Hospice at home service: the carer's perspective.
The aim of this study was to explore the bereaved caregivers' experience of the Hospice at Home service delivered in one region of the UK. Three hundred and ten bereaved caregivers identified by the Community Specialist Palliative Care Team or Hospice at Home nurse, who met inclusion criteria, were sent a postal questionnaire to explore their views and experiences of the Hospice at Home service. Data were collected during 2002. In total, 128 caregivers responded, providing a 41% response rate. Most caregivers believed that the Hospice at Home service enabled their loved one's wish to be cared for and to die at home to be fulfilled. A number of suggestions were made relating to increased awareness of the service, training for staff, coordination of service delivery and bereavement support. The bereaved caregivers were thankful for the Hospice at Home service; however, the need for practical support, increased awareness of the Hospice at Home service and bereavement support were also identified. Although the bereaved caregivers provided a valuable insight in evaluating service provision, it is acknowledged that some caregivers are often so grateful for the treatment and care received that they tend to forget or ignore their less pleasant experiences. Further research is therefore required using an in-depth qualitative approach investigating on the carers' views and experiences of accessing the Hospice at Home service.


Addition of trans fat and alcohol has divergent effects on atherogenic diet-induced liver injury in rodent models of steatohepatitis.
Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are common causes of chronic liver disease. The overlap between ALD and NAFLD suggests the existence of metabolic steatohepatitis. Development of in vivo models that reflect various aspects of human steatohepatitis is essential for drug discovery. We aimed to characterize several models of steatohepatitis (SH) and to investigate whether the pathology could be modulated. Sprague-Dawley rats were fed a high-fat diet (HFD) for 9 wk, followed by either a high-fat, high-cholesterol and cholate diet (HFC) or a HFC diet containing 13% trans fat (HFC-TF). A subset received 15% ethanol-water twice a week for 12 wk. Serum triglycerides, cholesterol, LDL, HDL, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and rodent NH2-terminal propeptide of type III collagen (rPRO-C3) were assessed. The liver was weighed and evaluated using modified Nonalcoholic Steatohepatitis Clinical Research Network histological score system criteria. All diets induced hepatomegaly, but only HFC-TF increased the size of visceral adipose tissue. Trans fat augmented HFC-induced dyslipidemia, and cholesterol was higher and HDL was lower in the HFC-TF groups. Alcohol lowered triglycerides in both dietary groups. HFC elevated ALT and AST, which were lowered by trans fat. All diets induced histological SH, addition of trans fat induced more steatosis but less inflammation. Inclusion of alcohol augmented the HFC-induced inflammation. All diets induced mild fibrosis. Inclusion of trans fat and alcohol significantly increased rPRO-C3. The addition of trans fat reduced the HFC-induced inflammation but augmented steatosis and dyslipidemia. Inclusion of alcohol induced a more inflammatory and fibrogenic phenotype.NEW & NOTEWORTHY Alcoholic liver disease and nonalcoholic liver disease share significant overlap, which suggests the existence of metabolic steatohepatitis. Trans fat has been implicated in steatohepatitis development. Here, we show that the addition of trans fat to an atherogenic diet results in a more steatotic but less inflammatory phenotype, whereas the addition of alcohol to an atherogenic diet augments the inflammatory and fibrogenic properties of the diet.


How Large Is the Role of Emotion in Judgments of Moral Dilemmas?
Moral dilemmas often pose dramatic and gut-wrenching emotional choices. It is now widely accepted that emotions are not simply experienced alongside people's judgments about moral dilemmas, but that our affective processes play a central role in determining those judgments. However, much of the evidence purporting to demonstrate the connection between people's emotional responses and their judgments about moral dilemmas has recently been called into question. In the present studies, we reexamined the role of emotion in people's judgments about moral dilemmas using a validated self-report measure of emotion. We measured participants' specific emotional responses to moral dilemmas and, although we found that moral dilemmas evoked strong emotional responses, we found that these responses were only weakly correlated with participants' moral judgments. We argue that the purportedly strong connection between emotion and judgments of moral dilemmas may have been overestimated.


Device-Measured Sedentary Behavior, Physical Activity and Aerobic Fitness Are Independent Correlates of Cognitive Performance in Healthy Middle-Aged Adults-Results from the SCAPIS Pilot Study.
High aerobic fitness, more moderate to vigorous physical activity (MVPA) and less sedentary behavior (SED) have all been suggested to promote cognitive functions, but it is unclear whether they are independent predictors of specific cognitive domains. This study aimed to investigate to what extent aerobic fitness MVPA and SED are independently associated with cognitive performance among middle-aged Swedish adults. We acquired device-based measures of aerobic fitness, cognitive performance and percent daily time spent in MVPA and SED in Swedish adults (n = 216; 54-66 years old). Aerobic fitness was associated with better performance at one out of two tests of speed/attention and one out of four tests of executive attention, and with worse performance at one of seven tests of memory. Increasing %MVPA was associated with better performance at one out of seven tests of memory and two out of three tests of verbal ability, whereas increasing %SED was associated with better performance at all four tests of executive attention and four out of seven tests of memory. These findings suggest that aerobic fitness, %MVPA and %SED are partly independent correlates of cognitive performance. To fully understand the association between SED and performance at several tests of cognitive function, future investigations might attempt to investigate intellectually engaging SED (such as reading books) separately from mentally undemanding SED (such as watching TV).


A qualitative study of influences on older women's practitioner choices for back pain care.
Back pain is an increasingly prevalent health concern amongst Australian women for which a wide range of treatment options are available, offered by biomedical, allied health and complementary and alternative medicine (CAM) providers. Although there is an emerging literature on patterns of provider utilisation, less is known about the reasons why women with back pain select their chosen practitioner. In this paper we explore the influences on back pain sufferers' decision-making about treatment seeking with practitioners for their most recent episode of back pain. Drawing on 50 semi-structured interviews with women aged 60-65 years from the Australian Longitudinal Study on Women's Health (ALSWH) who have chronic back pain, we focus on the factors which influence their choice of practitioner. Analysis followed a framework approach to qualitative content analysis, augmented by NVivo 9 qualitative data analysis software. Key themes were identified and tested for rigour through inter-rater reliability and constant comparison. The women identified four predominant influences on their choice of practitioner for back pain: familiarity with treatment or experiences with individual practitioners; recommendations from social networks; geographical proximity of practitioners; and, qualifications and credentials of practitioners. The therapeutic approach or evidence-base of the practices being utilised was not reported by the women as central to their back pain treatment decision making. Choice of practitioner appears to be unrelated to the therapeutic approaches, treatment practices or the scientific basis of therapeutic practices. Moreover, anecdotal lay reports of effectiveness and the 'treatment experience' may be more influential than formal qualifications in guiding women's choice of practitioner for their back pain. Further work is needed on the interpersonal, collective and subjective underpinnings of practitioner choice, particularly over time, in order to better understand why women utilise certain practitioners for back pain.


Asymmetric expression level of clock genes in left vs. right nasal mucosa in humans with and without allergies and in rats: Circadian characteristics and possible contribution to nasal cycle.
Numerous peripheral tissues possess self-sustaining daily biologic rhythms that are regulated at the molecular level by clock genes such as PER1, PER2, CLOCK, and BMAL1. Physiological function of nasal mucosa exhibits rhythmic variability to a day-night environmental cycle. Nevertheless, little is known of the expression and distribution pattern of clock genes in nasal mucosa. The present study investigates the expression level and distribution pattern of PER1, PER2, CLOCK, and BMAL1 genes in nasal mucosa of healthy controls, allergic rhinitis patients, and normal rats. In human and rat nasal mucosa, the levels of these genes are asymmetrically expressed in nasal mucosa derived from right and left cavities in normal controls, allergic patients, and rat. In human nasal mucosa, the expression levels of these genes were higher in the decongested side than the congested mucosa. In rat nasal mucosa, these clock genes are expressed in a rhythmic circadian manner under the regular light/dark cycles. The expression levels of MUC5AC, a key mucin genes produced in superficial epithelium, are higher in decongested side than that congested side in human nasal mucosa. In rat nasal mucosa, MUC5AC levels showed a circadian rhythm which was associated with different expression levels in nasal mucosa derived from the right and left nasal cavities. Taken together with these results, the present study shows that the clock genes such as PER1, PER2, CLOCK, and BMAL1 are present in human and rat nasal mucosa, and suggest that these clock genes may control the pathophysiological function of nasal mucosa as circadian oscillators and affect the maintenance of the nasal cycle.


Medical education for a healthier population: reflections on the Flexner Report from a public health perspective.
Abraham Flexner's 1910 report is credited with promoting critical reforms in medical education. Because Flexner advocated scientific rigor and standardization in medical education, his report has been perceived to place little emphasis on the importance of public health in clinical education and training. However, a review of the report reveals that Flexner presciently identified at least three public-health-oriented principles that contributed to his arguments for medical education reform: (1) The training, quality, and quantity of physicians should meet the health needs of the public, (2) physicians have societal obligations to prevent disease and promote health, and medical training should include the breadth of knowledge necessary to meet these obligations, and (3) collaborations between the academic medicine and public health communities result in benefits to both parties. In this article, commemorating the Flexner Centenary, the authors review the progress of U.S. and Canadian medical schools in addressing these principles in the context of contemporary societal health needs, provide an update on recent efforts to address what has long been perceived as a deficit in medical education (inadequate grounding of medical students in public health), and provide new recommendations on how to create important linkages between medical education and public health. Contemporary health challenges that require a public health approach in addition to one-on-one clinical skills include containing epidemics of preventable chronic diseases, reforming the health care system to provide equitable high-quality care to populations, and responding to potential disasters in an increasingly interconnected world. The quantitative skills and contextual knowledge that will prepare physicians to address these and other population health problems constitute the basics of public health and should be included throughout the continuum of medical education.


The role of single cell mechanical behavior and polarity in driving collective cell migration.
The directed migration of cell collectives is essential in various physiological processes, such as epiboly, intestinal epithelial turnover, and convergent extension during morphogenesis as well as during pathological events like wound healing and cancer metastasis. Collective cell migration leads to the emergence of coordinated movements over multiple cells. Our current understanding emphasizes that these movements are mainly driven by large-scale transmission of signals through adherens junctions. In this study, we show that collective movements of epithelial cells can be triggered by polarity signals at the single cell level through the establishment of coordinated lamellipodial protrusions. We designed a minimalistic model system to generate one-dimensional epithelial trains confined in ring shaped patterns that recapitulate rotational movements observed in vitro in cellular monolayers and in vivo in genitalia or follicular cell rotation. Using our system, we demonstrated that cells follow coordinated rotational movements after the establishment of directed Rac1-dependent polarity over the entire monolayer. Our experimental and numerical approaches show that the maintenance of coordinated migration requires the acquisition of a front-back polarity within each single cell but does not require the maintenance of cell-cell junctions. Taken together, these unexpected findings demonstrate that collective cell dynamics in closed environments as observed in multiple in vitro and in vivo situations can arise from single cell behavior through a sustained memory of cell polarity.


Complementary and alternative provider use by insured patients with diabetes in Washington State.
The authors investigated whether insurance coverage for complementary and alternative medicine (CAM) providers is associated with increased medical care use among diabetes patients. Predictors of CAM use and how CAM affects health care use and expenditures under insurance coverage were examined. Claims data from two large insurers in Washington State were obtained for 2002. Types of providers used, comorbid medical conditions, number of visits, and expenditures were calculated for the study sample and compared to a nondiabetic matched group. Of the 20,722 adults with diabetes, 3605 (17.4%) had one or more visits to any licensed CAM provider (mostly chiropractors). This was lower than the 20% CAM use in the comparison group. Diabetes patients who used CAM were more likely to have multiple other medical problems than CAM nonusers. CAM users had a higher average number of annual outpatient visits compared to nonusers (28 versus 16), and higher average annual expenditures (8,736 dollars versus 7,356 dollars); however, after adjustment for disease load and other factors, CAM use was not a significant predictor of expenditures. CAM use was <2% of the overall mean medical expenditures for diabetes patients. Quality of conventional care was similar for CAM users and nonusers. CAM provider usage when covered by insurance is lower among diabetes patients than in adults without diabetes and represents a small proportion of diabetes care costs. Very few CAM visits were related directly to diabetes care. CAM-using patients often have heavy disease burdens and high total expected resource use compared to those not using CAM.


Surgical options in the management of groin hernias.
Inguinal and femoral hernias are the most common conditions for which primary care physicians refer patients for surgical management. Hernias usually present as swelling accompanied by pain or a dragging sensation in the groin. Most hernias can be diagnosed based on the history and clinical examination, but ultrasonography may be useful in differentiating a hernia from other causes of groin swelling. Surgical repair is usually advised because of the danger of incarceration and strangulation, particularly with femoral hernias. Three major types of open repair are currently used, and laparoscopic techniques are also employed. The choice of technique depends on several factors, including the type of hernia, anesthetic considerations, cost, period of postoperative disability and the surgeon's expertise. Following initial herniorrhaphy, complication and recurrence rates are generally low. Laparoscopic techniques make it possible for patients to return to normal activities more quickly, but they are more costly than open procedures. In addition, they require general anesthesia, and the long-term hernia recurrence rate with these procedures is unknown.


Estimating the functional dimensionality of neural representations.
Recent advances in multivariate fMRI analysis stress the importance of information inherent to voxel patterns. Key to interpreting these patterns is estimating the underlying dimensionality of neural representations. Dimensions may correspond to psychological dimensions, such as length and orientation, or involve other coding schemes. Unfortunately, the noise structure of fMRI data inflates dimensionality estimates and thus makes it difficult to assess the true underlying dimensionality of a pattern. To address this challenge, we developed a novel approach to identify brain regions that carry reliable task-modulated signal and to derive an estimate of the signal's functional dimensionality. We combined singular value decomposition with cross-validation to find the best low-dimensional projection of a pattern of voxel-responses at a single-subject level. Goodness of the low-dimensional reconstruction is measured as Pearson correlation with a test set, which allows to test for significance of the low-dimensional reconstruction across participants. Using hierarchical Bayesian modeling, we derive the best estimate and associated uncertainty of underlying dimensionality across participants. We validated our method on simulated data of varying underlying dimensionality, showing that recovered dimensionalities match closely true dimensionalities. We then applied our method to three published fMRI data sets all involving processing of visual stimuli. The results highlight three possible applications of estimating the functional dimensionality of neural data. Firstly, it can aid evaluation of model-based analyses by revealing which areas express reliable, task-modulated signal that could be missed by specific models. Secondly, it can reveal functional differences across brain regions. Thirdly, knowing the functional dimensionality allows assessing task-related differences in the complexity of neural patterns.


Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey.
Recent studies suggest a role for vitamin D in innate immunity, including the prevention of respiratory tract infections (RTIs). We hypothesize that serum 25-hydroxyvitamin D (25[OH]D) levels are inversely associated with self-reported recent upper RTI (URTI). We performed a secondary analysis of the Third National Health and Nutrition Examination Survey, a probability survey of the US population conducted between 1988 and 1994. We examined the association between 25(OH)D level and recent URTI in 18 883 participants 12 years and older. The analysis adjusted for demographics and clinical factors (season, body mass index, smoking history, asthma, and chronic obstructive pulmonary disease). The median serum 25(OH)D level was 29 ng/mL (to convert to nanomoles per liter, multiply by 2.496) (interquartile range, 21-37 ng/mL), and 19% (95% confidence interval [CI], 18%-20%) of participants reported a recent URTI. Recent URTI was reported by 24% of participants with 25(OH)D levels less than 10 ng/mL, by 20% with levels of 10 to less than 30 ng/mL, and by 17% with levels of 30 ng/mL or more (P < .001). Even after adjusting for demographic and clinical characteristics, lower 25(OH)D levels were independently associated with recent URTI (compared with 25[OH]D levels of > or =30 ng/mL: odds ratio [OR], 1.36; 95% CI, 1.01-1.84 for <10 ng/mL and 1.24; 1.07-1.43 for 10 to <30 ng/mL). The association between 25(OH)D level and URTI seemed to be stronger in individuals with asthma and chronic obstructive pulmonary disease (OR, 5.67 and 2.26, respectively). Serum 25(OH)D levels are inversely associated with recent URTI. This association may be stronger in those with respiratory tract diseases. Randomized controlled trials are warranted to explore the effects of vitamin D supplementation on RTI.


Skin manifestation of Stenotrophomonas maltophilia infection--a case report and review article.
Stenotrophomonas maltophilia is an aerobic gram-negative bacillus that is a frequent coloniser of fluids used in the hospital setting. It causes infection in immunosuppressed hosts, especially those who are neutropaenic, on chemotherapy and broad spectrum antibiotics. Skin and soft tissue manifestations of Stenotrophomonas maltophilia infection are becoming an increasingly recognised entity; the clinical spectrum ranges from mucocutaneous, skin to soft tissue infections. We present a case of an 8-year-old girl with acute myeloid leukaemia who developed metastatic skin lesions secondary to Stenotrophomonas maltophilia bacteraemia. The authors reviewed a total of 24 reported cases of mucocutaneous, skin and soft tissue infections by Stenotrophomonas maltophilia. The presentations include metastatic cellulitis, primary cellulitis and infected mucocutaneous ulcers. This is the first locally reported case of metastatic nodular skin lesions caused by Stenotrophomonas maltophilia bacteraemia. This is also the first reported paediatric case of embolic skin lesions caused by Stenotrophomonas maltophilia. Of the 6 cases of Stenotrophomonas maltophilia bacteraemia seen in the paediatric oncology patients from year 2000 to 2004 at our hospital, only 1 case developed metastatic skin lesions. Stenotrophomonas maltophilia skin infection should be included into the list of differential diagnoses for metastatic skin lesions in neutropaenic patients, especially with an underlying haematologic malignancy who has received recent chemotherapy and broad spectrum antibiotics. Haematologic malignancy, transplantation, neutropaenic, immunosuppressive therapy and a high severity of illness score were important prognostic factors.


Multiple phosphorylation sites confer reproducibility of the rod's single-photon responses.
Although signals controlled by single molecules are expected to be inherently variable, rod photoreceptors generate reproducible responses to single absorbed photons. We show that this unexpected reproducibility-the consistency of amplitude and duration of rhodopsin activity-varies in a graded and systematic manner with the number but not the identity of phosphorylation sites on rhodopsin's C terminus. These results indicate that each phosphorylation site provides an independent step in rhodopsin deactivation and that collectively these steps tightly control rhodopsin's active lifetime. Other G protein cascades may exploit a similar mechanism to encode accurately the timing and number of receptor activation.


Biomechanics of the ski cross start indoors on a customised training ramp and outdoors on snow.
An effective start enhances an athlete's chances of success in ski cross competitions. Accordingly, this study was designed to investigate the biomechanics of start techniques used by elite athletes and assess the influence of different start environments. Seven elite ski cross athletes performed starts indoors on a custom-built ramp; six of these also performed starts on an outdoor slope. Horizontal and vertical forces were measured by force transducers located in the handles of the start gate and a 12-camera motion capture system allowed monitoring of the sagittal knee, hip, shoulder, and elbow kinematics. The starting movement involved Pre, Pull, and Push phases. Significant differences between body sides were observed for peak vertical and resultant forces, resultant impulse, and peak angular velocity of the shoulder joint. Significantly lower peak vertical forces (44 N), higher resultant impulse (0.114 Ns/kg), and knee joint range of motion (12°) were observed indoors. Although movement in the ski cross start is generally symmetrical, asymmetric patterns of force were observed among the athletes. Two different movement strategies, i.e. pronounced hip extension or more accentuated elbow flexion, were utilised in the Pull phase. The patterns of force and movement during the indoor and outdoor starts were similar.


Hybrid mouse diversity panel: a panel of inbred mouse strains suitable for analysis of complex genetic traits.
We have developed an association-based approach using classical inbred strains of mice in which we correct for population structure, which is very extensive in mice, using an efficient mixed-model algorithm. Our approach includes inbred parental strains as well as recombinant inbred strains in order to capture loci with effect sizes typical of complex traits in mice (in the range of 5% of total trait variance). Over the last few years, we have typed the hybrid mouse diversity panel (HMDP) strains for a variety of clinical traits as well as intermediate phenotypes and have shown that the HMDP has sufficient power to map genes for highly complex traits with resolution that is in most cases less than a megabase. In this essay, we review our experience with the HMDP, describe various ongoing projects, and discuss how the HMDP may fit into the larger picture of common diseases and different approaches.


External validation of a 'response score' after neoadjuvant chemotherapy in patients with high-grade serous ovarian carcinoma with complete clinical response.
The chemotherapy response score (CRS) has been developed for measuring response to neoadjuvant chemotherapy in tubo-ovarian high-grade serous carcinoma. This study aimed to validate the ability of this three-tier scoring system of pathologic response on omental specimens to determine prognosis in a subgroups of patients who had clinical complete response to neoadjuvant chemotherapy. This was a retrospective study, conducted in women receiving interval debulking surgery at the Division of Gynecologic Oncology, between December 2007 and April 2017. Inclusion criteria were: high-grade serous ovarian cancer, FIGO stage IIIC/IV, platinum-based neoadjuvant chemotherapy, and clinical complete response after neoadjuvant chemotherapy (normalization in CA125 levels, disappearance of all target and non-target lesions according to RECIST 1.1). CRS was defined by a single pathology review and classified as previously reported: CRS1, no or minimal tumor response with fibroinflammatory changes limited to a few foci ranging from multifocal or diffuse regression-associated fibroinflammatory changes with viable tumor in sheets, or nodules to extensive regression-associated fibroinflammatory changes with multifocal residual tumor; CRS2, appreciable tumor response with viable tumor readily identifiable; and CRS3, complete absence of tumor or nodules with maximum size of 2 mm. CRS was analyzed according to clinical variables and survival. A total of 108 patients were eligible for analysis. The average age was 65 (range 36-85) years. A total of 91 (84.3%) patients had stage IIIC disease and 17 (15.7%) patients had stage IV disease. No statistically significant differences were observed in terms of age, FIGO stage, CA125 serum levels, type of chemotherapy schedules, and number of cycles between the three groups. Patients in the CRS3 group had a longer median progression-free survival (25.8 months) compared with CRS2 or CRS 1 (20.3 vs 17.4 months, respectively; p=0.001). Median overall survival was 68.9 months for CRS3, 35.0 months for CRS2, and 45.9 months for CRS1 (p=0.034). Complete or near-complete pathologic response assessed in the omental specimens of advanced epithelial ovarian carcinoma patients after neoadjuvant chemotherapy (CRS3) is predictive of prolonged progression-free and overall survival. In particular, this is true in women with a clinical complete response.


Hyperbaric oxygen treatment and enteral nutrition support with glutamine relieves traumatic brain injury in the rats.
The abnormal metabolic processes following traumatic brain injury (TBI) have been proposed to contribute to secondary injuries after TBI. Therefore, enteral nutrition (EN) support for TBI patients has received more attention. This study aimed to evaluate the complimentary effects of enteral nutrition with glutamine and hyperbaric oxygen (HBO) on the recovery of TBI. TBI model was established in SD rats, which were randomly divided into four groups: TBI, TBI + HBO, TBI + GLN, and TBI + HBO + GLN. Neuronal apoptosis in penumbra area was detected by TUNEL. Serum prealbumin level was detected by ELISA. Motor function was evaluated by beam-balance test. We found that the body weight of the rats had no significant differences in different groups before and after injury. Among the four groups, beam-balance test score was the lowest, serum prealbumin level was the highest, and neuronal apoptosis rate was the lowest in TBI + HBO + GLN group on day 3 and 7 after TBI. In conclusion, our data suggest that hyperbaric oxygen combined with enteral nutrition support with glutamine is effective in reducing neuronal apoptosis, increasing serum prealbumin concentration and improving neurological function after TBI injury.


Plasma Phospholipid and Sphingolipid Alterations in Presenilin1 Mutation Carriers: A Pilot Study.
Aberrant lipid metabolism has been implicated in sporadic Alzheimer's disease (AD). The current study investigated plasma phospholipid and sphingolipid profiles in individuals carrying PSEN1 mutations responsible for autosomal dominant AD (ADAD). Study participants evaluated were from the Perth and Melbourne sites of the Dominantly Inherited Alzheimer Network (DIAN) study. Plasma phospholipid and sphingolipid profiles were measured using liquid chromatography coupled with mass spectrometry in 20 PSEN1 mutation carriers (MC; eight of whom were symptomatic and twelve asymptomatic, based on Clinical Dementia Rating scores) and compared with six non carriers (NC) using linear mixed models. Further, AD gold standard biomarker data obtained from the DIAN database were correlated with lipid species significantly altered between MC and NC, using Spearman's correlation coefficient. One-hundred and thirty-nine plasma phospholipid and sphingolipid species were measured. Significantly altered species in MC compared to NC primarily belonged to choline and ethanolamine containing phospholipid classes and ceramides. Further phosphatidylcholine species (34:6, 36:5, 40:6) correlated with cerebrospinal fluid tau (p < 0.05), and plasmalogen ethanolamine species (34:2, 36:,4) correlated with both cerebrospinal fluid tau and brain amyloid load within the MC group (p < 0.05). These findings indicate altered phospholipid and sphingolipid metabolism in ADAD and provide insight into the pathomolecular changes occurring with ADAD pathogenesis. Further, findings reported in this study allow comparison of lipid alterations in ADAD with those reported previously in sporadic AD. The findings observed in the current pilot study warrant validation in the larger DIAN cohort.


Heparanase tailors syndecan for exosome production.
Exosomes are secreted vesicles involved in signaling processes. The biogenesis of a class of these vesicles depends on syntenin and syndecans. Heparanase acts as a regulator of the syndecan-syntenin-exosome biogenesis pathway. The upregulation of syntenin and heparanase in cancers may support the suspected roles of exosomes in tumor biology.


The development and evaluation of a novel thoracoscopic diaphragmatic hernia repair simulator.
Thoracoscopic diaphragmatic hernia (DH) repair has a high recurrence rate. Effective simulation modeling may improve technical performance for thoracoscopic DH repair. The study purpose was to evaluate measures of validity evidence for a low-cost thoracoscopic DH simulator. Synthetic diaphragm/intestine was connected to a to-scale left-sided neonatal rib cage and then covered with synthetic skin. Forty participants evaluated the DH repair simulator, using survey ratings that were analyzed for test content and internal structure validity evidence. Observed averages (on a scale of 0-5) for the domains were 4.6 for Relevance, 4.5 for Value, 4.3 for Physical attributes, 4.0 for Realism of experience, 3.8 for Realism of materials, and 4.2 for Ability to perform. The highest observed averages were "relevance to practice" and "value, testing tool," whereas the lowest ratings were realism, intestines and realism, diaphragm. The observed average of global opinion ratings was 2.84/4.0, indicating the simulator can be considered for teaching thoracoscopic DH repair but could be improved. Experienced surgeons (more than eight DH repairs, at least four thoracoscopic repairs) had higher overall ratings than inexperienced surgeons (4.4 versus 4.1, P=.001). We successfully created a thoracic space relevant to a thoracoscopic DH repair and completed the model using inexpensive, readily accessible materials. After participants performed a simulated thoracoscopic DH repair, their ratings indicated the simulator was relevant to clinical practice and valuable as a learning tool but still requires improvements. Improvements and additional evaluation of validity evidence (content, internal structure, response processes, and relationship to other variables) are necessary prior to full implementation of this model as an educational tool.


Anterior Cranial Vault Reconstruction With Distraction for Primary and Secondary Craniosynostosis Repair.
Traditional fronto-orbital advancement continues to be a useful operation for correction of craniosynostosis involving the coronal or metopic sutures. Recently, distraction osteogenesis has been used to correct a variety of cranial deformities. Studies have mostly focused on posterior vault distraction due to its simplicity and greater volume gain when compared with anterior vault distraction. However, certain patients are not candidates for posterior distraction due to anterior deformity and need for expansion of the frontal skull. The authors have developed a technique that allows for both reshaping as well as distraction of the anterior cranial vault.This was a retrospective chart review performed between March 2012 and October 2016 at a single institution by a single plastic surgeon. Thirty-nine (39) patients were included in this study. The indications for surgical intervention were signs of increased intracranial pressure or severe anterior skull deformity in the setting of craniosynostosis. The authors reviewed patient characteristics, length of follow-up, number of previous and subsequent surgeries, complications, and rate of relapse.The average age of patients undergoing the procedure was 5.2 years (range 6 months-15 years). Twenty-four (24) patients had 1 previous surgery, 3 had 2 previous surgeries, 1 had 3 previous surgeries, and 11 had no previous surgeries. The average follow-up was 2.5 years (range 6 months-4 years). One patient had a broken activation wire requiring return to the operating room. Three (3) patients (2 Apert and 1 Crouzon) underwent subsequent posterior vault distraction surgery. All patients demonstrated significant improvement in forehead cosmesis.Anterior cranial vault reconstruction with distraction is a safe alternative to traditional cranial vault reconstruction. It can improve forehead shape and position in older children who have had previous surgery as well as patients with severe anterior skull deformity associated with craniosynostosis.


Microdroplets: a sea of applications?
The exploitation of microdroplets produced within microfluidic environments has recently emerged as a new and exciting technological platform for applications within the chemical and biological sciences. Interest in microfluidic systems has been stimulated by a range of fundamental features that accompany system miniaturization. Such features include the ability to process and handle small volumes of fluid, improved analytical performance when compared to macroscale analogues, reduced instrumental footprints, low unit cost, facile integration of functional components and the exploitation of atypical fluid dynamics to control molecules in both time and space. Moreover, microfluidic systems that generate and utilize a stream of sub-nanolitre droplets dispersed within an immiscible continuous phase have the added advantage of allowing ultra-high throughput experimentation and being able to mimic conditions similar to that of a single cell (in terms of volume, pH, and salt concentration) thereby compartmentalizing biological and chemical reactions. This review provides an overview of methods for generating, controlling and manipulating droplets. Furthermore, we discuss key fields of use in which such systems may make a significant impact, with particular emphasis on novel applications in the biological and physical sciences.


Patient reports of the outcomes of treatment: a structured review of approaches.
Patient reports or ratings are essential for measuring the quality of patient care. Measures designed for this purpose tend to focus on the processes and structures of care rather than the outcomes of it. The latter is arguably the most valid indicator of the quality of care patients receive. Typically this information is gathered by probing patient satisfaction with treatment as part of an investigation of satisfaction with hospital care. More recently patient ratings of the outcome of treatment have been obtained to measure treatment efficacy in clinical trials. However, a more direct approach is to ask patients to assess the benefit of treatment on their current health status. We performed a structured literature review on patient reported satisfaction with outcomes of treatment and direct patient assessments of the same. The purpose of this was to identify suitable candidate questions for a short instrument to tap patient evaluations of in-patient hospital interventions. Articles were included if they dealt with patient satisfaction or patient assessment of the outcomes of treatment. Articles were excluded if they dealt more generally with patient satisfaction with care. We identified 169 papers, 79 were included in the review. The findings of this review suggest that there are a number of benefits of directly asking patients to assess the outcome of hospital treatment. Importantly this approach reflects outcomes relevant to the patient and is also more likely to reflect patient report in routine clinical practice. There is also evidence that such approaches have face validity and construct validity. The problems associated with this approach (i.e. response bias), are those common to patient reported outcome surveys, but employing appropriate strategies can minimize them. Furthermore, employing a simple set of questions that asks patients to assess the outcomes of treatment they receive can be time and resource efficient in comparison to administering lengthy measures. This approach could be tested for potential generic use as an evaluative measure for patients in hospital settings.


Lessons learned about ageing and gerontological nursing in South Africa.
The unprecedented global growth in older adults merits high-quality gerontological nursing care. As gerontological nursing grows in visibility in developed and developing countries, nurses must possess a broader worldview of ageing with knowledge of physiological, psychosocial, and cultural issues. The purpose of this article is to: (1) highlight lessons learned on differences and similarities in ageing and care of older adults in the United States of America (USA) and South Africa (SA); and (2) provide recommendations on how to advance gerontological nursing education in SA. A two-week international service-learning project was undertaken by visiting SA and learning about their nursing system and care of older adults. Service-learning is an innovative teaching-learning-service method that provided reflective and hands-on experience of gerontological nursing. This article provides a personal reflection of lessons learned about ageing and gerontological nursing during the service-learning project. Care of older adults in SA is in many ways different from and similar to that in the USA. Consequently global nurses should recognise those differences and provide culturally appropriate care. This service-learning experience also demonstrated the need for gerontological nursing education in SA. Based on this, recommendations on how to infuse and advance gerontological nursing education in SA are provided. Caring for older adults in a global context requires knowledge and understanding of cultures and their values and practices. With a growing population of diverse older adults, there is a need for incorporation.


In situ detection of beta-galactosidase in lenses of transgenic mice with a gamma-crystallin/lacZ gene.
Transgenic mice carrying the gamma 2-crystallin promoter fused to the coding region of the bacterial lacZ gene were generated. The offspring of three founder mice expressed high levels of the enzyme solely in the central nuclear fiber cells of the lens as measured by an in situ assay for the detection of beta-galactosidase activity. These results suggest that gamma 2-crystallin sequences between -759 to +45 contain essential information required for appropriate tissue-specific and temporal regulation of the mouse gamma 2-crystallin gene. In a broader context, this study also demonstrates the utility of beta-galactosidase hybrid gene constructs for monitoring the activity of gene regulatory elements in transgenic mice.


Pharmaceutical availability across levels of care: evidence from facility surveys in Ghana, Kenya, and Uganda.
In this study we use facility-level data from nationally representative surveys conducted in Ghana, Kenya, and Uganda to understand pharmaceutical availability within the three countries. In 2012, we conducted a survey to capture information on pharmaceuticals and other facility indicators from over 200 facilities in each country. We analyze data on the availability of pharmaceuticals and quantify its association with various facility-level indicators. We analyze both availability of essential medicines, as defined by the various essential medicine lists (EMLs) of each respective country, and availability of all surveyed pharmaceuticals deemed important for treatment of various high-burden diseases, including those on the EMLs. We find that there is heterogeneity with respect to availability across the three countries with Ghana generally having better availability than Uganda and Kenya. To analyze the relationship between facility-level factors and pharmaceutical stock-out we use a binomial regression model. We find that the factors associated with stock-out vary by country, but across all countries both presence of a laboratory at the facility and presence of a vehicle at the facility are significantly associated with reduced stock-out. The results of this study highlight the poor availability of essential medicines across these three countries and suggest more needs to be done to strengthen the supply system so that stock remains uninterrupted.


Anthocyanins remain stable during commercial blackcurrant juice processing.
It remains important to establish the stability of anthocyanins throughout commercial processing in order to maintain the bioactivity of the processed food/s. The present study aimed to assess the recovery and formation of anthocyanins and their free phenolic acid degradation products during the commercial processing of blackcurrant juice concentrate. A bench-scale processing model was also established to allow for alteration of predefined parameters to identify where commercial processes could be modified to influence anthocyanin yield. No significant loss in anthocyanins was observed throughout the commercial processing of blackcurrants, from whole berry through milling, to pectin hydrolysis and sodium bisulphite addition (P ≥ 0.7). No significant loss in anthocyanins was observed following the subsequent processing of pressed juice, through pasteurization, decantation, filtration, and concentration (P ≥ 0.9). Similarly, the bench-scale model showed no significant losses in anthocyanin content except during pasteurization (22%± 0.7%, P < 0.001). In the full-factorial Design of Experiment model analysis, only sodium bisulphite concentration had an impact on anthocyanin recovery, which resulted in an increase (23% to 27%; P < 0.001) in final anthocyanin concentration. No phenolic degradation products (free protocatechuic acid or gallic acid derived from cyanidin and delphinin species, respectively) were identified in any processed sample when compared to authentic analytical standards, analyzed by ultra-performance liquid chromatography DAD. This article provides crucial data directly applicable to commercial juice processing, such as improving anthocyanin yield and practical considerations for anthocyanin stability and degradation. This aspect is particularly pertinent considering the current commercial interest in anthocyanin-derived phenolic acids and their health-related benefits. Further research and development targets in the area of commercial juice product development are identified.


Scalable coating and properties of transparent, flexible, silver nanowire electrodes.
We report a comprehensive study of transparent and conductive silver nanowire (Ag NW) electrodes, including a scalable fabrication process, morphologies, and optical, mechanical adhesion, and flexibility properties, and various routes to improve the performance. We utilized a synthesis specifically designed for long and thin wires for improved performance in terms of sheet resistance and optical transmittance. Twenty Omega/sq and approximately 80% specular transmittance, and 8 ohms/sq and 80% diffusive transmittance in the visible range are achieved, which fall in the same range as the best indium tin oxide (ITO) samples on plastic substrates for flexible electronics and solar cells. The Ag NW electrodes show optical transparencies superior to ITO for near-infrared wavelengths (2-fold higher transmission). Owing to light scattering effects, the Ag NW network has the largest difference between diffusive transmittance and specular transmittance when compared with ITO and carbon nanotube electrodes, a property which could greatly enhance solar cell performance. A mechanical study shows that Ag NW electrodes on flexible substrates show excellent robustness when subjected to bending. We also study the electrical conductance of Ag nanowires and their junctions and report a facile electrochemical method for a Au coating to reduce the wire-to-wire junction resistance for better overall film conductance. Simple mechanical pressing was also found to increase the NW film conductance due to the reduction of junction resistance. The overall properties of transparent Ag NW electrodes meet the requirements of transparent electrodes for many applications and could be an immediate ITO replacement for flexible electronics and solar cells.


Parts per billion detection of uranium with a porphyrinoid-containing nanoparticle and in vivo photoacoustic imaging.
Chemical tools that can report radioactive isotopes would be of interest to the defense community. Here we report ∼250 nm polymeric nanoparticles containing porphyrinoid macrocycles with and without pre-complexed depleted uranium and demonstrate that the latter species may be detected easily and with high sensitivity via photoacoustic imaging. The porphyrinoid macrocycles used in the present study are non-aromatic in the absence of the uranyl cation, but aromatic after cation complexation. We solubilized both the freebase and metalated forms of the macrocycles in poly(lactic-co-glycolic acid) and found a peak in the photoacoustic spectrum at 910 nm excitation in the case of the uranyl complex. The signal was stable for at least 15 minutes and allowed detection of uranium concentrations down to 6.2 ppb (5.7 nM) in vitro and 0.57 ppm (19 fCi; 0.52 μM) in vivo. To the best of our knowledge, this is the first report of a nanoparticle that detects an actinide cation via photoacoustic imaging.


Genome-scale CRISPR-Cas9 knockout screening in human cells.
The simplicity of programming the CRISPR (clustered regularly interspaced short palindromic repeats)-associated nuclease Cas9 to modify specific genomic loci suggests a new way to interrogate gene function on a genome-wide scale. We show that lentiviral delivery of a genome-scale CRISPR-Cas9 knockout (GeCKO) library targeting 18,080 genes with 64,751 unique guide sequences enables both negative and positive selection screening in human cells. First, we used the GeCKO library to identify genes essential for cell viability in cancer and pluripotent stem cells. Next, in a melanoma model, we screened for genes whose loss is involved in resistance to vemurafenib, a therapeutic RAF inhibitor. Our highest-ranking candidates include previously validated genes NF1 and MED12, as well as novel hits NF2, CUL3, TADA2B, and TADA1. We observe a high level of consistency between independent guide RNAs targeting the same gene and a high rate of hit confirmation, demonstrating the promise of genome-scale screening with Cas9.


Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes mellitus: a randomized, blinded, prospective phase III study.
Dapagliflozin is a highly selective, orally active inhibitor of renal sodium-glucose cotransporter 2 that reduces hyperglycemia by increasing urinary glucose excretion. The goal of this study was to evaluate dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes whose disease was inadequately controlled with diet and exercise. In this Phase III, multicenter, parallel-group, double-blind study, drug-naive patients with glycosylated hemoglobin (HbA1c) levels ≥7.0% to ≤10.5% (≥53-≤91 mmol/mol) were randomized (by using an interactive voice response system) to receive placebo (n = 132), dapagliflozin 5 mg (n = 128), or dapagliflozin 10 mg (n = 133). The primary end point was mean change from baseline in HbA1c level at week 24 (last-observation-carried-forward). Secondary end points included changes in fasting plasma glucose, 2-hour postprandial glucose, body weight, and other glycemic parameters. Baseline characteristics were balanced across groups. Most patients (89%) were Chinese, median disease duration was 0.2 year, and mean HbA1c level was 8.26%. Most patients (87%) completed the study. At week 24, mean reductions in HbA1c were -0.29% for placebo versus -1.04% and -1.11% for dapagliflozin 5 and 10 mg, respectively (P < 0.0001 for both doses). Changes in fasting plasma glucose were 2.5, -25.1, and -31.6 mg/dL (0.14, -1.39, and -1.75 mmol/L) for placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg. Changes in 2-hour postprandial glucose were 1.1, -46.8, and -54.9 mg/dL (0.06, -2.60, and -3.05 mmol/L). Reductions in body weight were -0.27, -1.64, and -2.25 kg. Proportions of patients achieving HbA1c levels <7.0% (53 mmol/mol) were 21.3%, 42.6%, and 49.8%. Adverse events (AEs) occurred in 63.6%, 61.7%, and 60.9% of patients, and serious AEs occurred in 1.5%, 3.9%, and 3.0% of patients. No deaths occurred. Hypoglycemia was uncommon (1.5%, 0.8%, and 0.8%); no hypoglycemic event led to discontinuation. Genital infections occurred in 0.8%, 3.1%, and 4.5% of patients and urinary tract infections in 3.0%, 3.9%, and 5.3% of patients. No AEs of renal infection or pyelonephritis were reported. No changes in renal function or AEs of renal failure occurred. Compared with placebo, dapagliflozin 5 and 10 mg demonstrated clinically and statistically significant improvements in HbA1c levels after 24 weeks of treatment. Dose-dependent, statistically significant reductions in fasting plasma glucose, postprandial glucose, and weight were also observed for both doses compared with placebo. AEs and serious AEs were balanced across groups, with low rates of hypoglycemia and no increase in renal events. Genital infections and urinary tract infections were more common with dapagliflozin. Dapagliflozin as monotherapy in these drug-naive Asian patients was well tolerated, significantly improving glycemic control with the additional benefit of weight loss.


Regulatory networks define phenotypic classes of human stem cell lines.
Stem cells are defined as self-renewing cell populations that can differentiate into multiple distinct cell types. However, hundreds of different human cell lines from embryonic, fetal and adult sources have been called stem cells, even though they range from pluripotent cells-typified by embryonic stem cells, which are capable of virtually unlimited proliferation and differentiation-to adult stem cell lines, which can generate a far more limited repertoire of differentiated cell types. The rapid increase in reports of new sources of stem cells and their anticipated value to regenerative medicine has highlighted the need for a general, reproducible method for classification of these cells. We report here the creation and analysis of a database of global gene expression profiles (which we call the 'stem cell matrix') that enables the classification of cultured human stem cells in the context of a wide variety of pluripotent, multipotent and differentiated cell types. Using an unsupervised clustering method to categorize a collection of approximately 150 cell samples, we discovered that pluripotent stem cell lines group together, whereas other cell types, including brain-derived neural stem cell lines, are very diverse. Using further bioinformatic analysis we uncovered a protein-protein network (PluriNet) that is shared by the pluripotent cells (embryonic stem cells, embryonal carcinomas and induced pluripotent cells). Analysis of published data showed that the PluriNet seems to be a common characteristic of pluripotent cells, including mouse embryonic stem and induced pluripotent cells and human oocytes. Our results offer a new strategy for classifying stem cells and support the idea that pluripotency and self-renewal are under tight control by specific molecular networks.


Nicotinic acid decreases serum thyroid hormone levels while maintaining a euthyroid state.
To evaluate the effects of nicotinic acid on serum thyroid hormone levels in the absence of systemic illness or hepatic dysfunction. We determined the effect of treatment with nicotinic acid on serum thyroid hormone levels in one female and four male patients (mean age, 44.4 years) with hyperlipidemia. In the five study patients, we measured serum lipids in conjunction with serum thyroxine (T4), triiodothyronine (T3) resin uptake, T3, free T4, thyroid-stimulating hormone (TSH), and thyroxine-binding globulin before, during, and after treatment with nicotinic acid. Serum lipid levels responded appropriately to nicotinic acid treatment. Thyroid function studies done a mean of 1.3 years (range, 0.5 to 3.5) after initiation of nicotinic acid therapy (mean daily dose, 2.6 +/- 0.7 g) revealed significant decreases in serum levels of total T4 (21%), free T4 index (16%), T3 (13%), and thyroxine-binding globulin (23%) (P < 0.02), whereas no significant changes were noted in free T4, T3 resin uptake, and TSH levels. During the course of treatment, the patients, who were carefully questioned, had no symptoms of hypothyroidism. Hypothyroidism was further excluded in three patients who had a normal serum TSH response to administration of thyrotropin-releasing hormone. In two patients, measurements of thyroid function returned to pretreatment levels after discontinuation of nicotinic acid therapy. No patient had significant abnormalities in liver-associated enzymes or evidence of systemic illness during the course of treatment. These results suggest that nicotinic acid decreases serum thyroid hormone concentrations while maintaining a euthyroid state. This effect may be mediated through reduction in thyroxine-binding globulin, but other mechanisms may also be involved.


Phenological plasticity is a poor predictor of subalpine plant population performance following experimental climate change.
Phenological shifts, changes in the seasonal timing of life cycle events, are among the best documented responses of species to climate change. However, the consequences of these phenological shifts for population dynamics remain unclear. Population growth could be enhanced if species that advance their phenology benefit from longer growing seasons and gain a pre-emptive advantage in resource competition. However, it might also be reduced if phenological advances increase exposure to stresses, such as herbivores and, in colder climates, harsh abiotic conditions early in the growing season. We exposed subalpine grasslands to ~ 3 K of warming by transplanting intact turfs from 2000 m to 1400 m elevation in the eastern Swiss Alps, with turfs transplanted within the 2000 m site acting as a control. In the first growing season after transplantation, we recorded species' flowering phenology at both elevations. We also measured species' cover change for three consecutive years as a measure of plant performance. We used models to estimate species' phenological plasticity (the response of flowering time to the change in climate) and analysed its relationship with cover changes following climate change. The phenological plasticity of the 18 species in our study varied widely but was unrelated to their changes in cover. Moreover, early- and late-flowering species did not differ in their cover response to warming, nor in the relationship between cover changes and phenological plasticity. These results were replicated in a similar transplant experiment within the same subalpine community, established one year earlier and using larger turfs. We discuss the various ecological processes that can be affected by phenological shifts, and argue why the population-level consequences of these shifts are likely to be species- and context-specific. Our results highlight the importance of testing assumptions about how warming-induced changes in phenotypic traits, like phenology, impact population dynamics.


Redox and pH dual sensitive bone targeting nanoparticles to treat breast cancer bone metastases and inhibit bone resorption.
Bone is an especially prone metastatic site for breast cancer, and to block the vicious cycle between bone resorption and tumor growth is an important strategy for the treatment of breast cancer bone metastasis. In this paper, pH- and redox-sensitive as well as breast cancer bone metastasis-targeting nanoparticles (DOX@ALN-(HA-PASP)CL) were prepared, and also their anti-tumor activity and anti-bone resorption effect were investigated in detail. The in vitro experimental results indicated that DOX released from DOX@ALN-(HA-PASP)CL exhibited a GSH-, DTT- and pH-dependent manner. Moreover, in an in vitro 3D breast cancer bone metastasis model, DOX@ALN-(HA-PASP)CL decreased bone resorption through inhibiting the proliferation of human breast cancer cells (MDA-MB-231 cells) and reducing the activity of osteoclasts. The in vivo experimental results indicated that a large amount of DOX was delivered to a breast cancer bone metastasis site after tumor-bearing mice were treated with DOX@ALN-(HA-PASP)CL; meanwhile, DOX@ALN-(HA-PASP)CL significantly decreased the tumor volume and bone resorption in tumor-bearing mice without causing obvious systemic toxicity. In conclusion, the in vitro and in vivo experimental results indicate that DOX@ALN-(HA-PASP)CL has great potential in the treatment of breast cancer bone metastasis.


Structures of orbivirus VP7: implications for the role of this protein in the viral life cycle.
Bluetongue virus (BTV) is the prototypical virus of the genus orbivirus in the family Reoviridae and causes an economically important disease in domesticated animals, such as sheep. BTV is larger and more complex than any virus for which comprehensive atomic level structural information is available. Its capsid is made primarily from four structural proteins two of which, VP3 and VP7, form a core which remains intact as the virus penetrates the host cell. Each core particle contains 780 copies of VP7. The architecture of the trimeric VP7 molecule has been revealed by crystallographic analysis and is unlike other viral coat proteins reported to date. Two new crystal structures of VP7 have been solved, one (a cleavage product) at close to atomic resolution and the other at lower resolution. The VP7 subunit consists of two domains. The smaller, 'upper', domain is exposed on the core surface and has the beta jelly-roll motif common to many capsid proteins. The second, 'lower', domain is composed of a bundle of alpha helices. The cleavage product comprises the upper domain, which forms a rigid invariant trimeric fragment. The lower resolution structure of the intact molecule indicates that the alpha-helical domain can rotate about the linker to the upper domain to adopt radically different orientations with respect to the threefold axis in the intact protein. The crystal structures of VP7 reveal a remarkable mix of rigidity and flexibility that may provide insights towards understanding how VP7 interacts with the other capsid proteins of different stoichiometries. These results suggest that substantial conformational changes in VP7 occur at some stage in the viral life cycle. Such changes may be related to the central role that VP7 is likely to play in cell attachment and membrane penetration.


Feasibility of comprehensive, unattended ambulatory polysomnography in school-aged children.
Although unattended ambulatory polysomnography (PSG) is frequently performed in adults, few studies have been performed in children. The objective of this study was to evaluate the feasibility of comprehensive, ambulatory PSG, including electroencephalography, in school-aged children in the home environment. A total of 201 children, born premature with birth weights of 500-1,250 grams, currently aged 5-12 years and living in Canada and Australia, underwent unattended ambulatory PSG. PSG was initially technically satisfactory in 183 (91%) cases. Fourteen studies were satisfactory when repeated, resulting in an overall satisfactory rate of 197 (98%). Artifact-free signals were obtained for ≥ 75% of recording time in more than 92% of subjects, with the exception of nasal pressure, which was satisfactory for ≥ 75% of recording time in only 67% of subjects. However, thermistry signals were satisfactory for ≥ 75% of recording time in 92% of subjects, and some measure of airflow was present for ≥ 75% of recording time in 96% of subjects. Children slept very well, with a long total sleep time (534 ± 73 [mean ± SD] minutes), high sleep efficiency (92% ± 5%), and low arousal index (9 ± 3/h). Parents and children reported a high rate of satisfaction with the study. This large, international study has shown that comprehensive, unattended, ambulatory PSG is feasible, technically adequate and well-tolerated in school-aged children when performed under research conditions. Further studies regarding the cost efficacy of this approach, and generalizability of the findings to a clinical population, are warranted.


Editorial: Data repositories, registries, and standards in the search for valid and reproducible biomarkers.
The paucity of major scientific breakthroughs leading to new or improved treatments, and the inability to identify valid and reproducible biomarkers that improve clinical management, has produced a crisis in confidence in the validity of our pathogenic theories and the reproducibility of our research findings. This crisis in turn has driven changes in standards for research methodologies and prompted calls for the creation of open-access data repositories and the preregistration of research hypotheses. Although we should embrace the creation of repositories and registries, and the promise for greater statistical power, reproducibility, and generalizability of research findings they afford, we should also recognize that they alone are no substitute for sound design in minimizing study confounds, and they are no guarantor of faith in the validity of our pathogenic theories, findings, and biomarkers. One way, and maybe the only sure way, of knowing that we have a valid understanding of brain processes and disease mechanisms in human studies is by experimentally manipulating variables and predicting its effects on outcome measures and biomarkers.


Anxious Solitude, Unsociability, and Peer Exclusion in Middle Childhood: A Multitrait-Multimethod Matrix.
This study examines convergent and divergent validity for middle childhood anxious solitude, unsociability, and peer exclusion as assessed by five informants (peers, teachers, observers, the self, and parents). Participants were 163 (67 male, 96 female) third grade children (M age = 8.70 years). Parent reports were available for a subset of the sample (N = 95). Validity was analyzed via multitrait-multimethod correlation matrices and structural equation models. Results indicate that anxious solitude and peer exclusion have better convergent and divergent validity than unsociability, although there is evidence of shared method variance for all constructs. Peers have the best combination of convergent and divergent validity, and parents, the worst; teachers, observers, and the self demonstrated mid-level validity.


A Prospective Randomized Trial to Assess Oral Versus Intravenous Antibiotics for the Treatment of Postoperative Wound Infection After Extremity Fractures (POvIV Study).
Patients surgically treated for infection after extremity fractures are typically discharged with a 6- to 12-week antibiotic regimen. Intravenous (IV) antibiotics are associated with significant cost and potential complications of deep vein thrombosis, line clotting, and sepsis. Many of the pathogens that cause musculoskeletal infection have both oral (PO) and IV antibiotic options with adequate bioavailability and antibacterial effect, yet IV antibiotics remain the standard of care absent evidence that PO options are clinically as efficacious. The POvIV study is a prospective, multicenter, randomized trial to compare PO with IV antibiotic therapy in patients with postoperative wound infections after extremity fractures. Patients between the ages of 18 and 84 who have a culture-positive surgical site infection after internal fixation for fracture repair or arthrodesis are approached for this study, and if they provide consent, are randomly assigned to receive either PO or IV antibiotics. Antibiotic selection is based on culture and sensitivity results. Randomization determines the route of administration. Patients are followed for 1 year after study enrollment. This study will be the largest prospective randomized trial to evaluate the safety and effectiveness of PO antibiotic use for treatment of postoperative wound infections. Results will inform clinician decisions on antibiotic delivery in patients with postoperative wound infections.


Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4.
CDC37, an essential gene in Saccharomyces cerevisiae, interacts genetically with multiple protein kinases and is required for production of Cdc28p/cyclin complexes through an unknown mechanism. We have identified mammalian p50Cdc37 as a protein kinase-targeting subunit of the molecular chaperone Hsp90. Previously, p50 was observed in complexes with pp60v-src and Raf-1, but its identity and function have remained elusive. In mouse fibroblasts, a primary target of Cdc37 is Cdk4. This kinase is activated by D-type cyclins and functions in passage through G1. In insect cells, Cdc37 is sufficient to target Hsp90 to Cdk4 and both in vitro and in vivo, Cdc37/Hsp90 associates preferentially with the fraction of Cdk4 not bound to D-type cyclins. Cdc37 is coexpressed with cyclin Dl in cells undergoing programmed proliferation in vivo, consistent with a positive role in cell cycle progression. Pharmacological inactivation of Cdc37/Hsp90 function decreases the half-life of newly synthesized Cdk4, indicating a role for Cdc37/Hsp90 in Cdk4 stabilization. This study suggests a general role for p50Cdc37 in signaling pathways dependent on intrinsically unstable protein kinases and reveals a previously unrecognized chaperone-dependent step in the production of Cdk4/cyclin D complexes.


The anti-cancer drug chlorambucil as a substrate for the human polymorphic enzyme glutathione transferase P1-1: kinetic properties and crystallographic characterisation of allelic variants.
The commonly used anti-cancer drug chlorambucil is the primary treatment for patients with chronic lymphocytic leukaemia. Chlorambucil has been shown to be detoxified by human glutathione transferase Pi (GST P1-1), an enzyme that is often found over-expressed in cancer tissues. The allelic variants of GST P1-1 are associated with differing susceptibilities to leukaemia and differ markedly in their efficiency in catalysing glutathione (GSH) conjugation reactions. Here, we perform detailed kinetic studies of the allelic variants with the aid of three representative co-substrates. We show that the differing catalytic properties of the variants are highly substrate-dependent. We show also that all variants exhibit the same temperature stability in the range 10 degrees C to 45 degrees C. We have determined the crystal structures of GST P1-1 in complex with chlorambucil and its GSH conjugate for two of these allelic variants that have different residues at positions 104 and 113. Chlorambucil is found to bind in a non-productive mode to the substrate-binding site (H-site) in the absence of GSH. This result suggests that under certain stress conditions where GSH levels are low, GST P1-1 can inactivate the drug by sequestering it from the surrounding medium. However, in the presence of GSH, chlorambucil binds in the H-site in a productive mode and undergoes a conjugation reaction with GSH present in the crystal. The crystal structure of the GSH-chlorambucil complex bound to the *C variant is identical with the *A variant ruling out the hypothesis that primary structure differences between the variants cause structural changes at the active site. Finally, we show that chlorambucil is a very poor inhibitor of the enzyme in contrast to ethacrynic acid, which binds to the enzyme in a similar fashion but can act as both substrate and inhibitor.


CONFOLD: Residue-residue contact-guided ab initio protein folding.
Predicted protein residue-residue contacts can be used to build three-dimensional models and consequently to predict protein folds from scratch. A considerable amount of effort is currently being spent to improve contact prediction accuracy, whereas few methods are available to construct protein tertiary structures from predicted contacts. Here, we present an ab initio protein folding method to build three-dimensional models using predicted contacts and secondary structures. Our method first translates contacts and secondary structures into distance, dihedral angle, and hydrogen bond restraints according to a set of new conversion rules, and then provides these restraints as input for a distance geometry algorithm to build tertiary structure models. The initially reconstructed models are used to regenerate a set of physically realistic contact restraints and detect secondary structure patterns, which are then used to reconstruct final structural models. This unique two-stage modeling approach of integrating contacts and secondary structures improves the quality and accuracy of structural models and in particular generates better β-sheets than other algorithms. We validate our method on two standard benchmark datasets using true contacts and secondary structures. Our method improves TM-score of reconstructed protein models by 45% and 42% over the existing method on the two datasets, respectively. On the dataset for benchmarking reconstructions methods with predicted contacts and secondary structures, the average TM-score of best models reconstructed by our method is 0.59, 5.5% higher than the existing method. The CONFOLD web server is available at http://protein.rnet.missouri.edu/confold/.


A Kinetic Response Model for Standardized Regression Analyses of Inflammation-Triggered Hypothermic Body Temperature-Time Courses in Mice.
LPS is frequently used to induce experimental endotoxic shock, representing a standard model of acute inflammation in mice. The resulting inflammatory response leads to hypothermia of the experimental animals, which in turn can be used as surrogate for the severity of systemic inflammation. Although increasingly applied as a humane endpoint in murine studies, differences between obtained temperature-time curves are typically evaluated at a single time point with t-tests or ANOVA analyses. We hypothesized that analyses of the entire temperature-time curves using a kinetic response model could fit the data, which show a temperature decrease followed by a tendency to return to normal temperature, and could increase the statistical power. Using temperature-time curves obtained from LPS stimulated mice, we derived a biologically motivated kinetic response model based on a differential equation. The kinetic model includes four parameters: (i) normal body temperature (T n ), (ii) a coefficient related to the force of temperature autoregulation (r), (iii) damage strength (p 0), and (iv) clearance rate (k). Kinetic modeling of temperature-time curves obtained from LPS stimulated mice is feasible and leads to a high goodness-of-fit. Here, modifying key enzymes of inflammatory cascades induced a dominant impact of genotypes on the damage strength and a weak impact on the clearance rate. Using a likelihood-ratio test to compare modeled curves of different experimental groups yields strongly enhanced statistical power compared to pairwise t-tests of single temperature time points. Taken together, the kinetic model presented in this study has several advantages compared to simple analysis of individual time points and therefore may be used as a standard method for assessing inflammation-triggered hypothermic response curves in mice.


Socioeconomic deprivation in early life and symptoms of depression and anxiety in young adulthood: mediating role of hippocampal connectivity.
Experience of early-life socioeconomic deprivation (ELSD) may increase the risk of mental disorders in young adulthood. This association may be mediated by structural and functional alterations of the hippocampus. We conducted a prospective cohort study on 122 participants of the European Longitudinal Study of Pregnancy and Childhood. Information about ELSD was collected via questionnaire from mothers during the first 18 months of participants' lives. At age 23-24, participants underwent examination by structural magnetic resonance imaging, resting-state functional connectivity and assessment of depressive symptoms (Mood and Feelings Questionnaire) and anxiety (Spielberger State-Trait Anxiety Inventory). The association of ELSD with brain outcomes in young adulthood was assessed with correlations, linear regression (adjusting for sex, socioeconomic position and mother's mental health) and moderated mediation analysis. Higher ELSD was associated with greater depressive symptoms (B = 0.22; p = 0.001), trait anxiety (B = 0.07; p = 0.02) and lower global connectivity of the right hippocampus (B = -0.01; p = 0.02). These associations persisted when adjusted for covariates. In women, lower global connectivity of the right hippocampus was associated with stronger trait anxiety (B = -4.14; p = 0.01). Global connectivity of the right hippocampus as well as connectivity between the right hippocampus and the left middle temporal gyrus mediated the association between ELSD and trait anxiety in women. Higher ELSD correlated with a lower volume of the right hippocampus in men, but the volume of the right hippocampus was not related to mental health. Early preventive strategies targeted at children from socioeconomically deprived families may yield long-lasting benefits for the mental health of the population.


Structural and Dynamical Insight into PPARγ Antagonism: In Silico Study of the Ligand-Receptor Interactions of Non-Covalent Antagonists.
The structural and dynamical properties of the peroxisome proliferator-activated receptor γ (PPARγ) nuclear receptor have been broadly studied in its agonist state but little is known about the key features required for the receptor antagonistic activity. Here we report a series of molecular dynamics (MD) simulations in combination with free energy estimation of the recently discovered class of non-covalent PPARγ antagonists. Their binding modes and dynamical behavior are described in details. Two key interactions have been detected within the cavity between helices H3, H11 and the activation helix H12, as well as with H12. The strength of the ligand-amino acid residues interactions has been analyzed in relation to the specificity of the ligand dynamical and antagonistic features. According to our results, the PPARγ activation helix does not undergo dramatic conformational changes, as seen in other nuclear receptors, but rather perturbations that occur through a significant ligand-induced reshaping of the ligand-receptor and the receptor-coactivator binding pockets. The H12 residue Tyr473 and the charge clamp residue Glu471 play a central role for the receptor transformations. Our results also demonstrate that MD can be a helpful tool for the compound phenotype characterization (full agonists, partial agonists or antagonists) when insufficient experimental data are available.


Histological architectural classification determines recurrence pattern and prognosis after curative hepatectomy in patients with hepatocellular carcinoma.
The clinical impact of pathological classification based on architectural pattern in hepatocellular carcinoma (HCC) remains elusive in spite of its well-known and common feature. The prognostic impact of pathological classification was examined with prospective database. Three hundred and eighty HCC patients who underwent curative hepatectomy as an initial treatment in Kumamoto University were enrolled as a test cohort. The outcome was confirmed with a validation cohort in Kyushu University. Macrotrabecular (macro-T) subtype (n = 38) and compact subtype (n = 43) showed similar biological and prognostic features. Both showed higher AFP level and worse overall survival than microrabecular (micro-T) subtype (n = 266). Multivariate analysis for overall survival revealed that DCP ≥ 40, multiple tumor and macro-T/compact subtype were associated with poor overall survival (risk ratio = 2.2, 1.6 and 1.6; p = 0.002, 0.020, and 0.047, respectively). Of note, 32% of macro-T/compact subtype showed early recurrence within 1 year, which showed substantially low (5%) 5 year overall survival, whereas 16% of micro-T/PG subtype did. Twenty-one percent of macro-T/compact subtype showed multiple intrahepatic metastases (≥ 4) or distant metastases, which resulted in non-curative treatment, whereas 5% of micro-T/PG subtype did. In validation cohort, macro-T/compact subtype was an independent predictor of worse overall survival. Macro-T/compact subtype is biologically discriminated from micro-T and PG subtypes due to its aggressive features and poor prognosis after curative treatment. Additional treatment with curative hepatectomy on Macro-T/compact subtype should be discussed because of high possibility of systemic residual cancer cell.


Effect of simvastatin on castration-resistant prostate cancer cells.
In castration-resistant prostate cancer (CRPC), recent evidence has demonstrated the persistence of the intratumoral androgens. The multi-step androgen synthesis pathway originates from cholesterol, which can be obtained by cells from several major sources including intracellular synthesis through an enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). The inhibition of this enzyme by the use of statins has been investigated in prostate cancer as a possible therapeutic target for blocking the de novo androgen synthesis resulting in decreased tumor growth. However, the effectiveness of statins in CRPC has not been investigated. Castration-resistant C4-2 and androgen-sensitive LNCaP cells were treated with Simvastatin for 48 hours. Dose-dependent responses to Simvastatin were analyzed using cell proliferation and cytotoxicity assays. Cellular growth curve was generated using haemocytometer. HMGCR activity was assessed using 14C-acetic acid detected by thin layer chromatography, and the protein expression was quantified using western blot analysis. Intracellular cholesterol and prostate specific antigen (PSA) levels were quantified using enzyme-linked immunosorbent assays (ELISA). Significant decrease in cell viability and growth curve observed at 75 μM of Simvastatin compared to no treatment group in the castration-resistant C4-2 cells. HMGCR activity was significantly decreased up to 50% and 70% at 50 μM and 75 μM of Simvastatin respectively compared to the vehicle control in C4-2 cells. Simvastatin did not affect the protein expression. 80% decrease in the amount of total intracellular cholesterol levels was observed in 75 μM Simvastatin treatment group compared to vehicle control. PSA secretion levels were significantly reduced in the C4-2 cell line at 50 μM and 75 μM of Simvastatin compared to vehicle control. The inhibition of HMGCR via Simvastatin lowered the viability of castration-resistant C4-2 cells. Simvastatin's ability to limit the endogenous supply of cholesterol contributes to the effects seen in cell viability.


Neutralization of G-CSF inhibits ILK-induced heterophil influx: granulocyte-colony stimulating factor mediates the Salmonella enteritidis-immune lymphokine potentiation of the acute avian inflammatory response.
Hematopoietic colony stimulating factors (CSF) regulate the growth and development of phagocytic cell progenitors and also augment functional activation of phagocytes. Granulocyte-CSF (G-CSF) is the CSF that acts specifically upon granulocyte progenitor cells and mature granulocytes. We have shown that lymphokines (ILK) from T cells of birds immunized against Salmonella enteritidis (SE) induce a granulocytic (PMN) inflammatory response in chicks challenged with SE. This inflammatory response was characterized by: (a) a dramatic emigration of granulocytic cells from the bone marrow into the peripheral blood, (b) an enhancement of the biological functions of the circulating PMNs, and (c) a directed influx of these activated PMNs to the site of bacterial invasion. In the current study, we determined the presence of G-CSF in ILK by Western blot analysis using a goat polyclonal antihuman G-CSF antibody (Ab). Using this Ab, we then evaluated the role of G-CSF in the ILK-induced protective inflammatory response in chickens against SE. Pretreatment of ILK with the Ab totally abolished the colony-stimulating activity of the ILK. Furthermore, Ab treatment of ILK resulted in: (a) an elimination of the ILK-induced peripheral blood heterophilia with a dramatic inhibition of ILK-mediated protection against SE organ invasion and (b) an elimination of accumulation of inflammatory PMNs in the peritoneum with subsequent decrease in the survival rate of chicks challenged i.p. with SE. Taken together these studies demonstrate for the first time the contribution of G-CSF to avian PMN activation and the immunoprophylaxis of SE infection by ILK in neonatal chickens.


Azacytidine induces cell cycle arrest and suppression of neuroendocrine markers in carcinoids.
Neuroendocrine tumors (NETs) hypersecrete neuropeptides that cause debilitating symptoms of carcinoid syndrome, including cardiac abnormalities. Surgical resection is the only potentially curative treatment for NETs; however, 90% of NE cancer patients are not candidates for surgery due to extensive hepatic sites involved with NETs. Recently, DNA methyltransferase inhibitors (DNMTI) such as azacytidine (AzaC) have shown efficacy in clinical treatments of hematological malignancies, but effects on NETs are not well-studied. We hypothesized that this novel class of drugs inhibits NET cell growth and decreases NE markers. Three carcinoid types-human midgut (CDNT2.5), pulmonary (H727), and gastrointestinal (BON)- were treated with AzaC (0-100uM) over 6 days. MTT Assays were used to measure cellular proliferation. Western blots were performed with antibodies against chromogranin A (CgA), Neuron-Specific Enolase (NSE), and Cyclin B1. Flow cytometric data was collected from AzaC-treated CNDT2.5 cells for DNA cell cycle analysis. Results showed that treatment of CDNT2.5, H727, and BON carcinoid cells with AzaC resulted in a dose-dependent reduction in tumor cell proliferation. Flow cytometric analysis showed that AzaC-treated cells accumulate in the G2 Phase of cell cycle. AzaC treatment led to: significant decreases in CgA and NSE, indicating that AzaC inhibits neuroendocrine markers; and significant increases in the levels of Cyclin B1, further supporting the flow cytometric data and conclusion that AzaC induces G2/M arrest. The data indicate that AzaC suppresses cell growth in three different carcinoid types, reduces neuroendocrine markers in CNDT2.5 cells, and inhibits cell proliferation by inducing G2/M phase arrest. The results suggest that DNMTIs may be a novel class of therapeutic agents that can effectively control tumor growth and the release of bioactive peptides in patients with NETs.


Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation.
We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.


Neuroleptic sensitivity in patients with senile dementia of Lewy body type.
To determine the outcome of administration of neuroleptics to patients with senile dementia of Lewy body type confirmed at necropsy. Retrospective analysis of clinical notes blind to neuropathological diagnosis. Specialist psychogeriatric assessment units referring cases for necropsy to a teaching hospital neuropathology service. 41 elderly patients with diagnosis of either Alzheimer type dementia (n = 21) or Lewy body type dementia (n = 20) confirmed at necropsy. Clinical state including extrapyramidal features before and after neuroleptic treatment and survival analysis of patients showing severe neuroleptic sensitivity compared with the remainder in the group. 16 (80%) patients with Lewy body type dementia received neuroleptics, 13 (81%) of whom reacted adversely; in seven (54%) the reactions were severe. Survival analysis showed an increased mortality in the year after presentation to psychiatric services compared with patients with mild or no neuroleptic sensitivity (hazard ratio 2.70 (95% confidence interval 2.50-8.99); (chi 2 = 2.68, p = 0.05). By contrast, only one (7%) of 14 patients with Alzheimer type dementia given neuroleptics showed severe neuroleptic sensitivity. Severe, and often fatal, neuroleptic sensitivity may occur in elderly patients with confusion, dementia, or behavioural disturbance. Its occurrence may indicate senile dementia of Lewy body type and this feature has been included in clinical diagnostic criteria for this type of dementia.


New version of solid telescope.
This paper describes a new optical concept for a telescope. It is essentially made by a single refractive element used in a nontraditional way. The telescope is based upon the internal and multiple reflections over the surfaces of this refractive element. It offers important advantages in the alignment and stability. In this paper, some representative configurations of telescope and a focal adapter based on the same concept are presented, trying to underline the main advantages. A brief in-depth description of the performances is reported.


Accurate detection of circulating tumor DNA using nanopore consensus sequencing.
Levels of circulating tumor DNA (ctDNA) in liquid biopsies may serve as a sensitive biomarker for real-time, minimally-invasive tumor diagnostics and monitoring. However, detecting ctDNA is challenging, as much fewer than 5% of the cell-free DNA in the blood typically originates from the tumor. To detect lowly abundant ctDNA molecules based on somatic variants, extremely sensitive sequencing methods are required. Here, we describe a new technique, CyclomicsSeq, which is based on Oxford Nanopore sequencing of concatenated copies of a single DNA molecule. Consensus calling of the DNA copies increased the base-calling accuracy ~60×, enabling accurate detection of TP53 mutations at frequencies down to 0.02%. We demonstrate that a TP53-specific CyclomicsSeq assay can be successfully used to monitor tumor burden during treatment for head-and-neck cancer patients. CyclomicsSeq can be applied to any genomic locus and offers an accurate diagnostic liquid biopsy approach that can be implemented in clinical workflows.


Total articular resurfacing arthroplasty. Analysis of component failure in sixty-seven hips.
Total articular resurfacing arthroplasty with the Tara device was performed on sixty-seven hips in sixty-three patients from 1978 to 1981. I analyzed the results, paying particular attention to prosthetic failure. Loosening of the femoral component occurred in one hip and loosening of the acetabular component, in seven hips. All eight required revision to conventional total hip replacement. Fifteen other patients in the series had radiographic evidence of component failure but have had no significant pain to date. They were regarded as having impending failure. Four of the fifteen showed significant stress-shielding on the femoral side, two with simultaneous acetabular lucency at the bone-cement interface. The other eleven showed progressive acetabular lucency. The total anticipated failure rate was 34.3 per cent (11.9 per cent definite and 22.4 per cent anticipated). The ages of the patients at surgery averaged 49.1 years in the actual failure group and 34.2 years in the impending failure group. Factors that may have been responsible for the unacceptably high incidence of component failure include the young age of the patients in whom this operation was performed and their high activity level. Additional reasons for mechanical failure (both definite and anticipated) on the acetabular side include poor cement distribution with resultant micromotion and increased frictional torque with the larger-diameter component of the prosthesis.


Sex and dependence related neuroanatomical differences in regular cannabis users: findings from the ENIGMA Addiction Working Group.
Males and females show different patterns of cannabis use and related psychosocial outcomes. However, the neuroanatomical substrates underlying such differences are poorly understood. The aim of this study was to map sex differences in the neurobiology (as indexed by brain volumes) of dependent and recreational cannabis use. We compared the volume of a priori regions of interest (i.e., amygdala, hippocampus, nucleus accumbens, insula, orbitofrontal cortex (OFC), anterior cingulate cortex and cerebellum) between 129 regular cannabis users (of whom 70 were recreational users and 59 cannabis dependent) and 114 controls recruited from the ENIGMA Addiction Working Group, accounting for intracranial volume, age, IQ, and alcohol and tobacco use. Dependent cannabis users, particularly females, had (marginally significant) smaller volumes of the lateral OFC and cerebellar white matter than recreational users and controls. In dependent (but not recreational) cannabis users, there was a significant association between female sex and smaller volumes of the cerebellar white matter and OFC. Volume of the OFC was also predicted by monthly standard drinks. No significant effects emerged the other brain regions of interest. Our findings warrant future multimodal studies that examine if sex and cannabis dependence are specific key drivers of neurobiological alterations in cannabis users. This, in turn, could help to identify neural pathways specifically involved in vulnerable cannabis users (e.g., females with cannabis dependence) and inform individually tailored neurobiological targets for treatment.


Maturation of dengue virus nonstructural protein 4B in monocytes enhances production of dengue hemorrhagic fever-associated chemokines and cytokines.
High levels of viremia and chemokines and cytokines underlie the progression of severe dengue disease. Dengue virus (DENV) preferentially infects peripheral blood monocytes, which secrete elevated levels of immunomediators in patients with severe disease. Further, DENV nonstructural proteins (NS) are capable of modifying intracellular signaling, including interferon inhibition. We demonstrate that peak secretions of immunomediators such as IL-6, IL-8, IP-10, TNFα or IFNγ in DENV-infected monocytes correlate with maximum virus production and NS4B and NS5 are primarily responsible for the induction of immunomediators. Furthermore, we demonstrate that sequential NS4AB processing initiated by the viral protease NS2B3(pro) and via the intermediate 2KNS4B significantly enhances immunomediator induction. While the 2K-signal peptide is not essential for immunomediator induction, it plays a synergistic role with NS4B. These data suggest that NS4B maturation is important during innate immune signaling in DENV-infected monocytes. Given similar NS4B topologies and polyprotein processing across flaviviruses, NS4B may be an attractive target for developing Flavivirus-wide therapeutic interventions.


Assessing Efficacy of Canaloplasty Using Continuous 24-Hour Monitoring of Ocular Dimensional Changes.
We investigated whether 24-hour monitoring of corneoscleral limbus area (CSLA) with the Sensimed Triggerfish contact lens sensor (CLS) can be used clinically to assess midterm efficacy of canaloplasty and to assess the relationships of CSLA changes with the heart rhythm. Ten eyes of 10 patients, with POAG, which were qualified either to canaloplasty or canaloplasty and phacoemulsification, were included in this study. Eyes were washed out before the surgery and control visits were done at days 1, 7, and 3, 6, 12 months postoperatively, at which subjects were examined. We performed 24-hour monitoring of CSLA changes and Holter ECG at washout, and at 3- and 12-month postop visits. Raw CLS signals were processed to lead two parameters describing short-term 24-hour variability of CSLA (VAR, â). Heart activity parameters from CLS were compared to those acquired from Holter ECG. Mean post washout IOP was 20.6 ± 4.7 and decreased to 14.2 ± 3.0 mm Hg 1 year after surgery (P < 0.01). A decreasing trend in VAR and â parameters were noted. Statistically significant differences were found between the washout and 3-month postop visit for VAR and â (P = 0.014 and P = 0.027, respectively) as well as between the washout and 12-month postop result for the parameter â (P = 0.031). No statistically significant differences were found between the 3- and 12-month postop results for both considered parameters. Canaloplasty alone or combined with cataract surgery is a successful surgical method of lowering IOP in glaucoma patients. Canaloplasty decreases 24-hour CSLA fluctuation pattern measured with CLS.


Parkinson's disease in Aberdeen: survival after 3.5 years.
The increasing age of the general population and of patients suffering from Parkinson's disease suggests that a reappraisal of mortality rates and factors related to increased mortality should be carried out. A 3.5 year follow-up of a whole population sample of 267 patients and 233 controls matched by age, sex and general practitioner, yielded a relative mortality rate of 2.35 (99%-confidence interval: 1.60-3.43). Factors predicting death within the follow-up period were: cognitive impairment, old age, late age of onset, long history of smoking, lower blood pressure, and a variety of signs, symptoms and sequelae of Parkinson's disease associated with decreased mobility. However, age less than 70 years, age of onset before 66 years, absence of kyphosis or normal Webster posture score, mild impairment on the Hoehn & Yahr scale (1-2), or no impairment in a 10-question mental status questionnaire (9-10), were not associated with an increased risk of death.