The Effect of Mobile eHealth Education to Improve Knowledge, Skills, Self-Care, and Mobile eHealth Literacies Among Patients With Diabetes: Development and Evaluation Study.
The promotion of mobile health (mHealth) and eHealth technologies as tools for managing chronic diseases, particularly diabetes mellitus, is on the rise. Nevertheless, individuals with diabetes frequently face a literacy gap that hinders their ability to fully leverage the benefits offered by these resources. Enhancing technology literacy to facilitate the adoption of mobile eHealth services poses a significant challenge in numerous countries. This study aims to develop an educational mobile eHealth literacy (eHL) program for patients with diabetes and to evaluate its effect on patients' outcomes. This study designed a mobile eHL education program comprising 2 modules specifically tailored for individuals with type 2 diabetes (T2D). These modules focused on guiding participants through the process of effectively navigating reliable health websites and utilizing diabetes-related apps. Using a pre- and posttest experimental design, the study featured an intervention group and a control group. Participants were recruited from 3 outpatient departments in hospitals, and assessments were conducted both before and after the intervention, along with a follow-up measure at the 3-month mark. The evaluation encompassed sociodemographic characteristics, computer and internet proficiency, mobile app usage, mobile eHL, and patient outcomes such as self-care behaviors and glycated hemoglobin (HbA1c) levels. The analysis included a total of 132 eligible participants. Significant differences were observed in the mean scores of knowledge (P<.001) and skills (P<.001) related to computers, the web, and mobile devices at the initiation of the study and after the intervention. During the 3-month follow-up, the findings indicated a significant improvement in mobile eHL (t114=3.391, P=.001) and mHealth literacy (mHL, a subconcept of mobile eHL; t114=3.801, P<.001) within the intervention group, whereas no such improvement was observed in the control group. The chi-square values from the McNemar test underscored that individuals with uncontrolled diabetes (HbA1c≥7%) in the intervention group exhibited more improvement compared with the control group. The generalized estimating equations model unveiled a significant difference in the change of general mHL in the intervention group (β=1.91, P=.047) and self-care behavior in the control group from T0 to T2 (β=-8.21, P=.015). Despite being small, the effect sizes for mobile eHL (d=0.49) and HbA1c (d=0.33) in the intervention group were greater than those in the control group (d=0.14 and d=0.16, respectively). The implementation of a mobile eHL education intervention demonstrates a positive influence on the familiarity of patients with T2D regarding health technology, leading to favorable glycemic outcomes. While additional studies are warranted for a more comprehensive understanding, this program emerges as a promising solution for enhancing patients' uptake of digital health technology.


Therapeutic potential of vitamin D for multiple sclerosis.
Multiple sclerosis (MS) is a major inflammatory and demyelinating disease of the central nervous system and has an increasing prevalence in populations residing at higher latitudes. This observation may indicate a protective effect of sunlight exposure, which is reduced at higher latitudes and may contribute to insufficient levels of vitamin D in the MS population. The vitamin D hormone is important for bone metabolism and can regulate cell proliferation and differentiation as well as apoptosis and immune regulation in immune cells such as T helper cells and dendritic cells. Evidence from experimental autoimmune encephalomyelitis and prospective studies on MS suggests an important role of vitamin D as a modifiable environmental factor in MS. These provide guidance for future studies with regard to the potential role of vitamin D in the prevention and/or treatment of MS. Here, we first review the metabolism and immune functions of vitamin D. Then, we describe the current thinking on the etiology of vitamin D in MS and the accumulating evidence pointing to a link between vitamin D and MS. Further, we describe how genetic susceptibility interacts with environmental risk factors at the population level, MS-associated risk factors, and genetic studies related to the vitamin D receptor. This review also discusses the therapeutic potential of vitamin D for treating MS.


Validation of diagnoses of distress disorders in the US National Comorbidity Survey Replication Adolescent Supplement (NCS-A).
Research diagnostic interviews need to discriminate between closely related disorders in order to allow comorbidity among mental disorders to be studied reliably. Yet conventional studies of diagnostic validity generally focus on single disorders and do not examine discriminant validity. The current study examines the validity of fully-structured diagnoses of closely-related distress disorders (generalized anxiety disorder, post-traumatic stress disorder, major depressive episode, and dysthymic disorder) in the lay-administered Composite International Diagnostic Interview Version 3.0 (CIDI) with independent clinical diagnoses based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) in the US National Comorbidity Survey Replication Adolescent Supplement (NCS-A). The NCS-A is a national survey of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) among 10,148 adolescents. A probability sub-sample of 347 of these adolescents and their parents were administered blinded follow-up K-SADS interviews. Good concordance [area under the receiver operating characteristic curve (AUC)] was found between diagnoses based on the CIDI and the K-SADS for generalized anxiety disorder (AUC = 0.78), post-traumatic stress disorder (AUC = 0.79), and major depressive episode/dysthymic disorder (AUC = 0.86). Further, the CIDI was able to effectively discriminate among different types of distress disorders in the sub-sample of respondents with any distress disorder.


Narrow band green light effects on headache, photophobia, sleep, and anxiety among migraine patients: an open-label study conducted online using daily headache diary.
Narrow band green light (NbGL) has been shown to relieve headache in small numbers of subjects but large-scale real-world assessments are lacking. The goal of this prospective, observational, open-label, real world study was to determine whether treatment with NbGL during the ictal phase of migraine, improves patients' perception of their headache, photophobia, anxiety and same-night sleep. The study was conducted in purchasers of the NbGL Lamp in two phases. In Phase I purchasers of the Lamp completed a survey and were asked to participate in a 6-week diary study. In Phase 2 participants completed daily diaries for 6 weeks. Specifically, they were asked to use their judgement/impression/perception when choosing between headache-improved or headache-unimproved after using the NbGL during acute attacks. Diary outcomes of interest included rates of attacks improve in responders (≥50%), non-responders (<50%), super-responders (≥75%), and super non-responders (<30%). Of 3,875 purchasers of the Lamp for migraine, 698 (18%) agreed to participate, filled out a pre-study survey, and agreed to a 6-week daily headache diary. Complete data were provided by 181 (26%) participants. Using criteria above, 61, 39, 42, and 27% of participants were classified responder, non-responder, super-responder and super non-responder, respectively. Headache improved in 55% of all 3,232 attacks, in 82% of the 1,803 attacks treated by responders, and in 21% of the 1,429 attacks treated by non-responders. Photophobia improved in 53% of all attacks, 68% of the attacks in responders and in 35% of the attacks in non-responders. Anxiety improved in 34% of all attacks, 46% of the responders' attacks, and 18% of the non-responders' attacks. Sleep improved in 49% of all attacks, 59% of the responders' attacks, and 36% of the non-responders' attacks. This open-label real world study suggests that 2 h of treatment with the lamp during migraine attacks is associated with relief of pain and photophobia, reduction in anxiety, and improved sleep. The absence of rigorous diagnosis and a blinded contemporaneous control group limits the rigor of this interpretation. Improvement in photophobia, anxiety and sleep among the responders may be secondary to the improvement in the headache itself. ClinicalTrial.gov (NCT04841083).


Quercetin negatively regulates TLR4 signaling induced by lipopolysaccharide through Tollip expression.
Polyphenolic compounds have been regarded as one of the most promising dietary agents for the prevention and treatment of inflammation-related chronic diseases; however, the anti-inflammatory activities of flavonoids, such as quercetin, are not completely characterized, and many features remain to be elucidated. In this study, we showed the molecular basis for the downregulation of TLR4 signal transduction by quercetin. Quercetin markedly elevated the expression of the Toll-interacting protein, a negative regulator of TLR signaling. Lipopolysaccharide-induced expression of cell surface molecules (CD80, CD86, and MHC class I/II) and production of pro-inflammatory cytokines (tumor necrosis factor-α, IL-1β, IL-6, and IL-12p70) were inhibited by quercetin, and this action was prevented by Toll-interacting protein silencing. In addition, quercetin-treated macrophages inhibited lipopolysaccharide-induced activation of mitogen-activated protein kinases, such as extracellular signal-regulated kinase 1/2, p38, and c-Jun N-terminal kinase, and the translocation of nuclear factor-κB and p65 through Toll-interacting protein. Treatment with quercetin resulted in a significant decrease in prostaglandin E2 and cyclooxygenase-2 levels as well as inducible nitric oxide synthase-mediated nitric oxide production induced by lipopolysaccharide. Taken together, these findings represent new insights into the understanding of negative regulatory mechanisms of the TLR4 signaling pathway and effective therapeutic intervention for the treatment of inflammatory disease.


Clinical Case-Based Image Portfolios in Medical Histopathology.
This descriptive article describes the use of clinical case-based portfolios in histopathology teaching laboratories in conjunction with virtual microscopy not only to integrate histology and pathology disciplines for first and second year medical students but also to stimulate student engagement, promote self-directed and group-based learning and enhance student-to-student interaction in a structured manner. Portfolios consisted of PowerPoint files encompassing four to five clinical case studies relevant to the topics covered that week. Portfolios integrated study materials provided in the module-specific lectures, clinical skill lectures, and online interactive content. Two sets of portfolios, Individual and Group, were used. Individual Portfolios were completed by each student and uploaded prior to the laboratory session. Group Portfolios were completed by students working together in small groups during the laboratory session with minimal faculty assistance. The functional utility and acceptance of Individual and Group Portfolios among first- and second-year medical students was evaluated using electronic surveys and examination performances. Both first- and second-year students agreed that the use of portfolios in conjunction with virtual microscopy promoted understanding and encouraged discussion of the topics covered during the week and that group members worked well together and contributed to the completion of the portfolios. Performances on the Histology and Cell Biology and Pathology sections on the United States Medical Licensing Examination® (USMLE® ) remained consistent and in line with national averages. Overall, use of portfolios promoted peer teaching and contributed towards successful transition to the new system-based integrated curriculum with continued strong performance on the USMLE.


Biomedical information, peer review, and conflict of interest as they influence public health.
The peer review process serves a vital role in the publication of biomedical information. When properly functioning, review should focus exclusively on questions of scientific validity and should avoid becoming enmeshed in questions such as "authorization" and "data ownership." We present a case in which the dissenting views of a coinvestigator were suppressed because the principal investigator and grantee institution informed a medical journal that the coinvestigator was not "authorized" to use the data generated by a publicly funded grant and because the editor of a scholarly journal refused to review the dissenting manuscript and to submit that dissent to external reviewers for peer review. The current peer review system, as shown by this case, is unable to embrace dissent within the peer review process and to use dissent to serve scientific truth and the public interest.


Plasmon resonant cavities in vertical nanowire arrays.
We investigate tunable plasmon resonant cavity arrays in paired parallel nanowire waveguides. Resonances are observed when the waveguide length is an odd multiple of quarter plasmon wavelengths, consistent with boundary conditions of node and antinode at the ends. Two nanowire waveguides satisfy the dispersion relation of a planar metal-dielectric-metal waveguide of equivalent width equal to the square field average weighted gap. Confinement factors over 10(3) are possible due to plasmon focusing in the interwire space.


Efficacy of Humanized Cefiderocol Exposure Is Unaltered by Host Iron Overload in the Thigh Infection Model.
Cefiderocol is a siderophore-cephalosporin conjugate with greater in vitro potency under iron-depleted conditions. During infection, iron is scarce in host tissue; however, it is not known whether iron overload in the host, such as in cases of hereditary hemochromatosis, alters the efficacy of cefiderocol. We compared cefiderocol efficacy between iron-overloaded and standard murine thigh infection models. Female CD-1 mice rendered neutropenic received 2 weeks of iron dextran at 100 mg/kg of body weight/day intraperitoneally (iron-overloaded model) or no injections (standard model). Mice were inoculated (107 CFU/ml) with Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa with previously determined cefiderocol MICs from 0.25 to 64 mg/liter. Human-simulated regimens of cefiderocol or meropenem (2 g every 8 h [q8h], 3-h infusion) were administered for 24 h (31 strains) or 72 h (15 strains; cefiderocol only). Procedures were simultaneously performed in standard and iron-overloaded models. Mean bacterial burdens (log10 CFU/thigh) at baseline were 5.75 ± 0.47 versus 5.81 ± 0.51 in standard versus iron-overloaded models, respectively. At 24 h, mean burdens in standard versus iron-overloaded models decreased by -0.8 ± 1.9 versus -1.2 ± 2.0 (P = 0.25) in meropenem-treated mice and by -1.5 ± 1.4 versus -1.6 ± 1.5 (P = 0.54) in cefiderocol-treated mice. At 72 h, mean burdens in cefiderocol-treated mice decreased by -2.5 ± 1.5 versus -2.5 ± 1.4. No overall differences in efficacy between the models were observed for meropenem or cefiderocol. Human-simulated exposure of cefiderocol is equally efficacious in iron-overloaded and normal hosts. The potential clinical use of cefiderocol to treat Gram-negative infections in patients with iron overload is supported.


Intensive therapy and autotransplant for patients with an incomplete response to front-line therapy for lymphoma.
Patients with Hodgkin's disease (HD) and intermediate or high-grade non-Hodgkin's lymphoma (NHL) who fail to achieve a complete remission (CR) with standard induction therapy have a poor prognosis with conventional-dose salvage therapy alone. We examined the role of subsequent intensive therapy and autologous bone marrow transplantation (ABMT) in patients who demonstrated a response to conventional-dose therapy. Sixty-six patients with either HD (n = 30) or NHL (n = 36) underwent intensive therapy with etoposide (60 mg/kg), intravenous melphalan (160-180 mg/m2) followed by infusion of unpurged autologous bone marrow and/or blood cells. All patients had advanced stage or bulky disease at diagnosis and failed to achieve a CR after an anthracycline-containing front-line chemotherapy regimen (NHL) or ABVD or equivalent regimen (HD). Patients who achieved a CR after involved-field radiotherapy were excluded. All patients demonstrated sensitivity to conventional-dose salvage treatment before advancing to intensive therapy and ABMT. The CR, partial response (PR) and overall response rate (RR) following ABMT for HD patients was 48%, 17% and 65%, respectively. At a median follow-up of 35 months, the predicted three-year overall survival (OS) is 51% (95% CI: 44%-60%) and event-free survival (EFS) is 34% (95% CI: 26%-54%). For patients with NHL, the CR, PR and RR were 68%, 9% and 77%, respectively. At a median follow-up of 28 months, the predicted three-year OS is 51% (95% CI: 35%-66%) and EFS is 39% (95% CI: 21%-57%). Intensive therapy with etoposide and melphalan followed by ABMT results in prolonged survival in selected patients with lymphoma who fail to achieve a complete remission to front-line chemotherapy. Based on our previous studies of outcome to conventional-dose salvage chemotherapy, we estimate that of all patients failing induction therapy, 28% with HD and 15% with NHL will be event-free at three years after ABMT.


Physical properties of current dental nanohybrid and nanofill light-cured resin composites.
The purpose of this work was the detailed study of sorption characteristics of water or artificial saliva, the determination of flexural strength and the flexural modulus, and the study of the thermal stability of some current commercial dental light-cured nanocomposites containing nano-sized filler particles. Three nanohydrid dental composites (Tetric EvoCeram (TEC), Grandio (GR) and Protofill-nano (PR)) and two nanofill composites (Filtek Supreme Body (FSB) and the Filtek Supreme Translucent (FST)) were used in this work. The volumetric shrinkage due to polymerization was first determined. Also the sorption, solubility and volumetric increase were measured after storage of composites in water or artificial saliva for 30 days. The flexural strength and flexural modulus were measured using a three-point bending set-up according to the ISO-4049 specification, after immersion of samples in water or artificial saliva for 1 day or 30 days. Thermal analysis technique TGA method was used to investigate the thermal stability of composites. GR and TEC composites showed statistically no difference in volumetric shrinkage (%) which is lower than the other composites, which follow the order PR<FSB<FST. The amount of sorbed water and solubility is not statistically different than those in artificial saliva. In all the composites studied the amount of water, which is sorbed (% on composite) is not statistically different than the amount of water, which is desorbed and follows the order: GR<TEC<PR<FSB<FST. After immersion in water for 1 day the highest flexural strength showed the FSB and the lowest TEC. GR, PR and FST showed no statistically different flexural strength. The flexural modulus of composites after immersion for one day follows the order TEC<PR≤FST<FSB<GR. Among the composites studied, Grandio had the lowest polymer matrix content, consisting mainly of Bis-GMA. It showed the lowest polymerization shrinkage and water sorption and the highest flexural strength and flexural modulus after immersion in water or artificial saliva for 30 days. The water and artificial saliva generally showed the same effect on physical properties of the studied composites. Thermogravimetric analysis gave good information about the structure and the amount of organic polymer matrix of composites.


Noninvasive imaging of skin tumors.
In this article, the authors review different approaches to the diagnosis of skin tumors using noninvasive diagnostic tools, which are becoming increasingly reliable and, as a consequence, increasingly popular among physicians and patients. Especially in the realm of pigmented skin lesions, dermoscopy and sonography may add useful information to the clinical constellation, improving the diagnostic performance for early diagnosis of melanoma and for differentiating various melanocytic and nonmelanocytic pigmented lesions. More recently, confocal scanning laser microscopy was introduced as a novel technique that enables the in vivo study of the skin at a nearly histologic resolution, being of diagnostic value in various skin disorders, including basal cell carcinoma and pigmented skin lesions. These modalities have various other potential applications besides diagnosis, including lesion's selection for biopsy, determination of appropriate therapeutic modalities, verification of treatment efficacy, and decision of surgical margins. Finally, a hint to the use of cytodiagnosis for basal cell carcinoma is provided.


Optimizing Oleaginous Yeast Cell Factories for Flavonoids and Hydroxylated Flavonoids Biosynthesis.
Plants possess myriads of secondary metabolites with a broad spectrum of health-promoting benefits. To date, plant extraction is still the primary route to produce high-value natural products which inherently suffers from economics and scalability issues. Heterologous expression of plant biosynthetic gene clusters in microbial host is considered as a feasible approach to overcoming these limitations. Oleaginous yeast produces a large amount of lipid bodies, the abundant membrane structure and the lipophilic environment provide the ideal environment for the regioselectivity and stereoselectivity of many plant-derived P450 enzymes. In this work, we used modular method to construct, characterize, and optimize the flavonoid pathways in Yarrowia lipolytica. We also evaluated various precursor biosynthetic routes and unleashed the metabolic potential of Y. lipolytica to produce flavonoids and hydroxylated flavonoids. Specifically, we have identified that chalcone synthase (CHS) and cytochrome P450 reductases (CPR) were the bottlenecks of hydroxylated flavonoid production. We determined the optimal gene copy number of CHS and CPR to be 5 and 2, respectively. We further removed precursor pathway limitations by expressing genes associated with chorismate and malonyl-CoA supply. With pH and carbon-nitrogen ratio (C/N) optimization, our engineered strain produced 252.4 mg/L naringenin, 134.2 mg/L eriodictyol, and 110.5 mg/L taxifolin from glucose in shake flasks. Flavonoid and its hydroxylated derivatives are most prominently known as antioxidant and antiaging agents. These findings demonstrate our ability to harness the oleaginous yeast as the microbial workhorse to expand nature's biosynthetic potential, enabling us to bridge the gap between drug discovery and natural product manufacturing.


Far-space neglect in conjunction but not feature search following transcranial magnetic stimulation over right posterior parietal cortex.
Near- and far-space coding in the human brain is a dynamic process. Areas in dorsal, as well as ventral visual association cortex, including right posterior parietal cortex (rPPC), right frontal eye field (rFEF), and right ventral occipital cortex (rVO), have been shown to be important in visuospatial processing, but the involvement of these areas when the information is in near or far space remains unclear. There is a need for investigations of these representations to help explain the pathophysiology of hemispatial neglect, and the role of near and far space is crucial to this. We used a conjunction visual search task using an elliptical array to investigate the effects of transcranial magnetic stimulation delivered over rFEF, rPPC, and rVO on the processing of targets in near and far space and at a range of horizontal eccentricities. As in previous studies, we found that rVO was involved in far-space search, and rFEF was involved regardless of the distance to the array. It was found that rPPC was involved in search only in far space, with a neglect-like effect when the target was located in the most eccentric locations. No effects were seen for any site for a feature search task. As the search arrays had higher predictability with respect to target location than is often the case, these data may form a basis for clarifying both the role of PPC in visual search and its contribution to neglect, as well as the importance of near and far space in these.


Lignin-first biomass fractionation using a hybrid organosolv - Steam explosion pretreatment technology improves the saccharification and fermentability of spruce biomass.
For a transition to a sustainable society, fuels, chemicals, and materials should be produced from renewable resources. Lignocellulosic biomass constitutes an abundant and renewable feedstock; however, its successful application in a biorefinery requires efficient fractionation into its components; cellulose, hemicellulose and lignin. Here, we demonstrate that a newly established hybrid organosolv - steam explosion pretreatment can effectively fractionate spruce biomass to yield pretreated solids with high cellulose (72% w/w) and low lignin (delignification up to 79.4% w/w) content. The cellulose-rich pretreated solids present high saccharification yields (up to 61% w/w) making them ideal for subsequent bioconversion processes. Moreover, under high-gravity conditions (22% w/w) we obtained an ethanol titer of 61.7 g/L, the highest so far reported for spruce biomass. Finally, the obtained high-purity lignin is suitable for various advanced applications. In conclusion, hybrid organosolv pretreatment could offer a closed-loop biorefinery while simultaneously adding value to all biomass components.


Head and Neck Cancer in World Trade Center Responders: A Case Series.
The aim of this study was to report on cases of head and neck cancer (HNC) among World Trade Center (WTC) responders participating in the WTC Health Program and seen at Rutgers WTC Center of Clinical Excellence. Medical records were abstracted by two clinical reviewers and discrepancies resolved. Cases were defined as WTC responders diagnosed with HNC between December 9, 2005, and December 31, 2016. Sixteen HNC patients met the case definition, most (13) arrived at the WTC location on 9/11 or within the following 2 days, and half worked in law enforcement during the 9/1 response. An association between HNC and WTC exposure is biologically plausible and should be further investigated. Research to enumerate the risk factor profile for these cancers may contribute to understanding mechanisms by which WTC exposure can contribute to carcinogenesis and to prevention and early detection strategies.


Selkirk Rex: morphological and genetic characterization of a new cat breed.
Rexoid, curly hair mutations have been selected to develop new domestic cat breeds. The Selkirk Rex is the most recently established curly-coated cat breed originating from a spontaneous mutation that was discovered in the United States in 1987. Unlike the earlier and well-established Cornish and Devon Rex breeds with curly-coat mutations, the Selkirk Rex mutation is suggested as autosomal dominant and has a different curl phenotype. This study provides a genetic analysis of the Selkirk Rex breed. An informal segregation analysis of genetically proven matings supported an autosomal, incomplete dominant expression of the curly trait in the Selkirk Rex. Homozygous curl cats can be distinguished from heterozygous cats by head and body type, as well as the presentation of the hair curl. Bayesian clustering of short tandem repeat (STR) genotypes from 31 cats that represent the future breeding stock supported the close relationship of the Selkirk Rex to the British Shorthair, Scottish Fold, Persian, and Exotic Shorthair, suggesting the Selkirk as part of the Persian breed family. The high heterozygosity of 0.630 and the low mean inbreeding coefficient of 0.057 suggest that Selkirk Rex has a diverse genetic foundation. A new locus for Selkirk autosomal dominant Rex, SADRE, is suggested for the curly trait.


Hybrid Multimaterial 3D Printing Using Photocuring-While-Dispensing.
Three-dimensional (3D) printing methods, such as vat photopolymerization (VPP) and direct-ink-writing (DIW) processes, are known for their high-resolution and multimaterial capabilities, respectively. Here a novel hybrid 3D printing technique that combines the strengths of VPP and DIW processes to achieve multimaterial and high-resolution printing of functional structures and devices, is presented. The method involves dispensing liquid-like materials via syringes into a photocurable matrix material and subsequently using a Galvano mirror-controlled laser beam to selectively photocure the dispensed material trace or the matrix material surrounding the trace. The laser beam scanning and syringe dispensing are synchronized with a set delay to control liquid diffusion and in situ fixture. The versatility of the method is demonstrated by fabricating intricate 3D ant and wheel prototypes using various materials available for VPP and DIW technologies. The proposed photocuring-while-dispensing strategy offers advantages over conventional multimaterial 3D printing methods, such as integrating materials regardless of photocurability and viscosity, and fabricating heterogeneous structures with complex geometries and high resolution. With its principle demonstrated, this multimaterial 3D printing process will open up a wide range of potential applications with diverse functionalities and materials.


Transcranial Doppler sonography for detecting stenosis or occlusion of intracranial arteries in people with acute ischaemic stroke.
An occlusion or stenosis of intracranial large arteries can be detected in the acute phase of ischaemic stroke in about 42% of patients. The approved therapies for acute ischaemic stroke are thrombolysis with intravenous recombinant tissue plasminogen activator (rt-PA), and mechanical thrombectomy; both aim to recanalise an occluded intracranial artery. The reference standard for the diagnosis of intracranial stenosis and occlusion is intra-arterial angiography (IA) and, recently, computed tomography angiography (CTA) and magnetic resonance angiography (MRA), or contrast-enhanced MRA. Transcranial Doppler (TCD) and transcranial colour Doppler (TCCD) are useful, rapid, noninvasive tools for the assessment of intracranial large arteries pathology. Due to the current lack of consensus regarding the use of TCD and TCCD in clinical practice, we systematically reviewed the literature for studies assessing the diagnostic accuracy of these techniques compared with intra-arterial IA, CTA, and MRA for the detection of intracranial stenosis and occlusion in people presenting with symptoms of ischaemic stroke. To assess the diagnostic accuracy of TCD and TCCD for detecting stenosis and occlusion of intracranial large arteries in people with acute ischaemic stroke. We limited our searches from January 1982 onwards as the transcranial Doppler technique was only introduced into clinical practice in the 1980s. We searched MEDLINE (Ovid) (from 1982 to 2018); Embase (Ovid) (from 1982 to 2018); Database of Abstracts of Reviews of Effects (DARE); and Health Technology Assessment Database (HTA) (from 1982 to 2018). Moreover, we perused the reference lists of all retrieved articles and of previously published relevant review articles, handsearched relevant conference proceedings, searched relevant websites, and contacted experts in the field. We included all studies comparing TCD or TCCD (index tests) with IA, CTA, MRA, or contrast-enhanced MRA (reference standards) in people with acute ischaemic stroke, where all participants underwent both the index test and the reference standard within 24 hours of symptom onset. We included prospective cohort studies and randomised studies of test comparisons. We also considered retrospective studies eligible for inclusion where the original population sample was recruited prospectively but the results were analysed retrospectively. At least two review authors independently screened the titles and abstracts identified by the search strategies, applied the inclusion criteria, extracted data, assessed methodological quality (using QUADAS-2), and investigated heterogeneity. We contacted study authors for missing data. A comprehensive search of major relevant electronic databases (MEDLINE and Embase) from 1982 to 13 March 2018 yielded 13,534 articles, of which nine were deemed eligible for inclusion. The studies included a total of 493 participants. The mean age of included participants was 64.2 years (range 55.8 to 69.9 years). The proportion of men and women was similar across studies. Six studies recruited participants in Europe, one in south America, one in China, and one in Egypt. Risk of bias was high for participant selection but low for flow, timing, index and reference standard. The summary sensitivity and specificity estimates for TCD and TCCD were 95% (95% CI = 0.83 to 0.99) and 95% (95% CI = 0.90 to 0.98), respectively. Considering a prevalence of stenosis or occlusion of 42% (as reported in the literature), for every 1000 people who receive a TCD or TCCD test, stenosis or occlusion will be missed in 21 people (95% CI = 4 to 71) and 29 (95% CI = 12 to 58) will be wrongly diagnosed as harbouring an intracranial occlusion. However, there was substantial heterogeneity between studies, which was no longer evident when only occlusion of the MCA was considered, or when the analysis was limited to participants investigated within six hours. The performance of either TCD or TCCD in ruling in and ruling out a MCA occlusion was good. Limitations of this review were the small number of identified studies and the lack of data on the use of ultrasound contrast medium. This review provides evidence that TCD or TCCD, administered by professionals with adequate experience and skills, can provide useful diagnostic information for detecting stenosis or occlusion of intracranial vessels in people with acute ischaemic stroke, or guide the request for more invasive vascular neuroimaging, especially where CT or MR-based vascular imaging are not immediately available. More studies are needed to confirm or refute the results of this review in a larger sample of stroke patients, to verify the role of contrast medium and to evaluate the clinical advantage of the use of ultrasound.


Error-corrected next generation sequencing - Promises and challenges for genotoxicity and cancer risk assessment.
Error-corrected Next Generation Sequencing (ecNGS) is rapidly emerging as a valuable, highly sensitive and accurate method for detecting and characterizing mutations in any cell type, tissue or organism from which DNA can be isolated. Recent mutagenicity and carcinogenicity studies have used ecNGS to quantify drug-/chemical-induced mutations and mutational spectra associated with cancer risk. ecNGS has potential applications in genotoxicity assessment as a new readout for traditional models, for mutagenesis studies in 3D organotypic cultures, and for detecting off-target effects of gene editing tools. Additionally, early data suggest that ecNGS can measure clonal expansion of mutations as a mechanism-agnostic early marker of carcinogenic potential and can evaluate mutational load directly in human biomonitoring studies. In this review, we discuss promising applications, challenges, limitations, and key data initiatives needed to enable regulatory testing and adoption of ecNGS - including for advancing safety assessment, augmenting weight-of-evidence for mutagenicity and carcinogenicity mechanisms, identifying early biomarkers of cancer risk, and managing human health risk from chemical exposures.


Does Illness Perception Predict Posttraumatic Stress Disorder in Patients with Myocardial Infarction?
Myocardial infarction (MI) as a life-threatening event, carrying high risk of recurrence and chronic disabling complications, increases the risk of developing acute stress disorder (ASD), posttraumatic stress disorder (PTSD), or both. The aim of this study was to investigate the relationship between illness perceptions and having ASD, PTSD, or both in patients after MI. Seventy-six patients diagnosed with acute MI were enrolled into our prospective study. We evaluated patients during the first week and six months after MI. Patients were assessed by using the Clinician Administered PTSD Scale (CAPS), the Hamilton Depression Rating Scale (HDRS), the Hamilton Anxiety Rating Scale (HARS), the Brief Illness Perception Questionnaire (BIPQ), and a semi-structured interview for socio-demographic characteristics during both the first and second evaluations. Acute stress disorder (ASD) developed in 9.2% of patients and PTSD developed in 11.9% of patients with MI. Illness perception factors of 'consequences, identity and concern' predicted the occurrence of both ASD and PTSD, whereas 'emotion' predicted only PTSD. The factors of illness perceptions predicted the induction of ASD and PTSD in patients who had acute MI.


'Ugly and smelly or useful insect hunters?' Perceptions of and attitudes towards bats in the turn of the twentieth-century public sphere in Barcelona.
In recent years, historians and sociologists of science have shown how turn of the century natural history research and its public communication in Barcelona was intrinsically attached to certain political orientations and the historical context. Likewise, the way society perceived bats and promoted their ecological services has been increasingly researched by the community of bat researchers. In this article, I describe attitudes towards and perceptions of bats in the 'public sphere' of Barcelona in that period and examine them using public communication of science and history of science analytical tools. I performed an exhaustive search of the available newspaper and magazine articles using the Catalan and Spanish words for 'bat' in the online search engines of the national Catalan and Spanish libraries from 1888 to 1929. I compiled and reviewed a wide range of periodicals, covering different political orientations and representing several different types of publication. The articles were classified into four different categories. First, bats were commonly used as a symbol to represent the city and right-wing, conservative politics. Second, bats were often linked to negative adjectives that portrayed them as ugly, disgusting or diabolic. Third, many articles made an active effort to stop children chasing and killing bats. And fourth, I also identified a non-organised group of popularisers across the whole media spectrum who promoted what we call today the ecological services provided by bats, and especially their role as agricultural pest controllers. This study provides a better understanding of science popularisation, and specifically, perceptions of and attitudes towards bats during the studied period. This approach illustrates how historical accounts can be used today to improve perceptions of bats and suggest a more complex context of science popularisation.


Out-of-hospital cardiac arrest and ambient air pollution: A dose-effect relationship and an association with OHCA incidence.
Pollution has been suggested as a precipitating factor for cardiovascular diseases. However, data about the link between air pollution and the risk of out-of-hospital cardiac arrest (OHCA) are limited and controversial. By collecting data both in the OHCA registry and in the database of the regional agency for environmental protection (ARPA) of the Lombardy region, all medical OHCAs and the mean daily concentration of pollutants including fine particulate matter (PM10, PM2.5), benzene (C6H6), carbon monoxide (CO), nitrogen dioxide (NO2), sulphur dioxide (SO2), and ozone (O3) were considered from January 1st to December 31st, 2019 in the southern part of the Lombardy region (provinces of Pavia, Lodi, Cremona and Mantua; 7863 km2; about 1550000 inhabitants). Days were divided into high or low incidence of OHCA according to the median value. A Probit dose-response analysis and both uni- and multivariable logistic regression models were provided for each pollutant. The concentrations of all the pollutants were significantly higher in days with high incidence of OHCA except for O3, which showed a significant countertrend. After correcting for temperature, a significant dose-response relationship was demonstrated for all the pollutants examined. All the pollutants were also strongly associated with high incidence of OHCA in multivariable analysis with correction for temperature, humidity, and day-to-day concentration changes. Our results clarify the link between pollutants and the acute risk of cardiac arrest suggesting the need of both improving the air quality and integrating pollution data in future models for the organization of emergency medical services.


Post-Streptococcal Reactive Arthritis.
Post-Streptococcal Reactive Arthritis (PSRA) is defined as inflammatory arthritis of ≥1 joint associated with a recent group A streptococcal infection in a patient who does not fulfill the Jones criteria for the diagnosis of Acute Rheumatic Fever (ARF). In this narrative review, we conducted a systematic search on MEDLINE, EMBASE, Cochrane Library and Google Scholar using the words poststreptococcal reactive arthritis. The search covered the time period between 1982 and 2016. The purpose of this review is to summarize the current state of knowledge of PSRA with respect to the definition, epidemiology, clinical presentation and treatment. We also summarize the key differences between PSRA, reactive arthritis (ReA) and ARF. PSRA has a bimodal age distribution at ages 8-14 and 21-37 years with an almost equal male to female ratio. Clinically, it causes acute asymmetrical non-migratory polyarthritis, however, tenosynovitis and small joint arthritis may occur. This disease entity can be associated with extraarticular manifestations, including erythema nodosum, uveitis and glomerulonephritis. The frequency of HLA-B27 in PSRA does not differ from that of the normal population, which suggests that it is a separate entity from ReA. Involvement of the axial skeleton, including sacroiliitis, is uncommon in PSRA. PSRA tends to occur within 10 days of a group A streptococcal infection, as opposed to the 2 to 3 weeks delay for ARF. PSRA can be associated with prolonged or recurrent arthritis, in contrast to ARF, in which arthritis usually lasts a few days to 3 weeks. Treatment usually involves NSAIDs or corticosteroids. We summarize clinical features that help differentiate PSRA from ARF and ReA. First-line treatment options include NSAIDs and corticosteroids. Most cases resolve spontaneously within a few weeks, but some cases are recurrent or prolonged. There are no published randomized controlled trials of PSRA.


S. cerevisiae Vts1p induces deadenylation-dependent transcript degradation and interacts with the Ccr4p-Pop2p-Not deadenylase complex.
The Smaug family of sequence-specific RNA binding proteins regulates mRNA translation and degradation by binding to consensus stem-loop structures in target mRNAs. Vts1p is a member of the Smaug protein family that regulates the stability of target transcripts in Saccharomyces cerevisiae. Here we focus on the mechanism of Vts1p-mediated mRNA decay. Using RNA reporters that recapitulate Vts1p-mediated decay in vivo, we demonstrate that Vts1p stimulates mRNA degradation through deadenylation mediated by the Ccr4p-Pop2p-Not deadenylase complex. We also show that Vts1p interacts with the Ccr4p-Pop2p-Not complex suggesting that Vts1p recruits the Ccr4p-Pop2p-Not deadenylase complex to target mRNAs, resulting in transcript decay. Following deadenylation Vts1p target transcripts are decapped and subsequently degraded by the 5'-to-3' exonuclease Xrn1p. Decapping and 5'-to-3' decay is thought to occur in foci known as P-bodies, and we provide evidence that Vts1p function may involve P-bodies. Taken together with previous work, these data suggest that Smaug family members employ a conserved mechanism to induce transcript degradation that involves recruitment of the Ccr4-Pop2-Not deadenylase to target mRNAs.


Altering Shank-Rear-Foot Joint Coupling During Gait With Ankle Taping in Patients With Chronic Ankle Instability and Healthy Controls.
Lateral ankle sprain (LAS) is one of the most common injuries in active individuals. Chronic ankle instability (CAI) is a condition that commonly occurs after LAS and is associated with long-term disability and a high risk of multiple ankle sprains. Ankle taping is a commonly used intervention for the prevention of ankle sprains. To analyze the ankle-joint coupling using vector coding during walking and jogging gait with the application of ankle tape and without ankle tape in young adults with and without CAI. Observational laboratory study design. Patients walked and jogged on an instrumented treadmill while taped and not taped. Fifteen strides for each subject were collected and analyzed using a vector-coding technique to compare magnitude coupled motion, ratio of coupled motion, and the variability (VCV) within groups. Within-group means and 90% confidence intervals (CI) were compared between the taped and nontaped condition, and where the CIs did not overlap was considered significant. A 12-camera 3D motion-capture system with instrumented treadmill. 12 patients with CAI and 11 healthy controls. Magnitude to coupled motion, ratio of coupled motion, and the VCV of shank-rear-foot joint coupling. Magnitude of coupled motion and VCV were significantly lower in the taped condition than in the nontaped condition in both groups. Magnitude differences were identified near initial contact during walking and during swing phase of jogging. VCV differences were identified throughout the gait cycle at both walking and jogging. No differences were identified in theta between tape and nontaped conditions. A decrease in the magnitude of coupled motion and VCV may represent a protective mechanism of ankle taping in CAI and healthy patients during gait.


Pattern of bone mineral density in sickle cell disease patients with the high-Hb F phenotype.
Low bone mineral density (BMD) is common in sickle cell disease (SCD) patients of all ages due to erythropoietic stress and consequent bone marrow hyperplasia. Kuwaiti SCD patients have a mild clinical phenotype because of their high Hb F level. There has been no previous documentation of BMD in this population of patients. SCD patients (n = 81) and controls (n = 67) were recruited from hematology clinics of Mubarak Hospital, Kuwait. BMD was measured using dual X-ray absorptiometry (Hologic) in the lumbar spine and the hip (left femoral neck). Among the 53 adult patients, the prevalence of low BMD was 67.4% in the spine and 33.3% in the hip while among controls, the figures were 23.1 and 11.3%, respectively. These differences are significant (p < 0.01). In SCD children, the figures were 17.9% (in the lumbar spine) and 3.6% (in the hip), while in controls the figures were 13.3 and 0%, respectively. The differences are not significant (p > 0.05). Patients with frequent vaso-occlusive crisis had significantly lower mean BMD, but those with MRI evidence of avascular necrosis of the femoral head were more likely to have normal or osteosclerotic BMD. Our study showed that osteopenia/osteoporosis is uncommon among Kuwaiti children with SCD but quite common in adults.


Fatal hypereosinophilia with chromosome 15q- in a patient with multiple primary and familial neoplasms.
A man with large-cell carcinoma of the lung, cerebral meningioma, occult adenocarcinoma of the prostate, and follicular adenoma of the thyroid developed symptomatic, rapidly progressive hypereosinophilia with abnormalities of eosinophil ultrastructure and bone marrow karyotype (45,X,15q22-). Although the patient's eosinophilia defied strict classification as idiopathic hypereosinophilic syndrome (HES), simple tumor-associated eosinophilia, or eosinophilic leukemia, it appeared to be incited by the lung cancer and quickly acquired malignant independence. The family had an excess of prostate cancer and lymphoproliferative neoplasms.


Groupness in Preverbal Infants: Proof of Concept.
Infant sociability is generally conceived in terms of dyadic capacities and behaviors. Recently, quantitative evidence has been published to support arguments that infants achieve a criterion for groupness: the capacity to interact simultaneously with two others. Such studies equate this capacity with alternating dyadic acts to the two other members of an interacting trio. Here we propose a stricter threefold criterion for infant groupness, of which the crux is whether the social behavior of an infant at time B is shown to be influenced by what two or more group-members were previously doing at time A. We test the viability of this conceptualization: (a) through its justification of the novel laboratory procedure of studying infant sociability in infant-peer quartets (rather than trios); and, (b) in an analysis of a pilot study of gaze-behavior recorded in 5-min interactions among two quartets of infants aged 6-9 months. We call this a 'proof of concept' because our aim is to show that infants are capable of groupness, when groupness is conceptualized in a supra-dyadic way-not that all infants will manifest it, nor that all conditions will produce it, nor that it is commonplace in infants' everyday lives. We found that both quartets did achieve the minimum criterion of groupness that we propose: mutual gaze predicting coordinated gaze (where two babies, A and B, are looking at each other, and B is then looked at by C, and sometimes D) more strongly than the reverse. There was a significant absence of 'parallel mutual gaze,' where the four babies pair off. We conclude that, under specific conditions, preverbal infants can manifest supra-dyadic groupness. Infants' capacities to exhibit groupness by 9 months of age, and the paucity of parallel mutual gaze in our data, run counter to the assumption that infant sociability, when in groups, is always generated by a dyadic program. Our conceptualization and demonstration of groupness in 8-month-olds thus opens a host of empirical, theoretical, and practical questions about the sociability and care of young babies.


Stimulation of spermatogenesis by gonadotropins in men with hypogonadotropic hypogonadism.
We evaluated the efficacy of gonadotropin treatment in stimulating spermatogenesis in men with hypogonadotropic hypogonadism. When 21 men with hypogonadotropic hypogonadism were treated with human chorionic gonadotropin, the sperm count increased to within the normal range in the 6 in whom hypogonadism had begun after puberty, but in only 1 of the 15 in whom it had begun before puberty (P less than 0.002). When the remaining 14 men with prepubertal hypogonadism were treated with human menopausal gonadotropin in addition to human chorionic gonadotropin, the sperm count increased to normal in 5 of the 7 who had not had cryptorchidism, but in only 1 of the 7 who had (P less than 0.05). The need for human menopausal gonadotropin as a replacement for follicle-stimulating hormone could not be predicted by pretreatment serum and urinary levels of follicle-stimulating hormone. We conclude that gonadotropin treatment will usually increase the sperm count to normal in men with hypogonadotropic hypogonadism, unless cryptorchidism has occurred. The need for human menopausal gonadotropin treatment appears to depend on the time of onset of hypogonadism.


Adenosine actions on CA1 pyramidal neurones in rat hippocampal slices.
Intracellular recordings with a bridge amplifier of CA1 pyramidal neurones in vitro were employed to study the mechanisms of action of exogenously applied adenosine in the hippocampal slice preparation of the rat. Adenosine enhanced the calcium-dependent, long-duration after-hyperpolarization (a.h.p.) at least in part by a reduction in the rate of decay of the a.h.p. Both the reduced rate of decay and that of the control can be described with a single exponential. Antagonism of the calcium-dependent potassium current (and as a result, the a.h.p.) by bath application of CdCl2 or intracellular injection of EGTA (ethyleneglycolbis-(beta-aminoethyl ether)N,N'-tetraacetic acid) did not reduce the adenosine-evoked hyperpolarization or decrease in input resistance. Similarly, TEA (tetraethylammonium), which antagonizes both the voltage- and calcium-sensitive, delayed, outward rectification, had no effect on the adenosine-evoked changes in resting membrane properties. Adenosine did not affect the early, transient, outward rectification. During exposure to 4-aminopyridine (4-AP) in concentrations sufficient to antagonize this early rectification, the changes in resting membrane properties evoked by adenosine were unaffected. We conclude that the enhancement of the a.h.p. and accommodation by adenosine may be mediated by a change in the regulation of intracellular calcium. However, the mechanism responsible for the hyperpolarization and decrease in input resistance evoked by adenosine is both calcium and voltage insensitive. Thus, it appears distinct from that mediating the enhancement of the a.h.p. and accommodation.


B1 field homogeneity and SAR calculations for the birdcage coil.
The finite-difference time-domain (FDTD) method is used to model a birdcage resonator. All the coil components, including the wires, lumped capacitors and the source, are geometrically modelled together. As such, the coupling effects within the birdcage, including the interactions of coil, source and human head, are accurately computed. A study of the transverse magnetic (B1) field homogeneity and the specific absorption rate (SAR) is presented on an anatomically detailed human head model at 64 and 200 MHz representing 1.5 and 4.7 T MRI systems respectively. Unlike that at 64 MHz, the B1 field distribution is found to be inhomogeneous at 200 MHz. Also, high local SAR values are observed in the tissue near the source due to the coupling between the source and the head at 200 MHz.


GABA networks destabilize genetic oscillations in the circadian pacemaker.
Systems of coupled oscillators abound in nature. How they establish stable phase relationships under diverse conditions is fundamentally important. The mammalian suprachiasmatic nucleus (SCN) is a self-sustained, synchronized network of circadian oscillators that coordinates daily rhythms in physiology and behavior. To elucidate the underlying topology and signaling mechanisms that modulate circadian synchrony, we discriminated the firing of hundreds of SCN neurons continuously over days. Using an analysis method to identify functional interactions between neurons based on changes in their firing, we characterized a GABAergic network comprised of fast, excitatory, and inhibitory connections that is both stable over days and changes in strength with time of day. By monitoring PERIOD2 protein expression, we provide the first evidence that these millisecond-level interactions actively oppose circadian synchrony and inject jitter into daily rhythms. These results provide a mechanism by which circadian oscillators can tune their phase relationships under different environmental conditions.


[The status of pertussis infection and molecular epidemiological characteristics of pertussis in Tianjin, 2013].
To understand the status of pertussis infection and characteristics of molecular epidemiology of pertussis in 2013 in Tianjin. Totally, 181 suspected pertussis cases were selected and their nasopharyngeal swabs and serum were sampled at the Disease Monitoring Settings in Tianjin. Real-time PCR was used to detect Bordetella pertussis double target genes and enzyme linked immune-sorbent assay (ELISA) method was used to detect the specific pertussis toxin IgG (PT-IgG) antibody. Fimbriae 2 (FIM2) and Fimbriae 3 (FIM3) genes of pertussis was amplified by PCR for sequencing, from 30 pertussis DNA positive samples. The positive rate of Real-time PCR was 68.24% in 148 cases and the positive rate of PT-IgG antibody was 55.56% in 108 cases. Among 101 cases that nucleic acid were positive, the median duration of disease was 11 days. Among the PT-IgG Positive cases (60 cases), the median duration of disease was 21 days. In cases under 1 year old, the Real-time PCR testing positive rate was 84.28%. Positive rates among other age groups, the differences were statistically significant. Nucleotide homologies of FIM2 and FIM3 genes from 30 pertussis strains were 99.6%-100.0%, while it was 99% when compared to both international standard Tohama strain and Chinese vaccine strain. Detection of pertussis by Real-time PCR from clinical nasopharyngeal swab sample was quick and sensitive for the diagnosis. Bordetella pertussis epidemic strains in Tianjin area appeared close relation with both the international standards and China vaccine strains.


Construction of a recombinant single chain antibody recognizing nonreducing terminal mannose residues applicable to immunohistochemistry.
We recently reported characterization of 25 clones isolated from a phage library displaying human scFvs using a neoglycolipid Man3-DPPE, which was synthesized from mannotriose (Man3) and dipalmitoylphosphatidylethanolamine (DPPE). Of those, 5A3 scFv was successfully expressed and purified as a humanized scFv-Fc form (Sakai et al., Biochemistry 46:253, 2007, Zhang et al. ibid 263). To carry out immunohistochemistry (IHC) in human tissues, a HA tag sequence was introduced to the 5A3 scFv-Fc gene and the resulting construct was transfected to murine myeloma NS0 cells. The 5A3 scFv-Fc protein expressed was affinity-purified. Sodium dodecyl sulfate polyacrylamide gel electrophoresis under nonreducing and reducing conditions and enzyme-linked immunosorbent assay confirmed that 5A3 scFv-Fc protein is dimeric and retained the ability to recognize nonreducing terminal mannose residues. IHC staining of non-neoplastic tissues by this recombinant antibody revealed that no immunoreactivity was detectable in most of 16 tissues examined. Exceptions were found in IHC staining of kidney and pancreas, which demonstrated clear staining of proximal tubules and islet of Langerhans, respectively. These results demonstrated that nonreducing terminal mannose residues are not usually present under normal physiological conditions. This study thus provided a potentially useful tool for examination of the nonreducing terminal mannose residues, which may become exposed under certain pathophysiologycal conditions.


Hyperglycemia in the intensive care unit: is insulin the only option?
Current guidelines advocate the use of insulin for the management of hyperglycemia in the hospital setting. However, insulin is limited by a narrow therapeutic window, frequent errors, a need for expertise and systems-based monitoring, and lack of specificity for metabolic abnormalities that occur during critical illness. As a result, non-insulin alternatives have garnered increasing interest for managing hyperglycemia in the hospital. However, non-insulin therapies have had safety and tolerability concerns, patients may still need insulin for glycemic control, and there have been limited outcomes data supporting their use. In the study by Christiansen and colleagues in the previous issue of Critical Care, pre-admission metformin therapy was associated with reduced mortality in critically ill patients with type 2 diabetes. The mortality benefit persisted after controlling for other variables, and was particularly prominent when metformin was continued during admission. Furthermore, the reduction in mortality was observed despite a slightly increased prevalence of lactic acidosis in metformin users. The protective effects of metformin are purported to be related to pleiotropic, possibly anti-inflammatory mechanisms, raising the question of benefit in patients without diabetes. Thus, the findings warrant a re-appraisal of the risks and benefits of metformin use during critical illness. However, in order to justify the revision of multiple guidelines and changes in product labeling, clinical trials in carefully selected patient populations are indicated.


Personality and the acute subjective effects of d-amphetamine in humans.
There is evidence that subjective responses to psychoactive drugs are related to personality traits. Here, we extend previous findings by examining personality measures in relation to acute responses to d-amphetamine (AMPH) in a large sample of healthy volunteers. Healthy adults (n=286) completed the Multidimensional Personality Questionnaire Brief Form (MPQ-BF) and participated in four sessions during which they received oral AMPH (0, 5, 10, 20 mg), under double-blind conditions. Subjective responses to the drug were measured using the Profile of Mood States, Addiction Research Center Inventory, and Drug Effects Questionnaire. Drug responses were reduced via principal components analysis to three higher-order factors ('Euphoria', 'Arousal', 'Dysphoria'). Participants were rank ordered on selected MPQ-BF scales; the top and bottom third on each trait were compared on the drug response factors. High trait physical fearlessness was significantly associated with greater amphetamine-related Arousal, and high trait reward sensitivity was significantly associated with greater Euphoria. In addition, high trait impulsivity was significantly associated with greater Arousal and Euphoria. These results provide further evidence that individual differences in the subjective effects of AMPH are partially explained by differences in personality, and are consistent with the idea that both personality and responses to stimulants depend upon shared neurochemical systems.


Gastric cancer treatment: similarity and difference between China and Korea.
Chinese populations have many demographic similarities to Korean populations. However, the long-term survival rates of gastric cancer patients in China are still not satisfactory when compared with Korea, especially for the advanced cases. In this article, we discuss about the similarity and difference of gastric cancer treatment in terms of screening, surgical approach, stomach resection, digestive tract reconstruction, lymphadenectomy, harvested lymph nodes, operative morbidity and mortality, postoperative chemotherapy as well as follow-up between China and Korea. Given that a variety of factors ranging from tumor characteristics to different treatment strategies are seen between the two countries, the reasons accounting for the differences in survival should be focused and the corresponding strategy should be considered and finally promote to improve the prognosis of gastric cancer.


Immunotherapy for the First-Line Treatment of Patients with Metastatic Non-Small Cell Lung Cancer.
Immunotherapy has fundamentally changed the treatment landscape for many patients with cancer. mAbs targeting programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen-4 immune checkpoints have received regulatory approval across a wide range of tumor types, including non-small cell lung cancer (NSCLC). Indeed, treatment approaches for a majority of patients with newly diagnosed metastatic NSCLC are evolving rapidly. Only for the small proportion of patients with metastatic NSCLC and genomic-driven tumors with EGFR or anaplastic lymphoma kinase (ALK)-sensitizing mutations (5%-15%), and possibly BRAF mutations and ROS rearrangements, have initial treatment recommendations remained unchanged, with specific tyrosine kinase inhibitors as the preferred therapy. For the remaining patients, an immunotherapy-based regimen alone or in combination with chemotherapy is now the preferred option based on high-level evidence obtained from randomized controlled trials and in accordance with all available guidelines. Deciding between therapeutic options can be difficult due to the lack of direct cross-comparison studies, differences in chemotherapies and stratification factors, and differences in study populations resulting from inclusion criteria such as histology, PD-L1 expression, or tumor mutational burden (TMB). In an attempt to aid the decision-making process, we discuss and summarize the most recent data from studies using immunotherapies for the treatment of patients with previously untreated metastatic NSCLC.


Systemic myostatin inhibition via liver-targeted gene transfer in normal and dystrophic mice.
Myostatin inhibition is a promising therapeutic strategy to maintain muscle mass in a variety of disorders, including the muscular dystrophies, cachexia, and sarcopenia. Previously described approaches to blocking myostatin signaling include injection delivery of inhibitory propeptide domain or neutralizing antibodies. Here we describe a unique method of myostatin inhibition utilizing recombinant adeno-associated virus to overexpress a secretable dominant negative myostatin exclusively in the liver of mice. Systemic myostatin inhibition led to increased skeletal muscle mass and strength in control C57 Bl/6 mice and in the dystrophin-deficient mdx model of Duchenne muscular dystrophy. The mdx soleus, a mouse muscle more representative of human fiber type composition, demonstrated the most profound improvement in force production and a shift toward faster myosin-heavy chain isoforms. Unexpectedly, the 11-month-old mdx diaphragm was not rescued by long-term myostatin inhibition. Further, mdx mice treated for 11 months exhibited cardiac hypertrophy and impaired function in an inhibitor dose-dependent manner. Liver-targeted gene transfer of a myostatin inhibitor is a valuable tool for preclinical investigation of myostatin blockade and provides novel insights into the long-term effects and shortcomings of myostatin inhibition on striated muscle.


Anomalous origin of the left coronary artery from the pulmonary artery in an elderly patient, football player in youth.
Anomalous origin of the left coronary artery from the pulmonary artery is a rare congenital defect. Without surgical treatment, approximately 90% of infants die within the first year of life. Late presentation in the adult or elderly is rare. Factors that may lead to survival in advanced age include the development of intercoronary collaterals. Furthermore, the risk of sudden cardiac death due to ischaemic malignant ventricular dysrhythmias exists even in asymptomatic adult patients and, classically, is precipitated by exercise. We report the case of a 67-year-old man, a football player in his youth, always asymptomatic until presentation at our centre for symptomatic sustained ventricular tachycardia and shortness of breath on exertion. We show the features of the ECG, transthoracic echocardiography, angiography study of the coronary and the pulmonary system, myocardial basal and stress gated single photon emission computed tomography with Tc-tetrofosmin and cardiac CT 64 slices. The patient was referred to cardiac surgery. We believe that this patient's favourable course may be ascribed to the large network of collaterals from the right coronary artery supplying the entire heart. However, the exact reason why these favourable evolutions (both vascular and clinical) occur only in some individuals remains largely unknown.


Brazilian dialysis census, 2009.
National dialysis data are fundamental for treatment planning. To report data of the annual survey of the Brazilian Society of Nephrology about chronic renal failure patients on dialysis in January 2009. A survey based on data of dialysis units from the whole country. The data collection was performed by using a questionnaire filled out by the dialysis units in Brazil. 427 (69.8%) of the dialysis units in the country answered the questionnaire. National data were estimated for the overall dialysis population. In January 2009, the total estimated number of patients on dialysis was 77,589. The estimated prevalence and incidence rates of chronic renal failure on maintenance dialysis were 405 and 144 patients per million population, respectively. The estimated number of new patients starting dialysis program in 2009 was 27,612. The annual gross mortality rate was 17.1%. For prevalent patients, 39.9% were aged 60 years or older, 89.6% were on hemodialysis and 10.4% on peritoneal dialysis, 30,419 (39.2%) were on a waiting list of renal transplant, 27% were diabetics, 37.9% had serum phosphorus > 5.5 mg/dL and 42.8% hemoglobin < 11 g/dL. A venous catheter was the vascular access for 12.4% of the hemodialysis patients. The prevalence of chronic renal failure on maintenance dialysis is increasing in Brazil, although in 2009 the estimate is lower than in 2008. The data call attention to indicators of the quality of maintenance dialysis that need to be improved and highlight the importance of the census to guide chronic dialysis therapy.


An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML.
Acute myeloid leukemia with normal karyotype (NK-AML) represents a cytogenetic grouping with intermediate prognosis but substantial molecular and clinical heterogeneity. Within this subgroup, presence of FLT3 (FMS-like tyrosine kinase 3) internal tandem duplication (ITD) mutation predicts less favorable outcome. The goal of our study was to discover gene-expression patterns correlated with FLT3-ITD mutation and to evaluate the utility of a FLT3 signature for prognostication. DNA microarrays were used to profile gene expression in a training set of 65 NK-AML cases, and supervised analysis, using the Prediction Analysis of Microarrays method, was applied to build a gene expression-based predictor of FLT3-ITD mutation status. The optimal predictor, composed of 20 genes, was then evaluated by classifying expression profiles from an independent test set of 72 NK-AML cases. The predictor exhibited modest performance (73% sensitivity; 85% specificity) in classifying FLT3-ITD status. Remarkably, however, the signature outperformed FLT3-ITD mutation status in predicting clinical outcome. The signature may better define clinically relevant FLT3 signaling and/or alternative changes that phenocopy FLT3-ITD, whereas the signature genes provide a starting point to dissect these pathways. Our findings support the potential clinical utility of a gene expression-based measure of FLT3 pathway activation in AML.


Administration of first dose antibiotic in the ED in patients with minor skin and soft tissue infections.
Patients who present to the emergency department (ED) with mild skin and soft tissue infections (SSTIs) are often given a single dose of an antibiotic before being discharged home on oral antibiotics. The objective of this study was to determine if administration of antibiotics in the ED increases length of stay. This was cross-sectional study using data from the National Hospital Ambulatory Medical Care Survey. Patients with SSTIs who were discharged home with antibiotics were included. Patients were categorized into 2 groups based on whether any antibiotics were administered in the ED. The ED length of stay was compared between the groups. A multivariate analysis was conducted to adjust for pertinent confounders. There were 3000895 cases of patients with SSTIs who presented to the ED and directly discharged home on antibiotic therapy from 2008 to 2010. Of these, 46.8% (n = 1403710) involved the administration of an antibiotic in the ED, whereas the others only received antibiotic prescriptions upon discharge. The mean ED length of stay was 83.8 ± 160.6 minutes with no antibiotics vs 112.2 ± 193.6 minutes for antibiotic use in the ED (P < .05). After adjusting for confounders, there was a 43% increase in ED length of stay associated with administration of first dose of antibiotics in the ED (exp[b] = 1.43; 95% confidence interval, 1.19-1.70; P < .001). The administration of an antibiotic in the ED before discharge is associated with an increased ED length of stay in patients with SSTIs.


Clinical, genetic and neuropathological characterization of spinocerebellar ataxia type 37.
The autosomal dominant spinocerebellar ataxias (SCAs) consist of a highly heterogeneous group of rare movement disorders characterized by progressive cerebellar ataxia variably associated with ophthalmoplegia, pyramidal and extrapyramidal signs, dementia, pigmentary retinopathy, seizures, lower motor neuron signs, or peripheral neuropathy. Over 41 different SCA subtypes have been described evidencing the high clinical and genetic heterogeneity. We previously reported a novel spinocerebellar ataxia type subtype, SCA37, linked to an 11-Mb genomic region on 1p32, in a large Spanish ataxia pedigree characterized by ataxia and a pure cerebellar syndrome distinctively presenting with early-altered vertical eye movements. Here we demonstrate the segregation of an unstable intronic ATTTC pentanucleotide repeat mutation within the 1p32 5' non-coding regulatory region of the gene encoding the reelin adaptor protein DAB1, implicated in neuronal migration, as the causative genetic defect of the disease in four Spanish SCA37 families. We describe the clinical-genetic correlation and the first SCA37 neuropathological findings caused by dysregulation of cerebellar DAB1 expression. Post-mortem neuropathology of two patients with SCA37 revealed severe loss of Purkinje cells with abundant astrogliosis, empty baskets, occasional axonal spheroids, and hypertrophic fibres by phosphorylated neurofilament immunostaining in the cerebellar cortex. The remaining cerebellar Purkinje neurons showed loss of calbindin immunoreactivity, aberrant dendrite arborization, nuclear pathology including lobulation, irregularity, and hyperchromatism, and multiple ubiquitinated perisomatic granules immunostained for DAB1. A subpopulation of Purkinje cells was found ectopically mispositioned within the cerebellar cortex. No significant neuropathological alterations were identified in other brain regions in agreement with a pure cerebellar syndrome. Importantly, we found that the ATTTC repeat mutation dysregulated DAB1 expression and induced an RNA switch resulting in the upregulation of reelin-DAB1 and PI3K/AKT signalling in the SCA37 cerebellum. This study reveals the unstable ATTTC repeat mutation within the DAB1 gene as the underlying genetic cause and provides evidence of reelin-DAB1 signalling dysregulation in the spinocerebellar ataxia type 37.


Modeling effects of crop production, energy development and conservation-grassland loss on avian habitat.
Birds are essential components of most ecosystems and provide many services valued by society. However, many populations have undergone striking declines as their habitats have been lost or degraded by human activities. Terrestrial grasslands are vital habitat for birds in the North American Prairie Pothole Region (PPR), but grassland conversion and fragmentation from agriculture and energy-production activities have destroyed or degraded millions of hectares. Conservation grasslands can provide alternate habitat. In the United States, the Conservation Reserve Program (CRP) is the largest program maintaining conservation grasslands on agricultural lands, but conservation grasslands in the PPR have declined by over 1 million ha since the program's zenith in 2007. We used an ecosystem-services model (InVEST) parameterized for the PPR to quantify grassland-bird habitat remaining in 2014 and to assess the degradation status of the remaining grassland-bird habitat as influenced by crop and energy (i.e., oil, natural gas, and wind) production. We compared our resultant habitat-quality ratings to grassland-bird abundance data from the North American Breeding Bird Survey to confirm that ratings were related to grassland-bird abundance. Of the grassland-bird habitat remaining in 2014, about 19% was degraded by crop production that occurred within 0.1 km of grassland habitats, whereas energy production degraded an additional 16%. We further quantified the changes in availability of grassland-bird habitat under various land-cover scenarios representing incremental losses (10%, 25%, 50%, 75%, and 100%) of CRP grasslands from 2014 levels. Our model identified 1 million ha (9%) of remaining grassland-bird habitat in the PPR that would be lost or degraded if all CRP conservation grasslands were returned to crop production. Grassland regions world-wide face similar challenges in maintaining avian habitat in the face of increasing commodity and energy production to sate the food and energy needs of a growing world population. Identifying ways to model the impacts of the tradeoff between food and energy production and wildlife production is an important step in creating solutions.


Smc5/6 Antagonism by HBx Is an Evolutionarily Conserved Function of Hepatitis B Virus Infection in Mammals.
Chronic infection with hepatitis B virus (HBV) is a major cause of liver disease and cancer in humans. HBVs (family Hepadnaviridae) have been associated with mammals for millions of years. Recently, the Smc5/6 complex, known for its essential housekeeping functions in genome maintenance, was identified as an antiviral restriction factor of human HBV. The virus has, however, evolved to counteract this defense mechanism by degrading the complex via its regulatory HBx protein. Whether the antiviral activity of the Smc5/6 complex against hepadnaviruses is an important and evolutionarily conserved function is unknown. In this study, we used an evolutionary and functional approach to address this question. We first performed phylogenetic and positive selection analyses of the Smc5/6 complex subunits and found that they have been conserved in primates and mammals. Yet, Smc6 showed marks of adaptive evolution, potentially reminiscent of a virus-host "arms race." We then functionally tested the HBx proteins from six divergent hepadnaviruses naturally infecting primates, rodents, and bats. We demonstrate that despite little sequence homology, these HBx proteins efficiently degraded mammalian Smc5/6 complexes, independently of the host species and of the sites under positive selection. Importantly, all HBx proteins also rescued the replication of an HBx-deficient HBV in primary human hepatocytes. These findings point to an evolutionarily conserved requirement for Smc5/6 inactivation by HBx, showing that Smc5/6 antiviral activity has been an important defense mechanism against hepadnaviruses in mammals. It will be interesting to investigate whether Smc5/6 may further be a restriction factor of other, yet-unidentified viruses that may have driven some of its adaptation.IMPORTANCE Infection with hepatitis B virus (HBV) led to 887,000 human deaths in 2015. HBV has been coevolving with mammals for millions of years. Recently, the Smc5/6 complex, which has essential housekeeping functions, was identified as a restriction factor of human HBV antagonized by the regulatory HBx protein. Here we address whether the antiviral activity of Smc5/6 is an important evolutionarily conserved function. We found that all six subunits of Smc5/6 have been conserved in primates, with only Smc6 showing signatures of an "evolutionary arms race." Using evolution-guided functional analyses that included infections of primary human hepatocytes, we demonstrated that HBx proteins from very divergent mammalian HBVs could all efficiently antagonize Smc5/6, independently of the host species and sites under positive selection. These findings show that Smc5/6 antiviral activity against HBV is an important function in mammals. They also raise the intriguing possibility that Smc5/6 may restrict other, yet-unidentified viruses.


Body mass index and obesity in adolescents in a psychiatric medium secure service.
Obesity is more prevalent in adults with severe mental illness than in the general population. Little is known about the prevalence of obesity in mentally ill adolescents. The present study aimed to determine the prevalence of obesity and its complications among inpatients in a psychiatric medium secure service for adolescents and young people. The study comprised a cross-sectional survey of routinely collected data, including body mass index (BMI) both currently and 3 months previously, serum cholesterol and psychotropic prescription data, as well as the number of patients known to have type II diabetes mellitus and hypertension. Of the 95 patients studied, 33 (34.7%) were overweight and 45 (47.4%) were obese. Twenty-six (56.5%) females were obese, including seven who were morbidly obese. Nineteen (38.8%) males were obese, one of whom was morbidly obese. Prescription of antipsychotics was associated with obesity and the total percentage dose of antipsychotic correlated with BMI. Two patients had type 2 diabetes mellitus and two had hypertension. Seventeen patients had a serum cholesterol of over 5 mm. Being overweight and obesity were very common in the young people studied and appeared to be related to the prescription of antipsychotics. Interventions are needed to reduce unhealthy raised BMI and prevent the physical complications of obesity.


"Ensure that you are well aware of the risks you are taking…": actions and activities medical tourists' informal caregivers can undertake to protect their health and safety.
When seeking care at international hospitals and clinics, medical tourists are often accompanied by family members, friends, or other caregivers. Such caregiver-companions assume a variety of roles and responsibilities and typically offer physical assistance, provide emotional support, and aid in decision-making and record keeping as medical tourists navigate unfamiliar environments. While traveling abroad, medical tourists' caregiver-companions can find themselves confronted with challenging communication barriers, financial pressures, emotional strain, and unsafe environments. To better understand what actions and activities medical tourists' informal caregivers can undertake to protect their health and safety, 20 interviews were conducted with Canadians who had experienced accompanying a medical tourist to an international health care facility for surgery. Interview transcripts were subsequently used to identify inductive and deductive themes central to the advice research participants offered to prospective caregiver-companions. Advice offered to future caregiver-companions spanned the following actions and activities to protect health and safety: become an informed health care consumer; assess and avoid exposure to identifiable risks; anticipate the care needs of medical tourists and thereby attempt to guard against caregiver burden; become familiar with important logistics related to travel and anticipated recovery timelines; and take practical measures to protect one's own health. Given that a key feature of public health is to use research findings to develop interventions and policies intended to promote health and reduce risks to individuals and populations, the paper draws upon major points of advice offered by study participants to take the first steps toward the development of an informational intervention designed specifically for the health and safety needs of medical tourists' caregiver companions. While additional research is required to finalize the content and form of such an intervention, this study provides insight into what practical advice former caregiver-companions state should be shared with individuals considering assuming these roles and responsibilities in the future. In addition, this research draws attention to the importance of ensuring that such an intervention is web-based and readily accessible by prospective caregiver-companions.


Selective Anterior Lumbar Interbody Fusion for Low Back Pain Associated With Degenerative Disc Disease Versus Nonsurgical Management.
This is a retrospective cohort study. To evaluate the long-term outcomes of selective one- to two-level anterior lumbar interbody fusions (ALIFs) in the lower lumbar spine versus continued nonsurgical management. Low back pain associated with lumbar intervertebral disc degeneration is common with substantial economic impact, yet treatment remains controversial. Surgical fusion has previously provided mixed results with limited durable improvement of pain and function. Seventy-five patients with one or two levels of symptomatic Pfirrmann grades 3 to 5 disc degeneration from L3-S1 were identified. All patients had failed at least 6 months of nonsurgical treatment. Forty-two patients underwent one- or two-level ALIFs; 33 continued multimodal nonsurgical care. Patients were evaluated radiographically and the visual analog pain scale (VAS), Oswestry Disability Index (ODI), EuroQol five dimensions (EQ-5D), and Patient-Reported Outcomes Measurement Information System scores for pain interference, pain intensity, and anxiety. As-treated analysis was performed to evaluate outcomes at a mean follow-up of 7.4 years (range: 2.5-12). There were no differences in pretreatment demographics or nonsurgical therapy utilization between study arms. At final follow-up, the surgical arm demonstrated lower VAS, ODI, EQ-5D, and Patient-Reported Outcomes Measurement Information System pain intensity scores versus the nonsurgical arm. VAS and ODI scores improved 52.3% and 51.1% in the surgical arm, respectively, versus 15.8% and -0.8% in the nonsurgical arm. Single-level fusions demonstrated improved outcomes versus two-level fusions. The pseudarthrosis rate was 6.5%, with one patient undergoing reoperation. Asymptomatic adjacent segment degeneration was identified in 11.9% of patients. Selective ALIF limited to one or two levels in the lower lumbar spine provided improved pain and function when compared with continued nonsurgical care. ALIF may be a safe and effective treatment for low back pain associated with disc degeneration in select patients who fail nonsurgical management. 3.


Breast Imaging-Reporting and Data System (BI-RADS) classification in 51 excised palpable pediatric breast masses.
The American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) classification was developed to risk stratify breast lesions and guide surgical management based on imaging. Previous studies validating BI-RADS for US do not include pediatric patients. Most pediatric breast masses present as palpable lesions and frequently undergo ultrasound, which is often accompanied with a BI-RADS classification. Our study aimed to correlate BI-RADS with pathology findings to assess applicability of the classification system to pediatric patients. We performed a retrospective review of all patients who underwent excision of a breast mass at a single center from July 2010 to November 2013. We identified all patients who underwent preoperative ultrasound with BI-RADS classification. Demographic data, imaging results, and surgical pathology were analyzed and correlated. A total of 119 palpable masses were excised from 105 pediatric patients during the study period. Of 119 masses, 81 had preoperative ultrasound, and BI-RADS categories were given to 51 masses. Of these 51, all patients were female and the average age was 15.9 years. BI-RADS 4 was given to 25 of 51 masses (49%), and 100% of these lesions had benign pathology, the most common being fibroadenoma. Treatment algorithm based on BI-RADS classification may not be valid in pediatric patients. In this study, all patients with a BI-RADS 4 lesion had benign pathology. BI-RADS classification may overstate the risk of malignancy or need for biopsy in this population. Further validation of BI-RADS classification with large scale studies is needed in pediatric and adolescent patients.


A fast method for measuring psychophysical thresholds across the cochlear implant array.
A rapid threshold measurement procedure, based on Bekesy tracking, is proposed and evaluated for use with cochlear implants (CIs). Fifteen postlingually deafened adult CI users participated. Absolute thresholds for 200-ms trains of biphasic pulses were measured using the new tracking procedure and were compared with thresholds obtained with a traditional forced-choice adaptive procedure under both monopolar and quadrupolar stimulation. Virtual spectral sweeps across the electrode array were implemented in the tracking procedure via current steering, which divides the current between two adjacent electrodes and varies the proportion of current directed to each electrode. Overall, no systematic differences were found between threshold estimates with the new channel sweep procedure and estimates using the adaptive forced-choice procedure. Test-retest reliability for the thresholds from the sweep procedure was somewhat poorer than for thresholds from the forced-choice procedure. However, the new method was about 4 times faster for the same number of repetitions. Overall the reliability and speed of the new tracking procedure provides it with the potential to estimate thresholds in a clinical setting. Rapid methods for estimating thresholds could be of particular clinical importance in combination with focused stimulation techniques that result in larger threshold variations between electrodes.


Hematologic abnormalities preceding apparent recovery from feline leukemia virus infection.
A 5-month-old domestic short-haired cat was referred to the Western College of Veterinary Medicine because of hemorrhage from the mouth. Neutropenia and bone marrow dyscrasia developed within 2 weeks, and results of a fluorescent antibody test for feline leukemia virus (FeLV) were positive. During the next 6 months, the feline oncornavirus cell membrane-associated antibody titer increased, the hematologic abnormalities regressed, and the cat became negative to the FeLV fluorescent antibody test (FeLV test). The results of 3 consecutive FeLV tests were negative, and the cat has been clinically normal for the past 18 months.


On the nature and signatures of the solvated electron in water.
The hydrated electron is one of the simplest chemical transients and has been the subject of intense investigation and speculation since its discovery in 1962 by Hart and Boag. Although extensive kinetic and spectroscopic research on this species has been reported for many decades, its structure, i.e., the dominant electron-water binding motif, and its binding energy remained uncertain. A recent milestone in the research on the hydrated electron was the determination of its binding energy by liquid-jet photoelectron spectroscopy. It turned out that the assumption of a single electron binding motif in liquid water is an oversimplification. In addition to different isomers in cluster spectroscopy and different transient species of unknown structure in ultrafast experiments, long-lived hydrated electrons near the surface of liquid water have recently been discovered. The present article gives an account of recent work on the topic "solvated electrons" from the perspectives of cluster spectroscopy, condensed-phase spectroscopy, as well as theory. It highlights and critically discusses recent findings and their implications for our understanding of electron solvation in aqueous environments.


Paleontology and the comparative method: ancestral node reconstructions versus observed node values.
Comparative methods are used to reconstruct ancestral node values for continuously varying traits. The confidence intervals (CIs) around such estimates may be wider than the range of tip data from which they are calculated. Without historical data with which to compare estimates, it is not clear whether such broad CIs reflect evolutionary lability or methodological imprecision. In this study, a fully resolved phylogeny of fossil carnivorans, in which observed samples are found not only at the tree tips but also along branches and at nodes, is used to compare observed ancestral node values with node estimates based on a Brownian motion model of evolution. As in previous studies, the CIs surrounding node estimates were wider than the range of tree tip values, but observed values fell well within them, reasonably close to the values predicted by comparative methods. Confidence intervals calculated using paleontological rate estimates were comparable to those calculated using only terminal taxa. This implies that evolution of at least some traits is conservative enough for node reconstruction techniques to be useful, despite their large standard errors. The Brownian motion model of evolutionary change was a good predictor of node values.


A Randomized, Placebo-Controlled Phase 2 Trial of CNTO 6785 in Chronic Obstructive Pulmonary Disease.
Interleukin (IL)-17A may be an underlying factor in the pathophysiology of chronic obstructive pulmonary disease (COPD). Anti-IL-17 monoclonal antibodies have been used successfully in treating several immune-mediated inflammatory diseases. This phase 2, randomized, placebo-controlled, double-blind, parallel-group, proof-of-concept study is the first clinical study evaluating the efficacy and safety of the anti-IL-17A monoclonal antibody CNTO 6785 in patients with symptomatic moderate-to-severe COPD. Patients were treated with CNTO 6785 (n = 93) or placebo (n = 94) intravenously at Weeks 0, 2, and 4 (induction), then Weeks 8 and 12, and followed till Week 24. The primary efficacy endpoint was the change from baseline in pre-bronchodilator percent-predicted forced expiratory volume in 1 second at Week 16. Samples were collected at all visits for pharmacokinetic (PK) evaluation, and standard safety assessments were performed. The mean difference in the primary efficacy endpoint between CNTO 6785 and placebo was not statistically significant (-0.49%; p = 0.599). No other efficacy endpoints demonstrated clinically or statistically significant differences with CNTO 6785 compared with placebo. CNTO 6785 was generally well tolerated; no major safety signals were detected. The most frequently reported treatment-emergent adverse events were infections and infestations; however, no notable differences were observed between CNTO 6785 and placebo in terms of rates of infections. PK results suggested that the steady state of serum CNTO 6785 concentration was reached within 16 weeks. These results suggest that IL-17A is unlikely to be a dominant driver in the pathology of, or a viable therapeutic target for, COPD. ClinicalTrials.gov Identifier: NCT01966549; EudraCT Identifier: 2012-003607-36.


A first full outer capsid protein sequence data-set in the Orbivirus genus (family Reoviridae): cloning, sequencing, expression and analysis of a complete set of full-length outer capsid VP2 genes of the nine African horsesickness virus serotypes.
The outer capsid protein VP2 of African horsesickness virus (AHSV) is a major protective antigen. We have cloned full-length VP2 genes from the reference strains of each of the nine AHSV serotypes. Baculovirus recombinants expressing the cloned VP2 genes of serotypes 1, 2, 4, 6, 7 and 8 were constructed, confirming that they all have full open reading frames. This work completes the cloning and expression of the first full set of AHSV VP2 genes. The clones of VP2 genes of serotypes 1, 2, 5, 7 and 8 were sequenced and their amino acid sequences were deduced. Our sequencing data, together with that of the published VP2 genes of serotypes 3, 4, 6 and 9, were used to generate the first complete sequence analysis of all the (sero)types for a species of the Orbivirus genus. Multiple alignment of the VP2 protein sequences showed that homology between all nine AHSV serotypes varied between 47.6 % and 71.4 %, indicating that VP2 is the most variable AHSV protein. Phylogenetic analysis grouped together the AHSV VP2s of serotypes that cross-react serologically. Low identity between serotypes was demonstrated for specific regions within the VP2 amino acid sequences that have been shown to be antigenic and play a role in virus neutralization. The data presented here impact on the development of new vaccines, the identification and characterization of antigenic regions, the development of more rapid molecular methods for serotype identification and the generation of comprehensive databases to support the diagnosis, epidemiology and surveillance of AHS.


Spatial resolution dependence on spectral frequency in human speech cortex electrocorticography.
Electrocorticography (ECoG) has become an important tool in human neuroscience and has tremendous potential for emerging applications in neural interface technology. Electrode array design parameters are outstanding issues for both research and clinical applications, and these parameters depend critically on the nature of the neural signals to be recorded. Here, we investigate the functional spatial resolution of neural signals recorded at the human cortical surface. We empirically derive spatial spread functions to quantify the shared neural activity for each frequency band of the electrocorticogram. Five subjects with high-density (4 mm center-to-center spacing) ECoG grid implants participated in speech perception and production tasks while neural activity was recorded from the speech cortex, including superior temporal gyrus, precentral gyrus, and postcentral gyrus. The cortical surface field potential was decomposed into traditional EEG frequency bands. Signal similarity between electrode pairs for each frequency band was quantified using a Pearson correlation coefficient. The correlation of neural activity between electrode pairs was inversely related to the distance between the electrodes; this relationship was used to quantify spatial falloff functions for cortical subdomains. As expected, lower frequencies remained correlated over larger distances than higher frequencies. However, both the envelope and phase of gamma and high gamma frequencies (30-150 Hz) are largely uncorrelated (<90%) at 4 mm, the smallest spacing of the high-density arrays. Thus, ECoG arrays smaller than 4 mm have significant promise for increasing signal resolution at high frequencies, whereas less additional gain is achieved for lower frequencies. Our findings quantitatively demonstrate the dependence of ECoG spatial resolution on the neural frequency of interest. We demonstrate that this relationship is consistent across patients and across cortical areas during activity.