation of pro-inflammatory transcription factors NF-kappaB and STAT-4 in mild, activated epithelial and endothelial cells in the more severe disease may contribute to this differential prevalence of infiltrating cells.


Harvey Cushing and early spinal dysraphism repair at Johns Hopkins Hospital.
As neurological surgery began developing into a surgical subspecialty in the US at the turn of the 20th century, with Harvey Cushing at the forefront, the operative treatment of spinal dysraphism was refined with attempts to minimize complications. Following institutional approval, and through the courtesy of the Alan Mason Chesney Archives, the authors reviewed the Johns Hopkins Hospital surgical files from 1896 to 1912. Patients presenting with spinal dysraphism who underwent surgical intervention by Dr. Harvey Cushing were selected for further analysis. Ten patients presented for surgical intervention for spinal dysraphism, and 7 of these had concurrent hydrocephalus. The mean age of these patients was 5.8 months (range 1-14 months). The mean length of stay was 20.4 days. There were 6 inpatient deaths. At the time of last follow-up, 2 patients were well, 1 patient remained unimproved, and 1 patient (for whom no discharge outcome was available) had died. The cases described in detail offer insight into the breadth of Cushing's practice and the varied approaches he employed. The use of Faradic stimulation to assess nerve root function, the use of complex multilayered closures, and the creation of operative tables for combined treatment of hydrocephalus and spinal dysraphism illustrate Cushing's contributions to developing the field of pediatric neurosurgery.


A prospective comparison of 18F-fluorodeoxyglucose positron emission tomography-computed tomography, magnetic resonance imaging and whole-body planar radiographs in the assessment of bone disease in newly diagnosed multiple myeloma.
Bone lesions in multiple myeloma (MM) have been traditionally detected by whole body X-ray (WBXR) survey although magnetic resonance imaging (MRI) has become the gold standard for detecting MM involvement of the spine and pelvis. The aim of this study was to compare a new technique, positron emission tomography (PET) with 18F fluorodeoxyglucose (FDG) integrated with computed tomography (18F-FDG PET-CT), with MRI and WBXR for baseline assessment of bone disease in MM. We prospectively compared 18F-FDG PET-CT, MRI of the spine-pelvis and WBXR in a series of 46 patients with newly diagnosed MM. In 23 patients who received up front autologous transplantation, we also compared post-treatment PET-CT scans with MR images of the spine and pelvis. Overall, PET-CT was superior to planar radiographs in 46% of patients, including 19% with negative WBXR. In 30% of patients, PET-CT scans of the spine and pelvis failed to show abnormal findings in areas in which MRI revealed an abnormal pattern of bone marrow involvement, more frequently of diffuse type. In contrast, in 35% of patients PET-CT enabled the detection of myelomatous lesions in areas which were out of the field of view of MRI. By combining MRI of the spine- pelvis and 18F-FDG PET-CT, the ability to detect sites of active MM, both medullary and extramedullary, was as high as 92%. Following transplantation, 15 patients had negative PET-CT scans (including 13 with a very good partial response or at least a near complete response), but only 8 had normal MRI. MRI of the spine and pelvis still remains the gold standard imaging technique for the detection of bone marrow involvement in MM. 18F-FDG PET-CT provides additional and valuable information for the assessment of myeloma bone disease in areas not covered by MRI.


Effect of phage infection on toxin production by Clostridium difficile.
Infection with Clostridium difficile and subsequent production of toxins A and B may result in C. difficile-associated diarrhoea and pseudomembranous colitis in hospital patients. The effect of four temperate phages, obtained by induction of clinical C. difficile isolates, on toxin production by C. difficile was determined. None of these phages converted a lysogenized non-toxigenic C. difficile strain to toxin production. One of the accessory toxin genes, tcdE, was detected in three phages, phiC2, phiC6 and phiC8; however, the non-repeating regions of tcdA and tcdB encoding the enzymic domains were not carried on phage DNA. Phage infection of toxigenic strains increased toxin B production in four of six lysogens, although the level of tcdB transcription as determined by real-time RT-PCR was not significantly altered. However, levels of toxin A transcription in two lysogens were significantly altered without any corresponding differences in toxin A production.


Association between polymorphisms at the human IL-10 locus and systemic lupus erythematosus.
Recent studies have shown elevated IL-10 levels in several rheumatic autoimmune diseases, and particularly in systemic lupus erythematosus (SLE). Such changes may have a genetic basis. We studied two novel polymorphic dinucleotide repeats in the IL-10 promoter region (IL10.G and IL10.R) in order to investigate their possible significance in association with this condition in a group of 56 Caucasian SLE patients compared with 102 ethnically matched controls. The results show that there is an allelic imbalance between SLE patients and controls at the IL10.G microsatellite; this observation is supported by a significant difference in genotype distribution. The nature of autoantibody production and the presence or absence of renal involvement also appeared to be associated with certain IL10.G microsatellite alleles, although the small size of individual clinical sub-groupings may have influenced this result. No association with the IL10.R microsatellite was observed. Overall, the differences observed at the IL10.G microsatellite between SLE patients and controls suggest that the IL-10 locus contributes to the genetic background important for the development of this disease. Although the moderate sample size described in this study requires that the results be interpreted carefully, they provide an interesting and useful framework for future study.


Recommendations for rescue of a submerged unresponsive compressed-gas diver.
The Diving Committee of the Undersea and Hyperbaric Medical Society has reviewed available evidence in relation to the medical aspects of rescuing a submerged unresponsive compressed-gas diver. The rescue process has been subdivided into three phases, and relevant questions have been addressed as follows. Phase 1, preparation for ascent: If the regulator is out of the mouth, should it be replaced? If the diver is in the tonic or clonic phase of a seizure, should the ascent be delayed until the clonic phase has subsided? Are there any special considerations for rescuing rebreather divers? Phase 2, retrieval to the surface: What is a "safe" ascent rate? If the rescuer has a decompression obligation, should they take the victim to the surface? If the regulator is in the mouth and the victim is breathing, does this change the ascent procedures? If the regulator is in the mouth, the victim is breathing, and the victim has a decompression obligation, does this change the ascent procedures? Is it necessary to hold the victim's head in a particular position? Is it necessary to press on the victim's chest to ensure exhalation? Are there any special considerations for rescuing rebreather divers? Phase 3, procedure at the surface: Is it possible to make an assessment of breathing in the water? Can effective rescue breaths be delivered in the water? What is the likelihood of persistent circulation after respiratory arrest? Does the recent advocacy for "compression-only resuscitation" suggest that rescue breaths should not be administered to a non-breathing diver? What rules should guide the relative priority of in-water rescue breaths over accessing surface support where definitive CPR can be started? A "best practice" decision tree for submerged diver rescue has been proposed.