Changes in cigarette smoking initiation, cessation, and relapse among U.S. adults: a comparison of two longitudinal samples.
The tobacco epidemic in the U.S. has matured in the past decade. However, due to rapidly changing social policy and commercial environments, tailored prevention and interventions are needed to support further reduction in smoking. Using Tobacco Use Supplement to the Current Population Survey (TUS-CPS) 2002-2003 and 2010-2011 longitudinal cohorts, five smoking states are defined including daily-heavy, daily-light, non-daily, former and non-smoker. We quantified the changes between smoking states for the two longitudinal cohorts, and used a series of multivariable logistic regression models to examine the association of socio-demographic attributes and initial smoking states on smoking initiation, cessation, and relapse between waves within each cohort. The prevalence of adult heavy smoking decreased from 9.9% (95% CI: 9.6%, 10.2%) in 2002 to 7.1% (95% CI: 6.9%, 7.4%) in 2010. Non-daily smokers were less likely to quit in the 2010-2011 cohort than the 2002-2003 cohort (37.0% vs. 44.9%). Gender, age group, smoker type, race and marital status exhibit similar patterns in terms of their association to the odds of initiation, cessation and relapse between the two cohorts, while education groups showed some inconsistent results between the two cohorts regarding the odds of cessation. Transitions between smoking states are complex and increasingly unstable, requiring a holistic, population-based perspective to understand the stocks and flows that ultimately dictate the public health impact of cigarette smoking behavior. This knowledge helps to identify groups in need of increased tobacco control prevention and intervention efforts.


Stimulation of glycosaminoglycan synthesis in cultured human dermal fibroblasts by interleukin 1. Induction of hyaluronic acid synthesis by natural and recombinant interleukin 1s and synthetic interleukin 1 beta peptide 163-171.
Hyaluronic acid (HA) is believed to play a critical role in wound healing and in morphogenesis. Factors controlling the production of HA by fibroblasts in normal and pathological states are not completely understood. In this report we have observed that natural human interleukin (IL-1)1 beta and human recombinant (hrIL)-1 alpha and beta are potent stimulators of HA production by fibroblasts in vitro. Hyaluronic acid is the major species of glycosaminoglycan (GAG) stimulated by IL-1 in fibroblasts. PGE2 does not appear to be involved directly in this IL-1 effect on fibroblasts, but stimulation of HA production by IL-1 is dependent on protein synthesis. The synthetic human IL-1 beta peptide 163-171 (Val-Gln-Gly-Glu-Glu-Ser-Asn-Asp-Lys), which has been previously shown to stimulate thymocyte proliferation but not fibroblast PGE2 production, is also able to stimulate fibroblast HA production. The synthesis and secretion of IL-1 by mononuclear phagocytes at sites of inflammation and immune reactions in vivo could potentially serve as a signal for fibroblasts to synthesize HA, which in turn could serve to facilitate and modulate reparative and immune processes by virtue of its ability to alter cell-cell, cell matrix, and cell-membrane receptor interactions.


A UK wide survey of insulin initiation in children with type 1 diabetes and nurses' perceptions of associated decision-making.
The aim of this study was to examine insulin initiation practice across the UK in relation to children with newly diagnosed type 1 diabetes. Objectives of this study were to explore practices surrounding insulin initiation in children and nurses' perceptions of associated decision-making. There are comparative studies of insulin treatments and regimens for children but few that describe the insulin initiation process or associated decision-making. The literature suggests a heavy workload for nurses working in practice and insufficient resources for home initiation of insulin. A survey design. A questionnaire regarding insulin initiation was distributed to 247 diabetes specialist nurses working with children from all four UK countries. One hundred and twelve responses (45%). Only 37 (33%) started clinically well, newly diagnosed children on insulin at home, but most would do so with adequate resources. The most common insulin regimen at diagnosis was twice daily injections, with 86% (n = 96) using re-usable pens to deliver the insulin. As expected, no one commenced children on pump therapy at diagnosis. Analogue insulin was seen as the drug of choice by over a quarter of the nurses (29%, n = 32). Doctors appeared to be the main decision-makers, supplemented by other members of the paediatric diabetes multi-disciplinary team and decision-making aids. Approaches to treatment at onset of type 1 diabetes in children remain relatively traditional. Nurses expressed a desire to stabilise clinically well children at home but were restricted by lack of resources. Decision-making in most domains was largely medically dominated. The study provides an insight into current insulin initiation practice in childhood diabetes and offers a useful comparator as practices change in the light of advances in treatment (medication and equipment), changes in professional roles (e.g. independent prescribing) and policy shifts (the move away from hospitals and resource constraints).


Interventions for chronic blepharitis.
Blepharitis, an inflammatory condition associated with itchiness, redness, flaking, and crusting of the eyelids, is a common eye condition that affects both children and adults. It is common in all ethnic groups and across all ages. Although infrequent, blepharitis can lead to permanent alterations to the eyelid margin or vision loss from superficial keratopathy (abnormality of the cornea), corneal neovascularization, and ulceration. Most importantly, blepharitis frequently causes significant ocular symptoms such as burning sensation, irritation, tearing, and red eyes as well as visual problems such as photophobia and blurred vision. The exact etiopathogenesis is unknown, but suspected to be multifactorial, including chronic low-grade infections of the ocular surface with bacteria, infestations with certain parasites such as demodex, and inflammatory skin conditions such as atopy and seborrhea. Blepharitis can be categorized in several different ways. First, categorization is based on the length of disease process: acute or chronic blepharitis. Second, categorization is based on the anatomical location of disease: anterior, or front of the eye (e.g. staphylococcal and seborrheic blepharitis), and posterior, or back of the eye (e.g. meibomian gland dysfunction (MGD)). This review focuses on chronic blepharitis and stratifies anterior and posterior blepharitis. To examine the effectiveness of interventions in the treatment of chronic blepharitis. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 1), MEDLINE (January 1950 to February 2012), EMBASE (January 1980 to February 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We searched the reference lists of included studies for any additional studies not identified by the electronic searches. There were no date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 9 February 2012. We included randomized controlled trials (RCTs) and quasi-randomized controlled trials (CCTs) in which participants were adults aged 16 years or older and clinically diagnosed with chronic blepharitis. We also included trials where participants with chronic blepharitis were a subset of the participants included in the study and data were reported separately for these participants. Interventions within the scope of this review included medical treatment and lid hygiene measures. Two authors independently assessed search results, reviewed full-text copies for eligibility, examined risk of bias, and extracted data. Data were meta-analyzed for studies comparing similar interventions and reporting comparable outcomes with the same timing. Otherwise, results for included studies were summarized in the text. There were 34 studies (2169 participants with blepharitis) included in this review: 20 studies (14 RCTs and 6 CCTs) included 1661 participants with anterior or mixed blepharitis and 14 studies (12 RCTs and 2 CCTs) included 508 participants with posterior blepharitis (MGD). Due to the heterogeneity of study characteristics among the included studies, with respect to follow-up periods and types of interventions, comparisons, and condition of participants, our ability to perform meta-analyses was limited. Topical antibiotics were shown to provide some symptomatic relief and were effective in eradicating bacteria from the eyelid margin for anterior blepharitis. Lid hygiene may provide symptomatic relief for anterior and posterior blepharitis. The effectiveness of other treatments for blepharitis, such as topical steroids and oral antibiotics, were inconclusive. Despite identifying 34 trials related to treatments for blepharitis, there is no strong evidence for any of the treatments in terms of curing chronic blepharitis. Commercial products are marketed to consumers and prescribed to patients without substantial evidence of effectiveness. Further research is needed to evaluate the effectiveness of such treatments. Any RCT designed for this purpose should separate participants by type of condition (e.g. staphylococcal blepharitis or MGD) in order to minimize imbalances between groups (type I errors) and to achieve statistical power for analyses (prevent type II errors). Medical interventions and commercial products should be compared with conventional lid hygiene measures, such as warm compresses and eyelid margin washing, to determine effectiveness, as well as head-to-head to show comparative effectiveness between treatments. Outcomes of interest should be patient-centered and measured using validated questionnaires or scales. It is important that participants be followed long-term, at least one year, to assess chronic outcomes properly.


Improving pediatric liquid medication labeling of the hospital information system in Malaysia: qualitative analysis of pharmacists' perceptions.
Inadequacies of drug labeling have been frequently reported among Malaysian healthcare institutes, in which the Hospital Information System (HIS) is used. To identify potential areas to improve the existing labels used for pediatric liquid medications. This study was qualitative in nature, whereby focus group discussions (FGDs), face-to-face interviews (FTFIs), and onsite observation were used for data collection. Pharmacists stationed at three units (outpatient, inpatient and clinical pharmacy) of a tertiary hospital were targeted. Both FGDs and FTFIs were facilitated using a semi-structured interview guide, video-recorded and transcribed verbatim. All transcripts were thematically analyzed using content analysis approach. Thirteen pharmacists participated in FGDs, while five were approached for FTFIs. Data analysis resulted in four major themes: format of labels, presentation of medication instructions, insufficiency of information, and the need for external aids and education. Participants unanimously agreed on the need for enlarging font sizes of key information. Suggestions were made to use more specific instructions for administration times and pictograms to illustrate important directions. The absence of information about storage, stability and handling of liquid medications was also highlighted. While discussion mainly focused on improving drug labeling, participants consistently stressed the need for an instruction sheet and pharmacist-based, one-to-one education regarding medication instructions. This study provides important insights into critical shortcomings in current labeling practice, underlying the need for developing a new label that incorporates a new format, additional information and pictograms for pediatric liquid medications.


Effect of a multi-faceted quality improvement intervention on inappropriate antibiotic use in children with non-bloody diarrhoea admitted to district hospitals in Kenya.
There are few reports of interventions to reduce the common but irrational use of antibiotics for acute non-bloody diarrhoea amongst hospitalised children in low-income settings. We undertook a secondary analysis of data from an intervention comprising training of health workers, facilitation, supervision and face-to-face feedback, to assess whether it reduced inappropriate use of antibiotics in children with non-bloody diarrhoea and no co-morbidities requiring antibiotics, compared to a partial intervention comprising didactic training and written feedback only. This outcome was not a pre-specified end-point of the main trial. Repeated cross-sectional survey data from a cluster-randomised controlled trial of an intervention to improve management of common childhood illnesses in Kenya were used to describe the prevalence of inappropriate antibiotic use in a 7-day period in children aged 2-59 months with acute non-bloody diarrhoea. Logistic regression models with random effects for hospital were then used to identify patient and clinician level factors associated with inappropriate antibiotic use and to assess the effect of the intervention. 9, 459 admission records of children were reviewed for this outcome. Of these, 4, 232 (44.7%) were diagnosed with diarrhoea, with 130 of these being bloody (dysentery) therefore requiring antibiotics. 1, 160 children had non-bloody diarrhoea and no co-morbidities requiring antibiotics-these were the focus of the analysis. 750 (64.7%) of them received antibiotics inappropriately, 313 of these being in the intervention hospitals vs. 437 in the controls. The adjusted logistic regression model showed the baseline-adjusted odds of inappropriate antibiotic prescription to children admitted to the intervention hospitals was 0.30 times that in the control hospitals (95%CI 0.09-1.02). We found some evidence that the multi-faceted, sustained intervention described in this paper led to a reduction in the inappropriate use of antibiotics in treating children with non-bloody diarrhoea. International Standard Randomised Controlled Trial Number Register ISRCTN42996612.


Changes in the sialylation and sulfation of secreted thyrotropin in congenital hypothyroidism.
We have examined the oligosaccharide structure of secreted thyrotropin (TSH) in perinatal and mature rats with congenital primary hypothyroidism. Rat pituitaries from euthyroid control animals and those rendered hypothyroid by methimazole treatment were incubated with [3H]glucosamine in vitro. Secreted TSH was purified, and oligosaccharides were enzymatically released and characterized by anion-exchange HPLC. In perinatal hypothyroid animals compared with control animals, oligosaccharides from TSH alpha and beta subunits contained more species with three or more negative charges. Moreover, perinatal hypothyroid animals demonstrated a dramatic increase in the ratio of sialylated to sulfated species within oligosaccharides of the same negative charge (2.9- to 7.4-fold increase for TSH-alpha; 15.1- to 25.5-fold increase for TSH-beta). In mature hypothyroid 9-week-old animals compared with control animals, changes were less pronounced, suggesting that endocrine regulation of oligosaccharide structure is dependent upon the maturational state of the animal. These changes were specific for TSH because glycosylation of free alpha subunit (synthesized by the thyrotroph and gonadotroph) and of total glycoproteins was minimally altered by hypothyroidism. Together, these data provide direct evidence and characterization of specific changes in the structure of a secreted pituitary glycoprotein hormone occurring as a result of in vivo endocrine alterations during early development. Moreover, they provide a potential structural basis to explain the delayed clearance of both TSH and the gonadotropins with end-organ deficiency, which may have important implications for the in vivo biological activities of these hormones. Specifically, such posttranslational changes may be an important adaptive response to prevent the consequences of endocrine deficiency during early development.


Social inequality and fractures-secular trends in the Danish population: a case-control study.
We examined links between markers of social inequality and fracture risk in the Danish population, demonstrating that high income and being married are associated with a significantly lower risk. We explored whether the risk of hip, humerus, and wrist fracture was associated with markers of inequality using data from Danish health registries. All patients 50 years or older with a primary hip (ICD10 S720, S721, S722, and S729) humerus (ICD10 S422, S423, S424, S425, S426, and S427), or wrist (ICD10: S52) fracture were identified from 1/1/1995 to 31/12/2011. Fracture patients were matched 1:1 by age, sex, and year of fracture, to a non-fracture control. Markers of inequality were as follows: income (fifths); marital status (married, divorced, widowed, or unmarried); area of residence (remote, rural, intermediate, or urban). Conditional logistic regression was used to investigate associations between these exposures, and risk of fracture, adjusting for covariates (smoking, alcohol, and Charlson co-morbidity). Interactions were fitted between exposure and covariates where appropriate. A total of 189,838 fracture patients (37,500 hip, 45,602 humerus, and 106,736 wrist) and 189,838 controls were included. Mean age was 73.9 years (hip), 67.5 years (humerus), and 65.3 years (wrist). High income (5th quintile) was significantly associated with a lower odds ratio of all three fractures, compared to average income (3rd quintile). Married subjects had a significantly decreased odds ratio across all three fractures. However, no overall secular difference was observed regarding the influence of the markers of inequality. In conclusion, we have demonstrated important, stable associations between social inequality, assessed using income, marital status, and area of residence, and fracture at the population level. These findings can inform approaches to healthcare, and suggest that much thought should be given to novel interventions aimed especially at those living alone, and ideally societal measures to reduce social inequality.


Functional development of large-scale sensorimotor cortical networks in the brain.
Large-scale neuronal networks integrating several cortical areas mediate the complex functions of the brain such as sensorimotor integration. Little is known about the functional development of these networks and the maturational processes by which distant networks become functionally connected. We addressed this question in the postnatal rat sensorimotor system. Using epicranial multielectrode grids that span most of the cortical surface and intracortical electrodes, we show that sensory evoked cortical responses continuously maturate throughout the first 3 weeks with the strongest developmental changes occurring in a very short time around postnatal day 13 (P13). Before P13, whisker stimulation evokes slow, initially surface-negative activity restricted mostly to the lateral parietal area of the contralateral hemisphere. In a narrow time window of ∼48 h around P13, a new early, sharp surface-positive component emerges that coincides with subsequent propagation of activity to sensory and motor areas of both hemispheres. Our data show that this new component developing at the end of the second week corresponds principally to functional maturation of the supragranular cortical layers and appears to be crucial for the functional associations in the large-scale sensorimotor cortical network. It goes along with the onset of whisking behavior, as well as major synaptic and functional changes within the S1 cortex that are known to develop during this period.


Flexible docking of peptides to proteins using CABS-dock.
Molecular docking of peptides to proteins can be a useful tool in the exploration of the possible peptide binding sites and poses. CABS-dock is a method for protein-peptide docking that features significant conformational flexibility of both the peptide and the protein molecules during the peptide search for a binding site. The CABS-dock has been made available as a web server and a standalone package. The web server is an easy to use tool with a simple web interface. The standalone package is a command-line program dedicated to professional users. It offers a number of advanced features, analysis tools and support for large-sized systems. In this article, we outline the current status of the CABS-dock method, its recent developments, applications, and challenges ahead.


Magneto-Dendrite Effect: Copper Electrodeposition under High Magnetic Field.
Ionic vacancy is a by-product in electrochemical reaction, composed of polarized free space of the order of 0.1 nm with a 1 s lifetime, and playing key roles in nano-electrochemical processes. However, its chemical nature has not yet been clarified. In copper electrodeposition under a high magnetic field of 15 T, using a new electrode system called cyclotron magnetohydrodynamic (MHD) electrode (CMHDE) composed of a pair of concentric cylindrical electrodes, we have found an extraordinary dendritic growth with a drastic positive potential shift from hydrogen-gas evolution potential. Dendritic deposition is characterized by the co-deposition of hydrogen molecule, but such a positive potential shift makes hydrogen-gas evolution impossible. However, in the high magnetic field, instead of flat deposit, remarkable dendritic growth emerged. By examining the chemical nature of ionic vacancy, it was concluded that ionic vacancy works on the dendrite formation with the extraordinary potential shift.


Effect of visco-elastic foam mattresses on the development of pressure ulcers in patients with hip fractures.
This study had three aims: to investigate if visco-elastic foam mattresses are more effective than standard hospital mattresses in reducing the incidence of pressure ulcers in patients with hip fractures; to compare pressure ulcer grade and location and documented nursing prevention and treatment interventions in patients using the two types of mattresses; to identify possible predictors of pressure ulcer development. Using a prospective randomised controlled trial design 101 patients (mean age: 84 years) were randomly allocated either a visco-elastic foam mattress or a standard mattress. There was no significant difference in the incidence of pressure ulcers between the two groups, but patients on standard mattresses tended to develop more severe pressure ulcers. Furthermore, according to the documentation, patients with grade I pressure ulcers who were allocated a standard mattress received more preventive interventions, which may have reduced the differences in outcomes between the two groups. The researchers concluded that the results support the use of the test mattress. Significant predictors of pressure ulcer development were long waiting times for surgery and low haemoglobin levels at hospital admission.


Histological Observations of Rotylenchulus reniformis on Gossypium longicalyx and Interspecific Cotton Hybrids.
Observations on the development of reniform nematode (Rotylenchulus reniformis) on roots of Gossypium longicalyx, G. hirsutum, and two interspecific hybrids derived from them were made by light microscopy. Gossypium longicalyx is reported to be immune to reniform nematode, but the mechanism(s) for resistance are unknown. Penetration of G. longicalyx roots by female nematodes was confirmed, and incipient swelling of the females, indicating initiation of maturation of the reproductive system, was observed. Female maturation occurred up to the formation of a single embryo inside the female body but not beyond this point. In both hybrids, development was inhibited but progressed further than in the immune parent. Reactions ranged from highly compatible, with the formation of active syncytia and full development of females, to incompatible with little or no development of the female. Compatible plants showed characteristic hypertrophied cells, enlarged nuclei, dense cytoplasm, and partial dissolution of cell walls, whereas incompatible plant reactions included lignification of the cells adjacent to the nematode head, or the complete collapse and necrosis of the cells involved. The need to characterize reactions and to carefully select among the plants descended from the hybrids during the introgression process, as well as the importance of combining the results of reproduction tests with histological observation of the plant-nematode interactions, is discussed.


Cerebrovascular disease in sickle cell anemia: a clinical, pathological and radiological correlation.
An opportunity to study cerebrovascular changes in sickle cell anemia (SCA) presented itself when a black child with this disorder died of bihemispheric strokes. Angiography demonstrated severe occlusive vascular disease involving primarily the circle of Willis and major bifurcations of both internal carotid arteries. Collateral circulation to the distal branches of the internal carotid arteries occurred through transdural anastomoses from the external carotid system and via the leptomeningeal route. Perfusion of the basal ganglia was accomplished by vessels arising from the proximal internal carotid arteries. These changes resembled those of Moyamoya disease. Autopsy showed old and recent cerebral infarcts. Two vascular processes were responsible for the arterial occlusions: (1) exuberant intimal hyperplasia, and (2) old and recent thrombi with partial recanalization. The former has been described only once before in SCA. Small vessels in the basal ganglia were exceptionally numerous and dilated. We conclude that intimal hyperplasia within large cerebral arteries may be responsible for infarction and small vessel prliferation in basal ganglia in patients with SCA.


Aspartame-induced fibromyalgia, an unusual but curable cause of chronic pain.
We report for the first time an unusual musculoskeletal adverse effect of aspartame in two patients. A 50-year-old woman had been suffering from widespread pain and fatigue for more than 10 years leading to the diagnosis of fibromyalgia. During a vacation in a foreign country, she did not suffer from painful symptoms since she had forgotten to take her aspartame. All of the symptoms reappeared in the days following her return when she reintroduced aspartame into her daily diet. Thus, aspartame was definitively excluded from her diet, resulting in a complete regression of the fibromyalgia symptoms. A 43-year-old man consulted for a 3-year history of bilateral forearm, wrist, and hand and cervical pain with various unsuccessful treatments. A detailed questioning allowed to find out that he had been taking aspartame for three years. The removal of aspartame was followed by a complete regression of pain, without recurrence. We believe that these patients' chronic pain was due to the ingestion of aspartame, a potent flavouring agent, widely used in food as a calorie-saver. The benefit/ risk ratio of considering the diagnosis of aspartame-induced chronic pain is obvious: the potential benefit is to cure a disabling chronic disease, to spare numerous laboratory and imaging investigations, and to avoid potentially harmful therapies; the potential risk is to temporarily change the patient's diet. Thus, practitioners should ask patients suffering from fibromyalgia about their intake of aspartame. In some cases, this simple question might lead to the resolution of a disabling chronic disease.


Prognostic significance of plasma osteopontin in patients with locoregionally advanced head and neck squamous cell carcinoma treated on TROG 02.02 phase III trial.
High plasma osteopontin (OPN) levels have been reported to be an adverse prognostic factor in head and neck squamous cell carcinomas (HNSCC), correlate with tumor hypoxia, and be predictive of benefit from hypoxia-targeted therapy. We sought to confirm the prognostic and predictive significance of OPN in patients treated on a large international trial. Patients with stage III/IV HNSCC were randomized to receive definitive radiotherapy concurrently with cisplatin or cisplatin plus the hypoxic cell cytotoxin, tirapazamine (TPZ). Eligibility criteria for this prospective substudy included plasma sample availability for OPN assay by ELISA and absence of major radiation therapy deviations (N = 578). OPN concentrations were analyzed for overall survival (OS) and time to locoregional failure (TTLRF), adjusting for known prognostic factors. Additional analysis was carried out in patients with available tumor p16(INK4A) staining status. The median OPN level was 544 ng/mL (range: 7-2,640). High OPN levels were not associated with worse OS (relative HR, 1.03 for highest tertile) or TTLRF (relative HR 0.91 for highest tertile). There was no interaction between OPN and treatment arm for OS or TTLRF (P = 0.93 for OS; P = 0.87 for TTLRF). For the highest tertile the 2-year OS was 66% on control arm and 67% on TPZ arm (HR = 1.11, P = 0.67). Similarly for p16(INK4A) negative patients in the highest tertile, the 2-year OS was 61% on control arm and 63% on TPZ arm (HR = 1.05, P = 0.86). We found no evidence that high plasma OPN levels were associated with an adverse prognosis in HNSCC, or were predictive of benefit with hypoxia targeting therapy.


Mapping Splicing Quantitative Trait Loci in RNA-Seq.
One of the major mechanisms of generating mRNA diversity is alternative splicing, a regulated process that allows for the flexibility of producing functionally different proteins from the same genomic sequences. This process is often altered in cancer cells to produce aberrant proteins that drive the progression of cancer. A better understanding of the misregulation of alternative splicing will shed light on the development of novel targets for pharmacological interventions of cancer. In this study, we evaluated three statistical methods, random effects meta-regression, beta regression, and generalized linear mixed effects model, for the analysis of splicing quantitative trait loci (sQTL) using RNA-Seq data. All the three methods use exon-inclusion levels estimated by the PennSeq algorithm, a statistical method that utilizes paired-end reads and accounts for non-uniform sequencing coverage. Using both simulated and real RNA-Seq datasets, we compared these three methods with GLiMMPS, a recently developed method for sQTL analysis. Our results indicate that the most reliable and powerful method was the random effects meta-regression approach, which identified sQTLs at low false discovery rates but higher power when compared to GLiMMPS. We have evaluated three statistical methods for the analysis of sQTLs in RNA-Seq. Results from our study will be instructive for researchers in selecting the appropriate statistical methods for sQTL analysis.


Novel Mutation of Interferon-γ Receptor 1 Gene Presenting as Early Life Mycobacterial Bronchial Disease.
Mendelian susceptibility to mycobacterial diseases (MSMD) are a spectrum of inherited disorders characterized by localized or disseminated infections caused by atypical mycobacteria. Interferon-γ receptor 1 (IFNGR1) deficiency was the first identified genetic disorder recognized as MSMD. Mutations in the genes encoding IFNGR1 can be recessive or dominant and cause complete or partial receptor deficiency. We present the case of a 2½-year-old boy with a history of recurrent wheezing, diagnosed with endobronchial mycobacterial infection. Immunological workup revealed a homozygous nonsense mutation in the IFNGR1 gene, a novel mutation predicted in silico to cause complete IFNGR1 deficiency. This case demonstrates that (a) Interferon-γ receptor deficiency can present resembling common disorders of the lung; (b) mycobacterial infections should be suspected when parenchymal lung disease, hilar lymphadenopathy, and endobronchial disease are present; and (c) high index of suspicion for immunodeficiency should be maintained in patients with disseminated nontubercular mycobacterial infection.


Prime-sight in a blindsight subject.
A subject (D.B.) who had no experience of visual stimuli in a field defect caused by visual cortex damage but could discriminate them ('blindsight') nevertheless reported visible after-images of the stimuli when they were turned off ('prime-sight'). This was investigated using projected visual stimuli of varying colors, contrasts, shapes and spatial frequencies, and by measuring the properties of the after-images, including their duration, size scaling, color and interocular transfer, comparing the capacity of the blindsight and prime-sight modes. These phenomena offer a unique opportunity to compare conscious and unconscious neural events in response to the same visual events.


Behavioral interventions to reduce maladaptive responding in youth with dual sensory impairment. An analysis of direct and concurrent effects.
Many persons who have multiple sensory, physical, and developmental disabilities display behaviors that interfere significantly with adaptive functioning and social acceptance. In this investigation, the efficacy of multiple component behavioral interventions for reducing maladaptive responding exhibited by two individuals with dual sensory impairment and profound mental retardation was evaluated. Results indicated that differential reinforcement of other behavior (DRO) approaches were not effective in either case. However, when deceleration procedures (overcorrection or brief physical restraint) were added, target behaviors decreased quickly. Also, interventions were faded in such a way that gains were maintained for 6 months with only minimal effort by staff. Ongoing assessment of concurrent effects of behavior reduction strategies revealed increases in time on task or amount of work completed, even though these responses were not targeted specifically. Yet negative side effects (e.g., increases in self-stimulation) also were documented, highlighting the importance of evaluating multiple behaviors during intervention. Finally, despite the fact that objective assessments led to positive conclusions regarding treatment efficacy, ratings of baseline and treatment behavior samples by independent judges showed overall improvement in only one case. These findings suggest the need for multifaceted evaluation to determine the utility of interventions in applied settings.


VOIP for Telerehabilitation: A Risk Analysis for Privacy, Security, and HIPAA Compliance.
Voice over the Internet Protocol (VoIP) systems such as Adobe ConnectNow, Skype, ooVoo, etc. may include the use of software applications for telerehabilitation (TR) therapy that can provide voice and video teleconferencing between patients and therapists. Privacy and security applications as well as HIPAA compliance within these protocols have been questioned by information technologists, providers of care and other health care entities. This paper develops a privacy and security checklist that can be used within a VoIP system to determine if it meets privacy and security procedures and whether it is HIPAA compliant. Based on this analysis, specific HIPAA criteria that therapists and health care facilities should follow are outlined and discussed, and therapists must weigh the risks and benefits when deciding to use VoIP software for TR.


Triplet imaging of oxygen consumption during the contraction of a single smooth muscle cell (A7r5).
The measurement of tissue and cell oxygenation is important for understanding cell metabolism. We have addressed this problem with a novel optical technique, called triplet imaging, that exploits oxygen-induced triplet lifetime changes and is compatible with a variety of fluorophores. A modulated excitation of varying pulse widths allows the extraction of the lifetime of the essentially dark triplet state using a high-fluorescence signal intensity. This enables the monitoring of fast kinetics of oxygen concentration in living cells combined with high temporal and spatial resolution. First, the oxygen-dependent triplet-state quenching of tetramethylrhodamine is validated and then calibrated in an L-ascorbic acid titration experiment demonstrating the linear relation between triplet lifetime and oxygen concentration according to the Stern-Volmer equation. Second, the method is applied to a biological cell system, employing as reporter a cytosolic fusion protein of beta-galactosidase with SNAP-tag labeled with tetramethylrhodamine. Oxygen consumption in single smooth muscle cells A7r5 during an [Arg(8)]-vasopressin-induced contraction is measured. The results indicate a consumption leading to an intracellular oxygen concentration that decays monoexponentially with time. The proposed method has the potential to become a new tool for investigating oxygen metabolism at the single cell and the subcellular level.


Substoichiometric two-dimensional molybdenum oxide flakes: a plasmonic gas sensing platform.
Two-dimensional (2D) molybdenum oxides at their various stoichiometries are promising candidates for generating plasmon resonances in visible light range. Herein, we demonstrate plasmonic 2D molybdenum oxide flakes for gas sensing applications, in which hydrogen (H2) is selected as a model gas. The 2D molybdenum oxide flakes are obtained using a grinding-assisted liquid exfoliation method and exposed to simulated sunlight to acquire its substoichiometric quasi-metallic form. After the exposure to H2 gas molecules, the quasi-metallic molybdenum oxide flakes are partially transformed into semiconducting states, thus gradually losing their plasmonic properties. The novel 2D plasmonic sensing platform is tested using different concentrations of H2 gas at various operating temperatures to comprehensively assess its sensing performance. The presented 2D plasmonic system offers great opportunities for future sensing and optical applications.


Binocular visual performance with aberration correction as a function of light level.
The extent to which monocular visual performance of subjects with normal amounts of ocular aberrations can be improved with adaptive optics (AO) depends on both the pupil diameter and the luminance for visual testing. Here, the benefit of correction of higher order aberrations for binocular visual performance was assessed over a range of luminances for natural light-adapted pupil sizes with a binocular AO visual simulator. Results show that binocular aberration correction benefits for visual acuity and contrast sensitivity increase with decreasing luminances. Also, the advantage of binocular over monocular viewing increases when visual acuity becomes worse. The findings suggest that binocular summation mitigates poor visual performance under low luminance conditions.


Asymmetric elliptic-cone-shaped microlens for efficient coupling to high-power laser diodes.
A new scheme of asymmetric elliptic-cone-shaped microlens (AECSM) employing a single-step fabrication technique for efficient coupling between the high-power 980-nm laser diodes and the single-mode fibers is proposed. The AECSMs are fabricated by asymmetrically shaping the fiber during the single-step grinding process and elliptically lensing the fiber tip during the fusing process. A maximum coupling efficiency of 85% and a high-average coupling efficiency of 71% have been demonstrated for a 980-nm laser diode with a high aspect ratio of 5. In comparison with the previous works on asymmetric fiber microlenses fabricated by the multi-step processes with complicated fabrication, the advantages of the AECSM structure for achieving high coupling are a single-step fabrication, a reproducible process, and a high-yield output. Therefore, this AECSM can form different aspect ratios of asymmetric elliptical microlenses to match the far field of the high-power diode lasers that is suitable for use in commercial high-power pump laser modules.


One hour cycling performance is not affected by ingested fluid volume.
This study investigated the effect of differing fluid volumes consumed during exercise, on cycle time-trial (TT) performance conducted under thermoneutral conditions (20 degrees C, 70% RH). Ten minutes after consuming a bolus of 6 ml x kg(-1) body mass (BM) of a 6.4% CHO solution and immediately following a warm-up, 8 male cyclists undertook a 1-h self-paced TT on 4 separate occasions. During a "familiarization" trial, subjects were given three 5-min periods (15-20 min, 30-35 min, and 45-50 min) to consume fluid ad libitum. Thereafter subjects undertook, in random order, trials consuming high (HF), moderate (MF), or low fluid (LF) volumes, where 300, 150, and 40 ml of fluid were consumed at 15, 30, and 45 min of each trial, respectively, and total CHO intake was maintained at 57.6 g. During exercise, power output and heart rate were monitored continuously, whilst stomach fullness was rated every 10 min. Additionally, BM loss and BM loss corrected for fluid intake was calculated during each trial. At 40, 50, and 60 min differences in ratings of stomach fullness were found between trials (LF vs. HF and MF vs. HF). There were however no differences in performance or physiological variables (heart rate or BM loss) between trials. These results indicate that when a pre-exercise CHO bolus is consumed, there is no effect of subsequent consumption of different fluid volumes when trained cyclists undertake a 1-h performance task in a thermoneutral environment.


Biological oxygen demand optode analysis of coral reef-associated microbial communities exposed to algal exudates.
Algae-derived dissolved organic matter has been hypothesized to induce mortality of reef building corals. One proposed killing mechanism is a zone of hypoxia created by rapidly growing microbes. To investigate this hypothesis, biological oxygen demand (BOD) optodes were used to quantify the change in oxygen concentrations of microbial communities following exposure to exudates generated by turf algae and crustose coralline algae (CCA). BOD optodes were embedded with microbial communities cultured from Montastraea annularis and Mussismilia hispida, and respiration was measured during exposure to turf and CCA exudates. The oxygen concentrations along the optodes were visualized with a low-cost Submersible Oxygen Optode Recorder (SOOpR) system. With this system we observed that exposure to exudates derived from turf algae stimulated higher oxygen drawdown by the coral-associated bacteria than CCA exudates or seawater controls. Furthermore, in both turf and CCA exudate treatments, all microbial communities (coral-, algae-associated and pelagic) contributed significantly to the observed oxygen drawdown. This suggests that the driving factor for elevated oxygen consumption rates is the source of exudates rather than the initially introduced microbial community. Our results demonstrate that exudates from turf algae may contribute to hypoxia-induced coral stress in two different coral genera as a result of increased biological oxygen demand of the local microbial community. Additionally, the SOOpR system developed here can be applied to measure the BOD of any culturable microbe or microbial community.


Using human brain activity to guide machine learning.
Machine learning is a field of computer science that builds algorithms that learn. In many cases, machine learning algorithms are used to recreate a human ability like adding a caption to a photo, driving a car, or playing a game. While the human brain has long served as a source of inspiration for machine learning, little effort has been made to directly use data collected from working brains as a guide for machine learning algorithms. Here we demonstrate a new paradigm of "neurally-weighted" machine learning, which takes fMRI measurements of human brain activity from subjects viewing images, and infuses these data into the training process of an object recognition learning algorithm to make it more consistent with the human brain. After training, these neurally-weighted classifiers are able to classify images without requiring any additional neural data. We show that our neural-weighting approach can lead to large performance gains when used with traditional machine vision features, as well as to significant improvements with already high-performing convolutional neural network features. The effectiveness of this approach points to a path forward for a new class of hybrid machine learning algorithms which take both inspiration and direct constraints from neuronal data.


Opportunities for targeting the angiotensin-converting enzyme 2/angiotensin-(1-7)/mas receptor pathway in hypertension.
It is well known that the renin-angiotensin system (RAS) plays a pivotal role in the pathophysiology of cardiovascular diseases. This is well illustrated by the great success of ACE inhibitors and angiotensin (Ang) II AT(1) blockers in the treatment of hypertension and its complications. In the past decade, the classical concept of RAS orchestrated by a series of enzymatic reactions culminating in the linear generation and action of Ang II has expanded and become more complex. From the discoveries of new components such as the angiotensin converting enzyme 2 and the receptor Mas emerged a novel concept of dual opposite branches of the RAS: one vasoconstrictor and pro-hypertensive composed of ACE/Ang II/AT1; and other vasodilator and anti-hypertensive composed of ACE2/Ang-(1-7)/Mas. In this review we will discuss recent findings concerning the biological role of the ACE2/Ang-(1-7)/Mas arm in the cardiovascular system and highlight the initiatives to develop potential therapeutic strategies based on this axis for treating hypertension.


ASPP2 binds to hepatitis C virus NS5A protein via an SH3 domain/PxxP motif-mediated interaction and potentiates infection.
Hepatitis C virus (HCV) infects millions of people worldwide and is a leading cause of liver disease. Despite recent advances in antiviral therapies, viral resistance can limit drug efficacy and understanding the mechanisms that confer viral escape is important. We employ an unbiased interactome analysis to discover host binding partners of the HCV non-structural protein 5A (NS5A), a key player in viral replication and assembly. We identify ASPP2, apoptosis-stimulating protein of p53, as a new host co-factor that binds NS5A via its SH3 domain. Importantly, silencing ASPP2 reduces viral replication and spread. Our study uncovers a previously unknown role for ASPP2 to potentiate HCV RNA replication.


Distinct repair activities of human 7,8-dihydro-8-oxoguanine DNA glycosylase and formamidopyrimidine DNA glycosylase for formamidopyrimidine and 7,8-dihydro-8-oxoguanine.
7,8-dihydro-8-oxoguanine (8-oxoG) and 2,6-diamino-4-hydroxyformamidopyrimidine (Fapy) are major DNA lesions formed by reactive oxygen species and are involved in mutagenic and/or lethal events in cells. Both lesions are repaired by human 7, 8-dihydro-8-oxoguanine DNA glycosylase (hOGG1) and formamidopyrimidine DNA glycosylase (Fpg) in human and Escherichia coli cells, respectively. In the present study, the repair activities of hOGG1 and Fpg were compared using defined oligonucleotides containing 8-oxoG and a methylated analog of Fapy (me-Fapy) at the same site. The k(cat)/K(m) values of hOGG1 for 8-oxoG and me-Fapy were comparable, and this was also the case for Fpg. However, the k(cat)/K(m) values of hOGG1 for both lesions were approximately 80-fold lower than those of Fpg. Analysis of the Schiff base intermediate by NaBH(4) trapping implied that lower substrate affinity and slower hydrolysis of the intermediate for hOGG1 than Fpg accounted for the difference. hOGG1 and Fpg showed distinct preferences of the base opposite 8-oxoG, with the activity differences being 19.8- (hOGG1) and 12-fold (Fpg) between the most and least preferred bases. Surprisingly, such preferences were almost abolished and less than 2-fold for both enzymes when me-Fapy was a substrate, suggesting that, unlike 8-oxoG, me-Fapy is not subjected to paired base-dependent repair. The repair efficiency of me-Fapy randomly incorporated in M13 DNA varied at the sequence level, but orders of preferred and unpreferred repair sites were quite different for hOGG1 and Fpg. The distinctive activities of hOGG1 and Fpg including enzymatic parameters (k(cat)/K(m)), paired base, and sequence context effects may originate from the differences in the inherent architecture of the DNA binding domain and catalytic mechanism of the enzymes.


Evidence of rapid adaptive trait change to local salinity in the sperm of an invasive fish.
Invasive species may quickly colonize novel environments, which could be attributed to both phenotypic plasticity and an ability to locally adapt. Reproductive traits are expected to be under strong selection when the new environment limits reproductive success of the invading species. This may be especially important for external fertilizers, which release sperm and eggs into the new environment. Despite adult tolerance to high salinity, the invasive fish Neogobius melanostomus (round goby) is absent from fully marine regions of the Baltic Sea, raising the possibility that its distribution is limited by tolerance during earlier life stages. Here, we investigate the hypothesis that the spread of N. melanostomus is limited by sperm function in novel salinities. We sampled sperm from two invasion fronts with higher and lower salinities in the Baltic Sea and tested them across a range of salinity levels. We found that sperm velocity and percentage of motile sperm declined in salinity levels higher and lower than those currently experienced by the Baltic Sea populations, with different performance curves for the two fronts. Sperm velocity also peaked closer to the home salinity conditions in each respective invasion front, with older localities showing an increased fit to local conditions. By calculating how the sperm velocity has changed over generations, we show this phenotypic shift to be in the range of other fish species under strong selection, indicating ongoing local adaptation or epigenetic acclimation to their novel environment. These results show that while immigrant reproductive dysfunction appears to at least partly limit the distribution of invasive N. melanostomus in the Baltic Sea, local adaptation to novel environments could enable future spread beyond their current boundaries.


XAP5 CIRCADIAN TIMEKEEPER coordinates light signals for proper timing of photomorphogenesis and the circadian clock in Arabidopsis.
Numerous, varied, and widespread taxa have an internal circadian clock that allows anticipation of rhythmic changes in the environment. We have identified XAP5 CIRCADIAN TIMEKEEPER (XCT), an Arabidopsis thaliana gene important for light regulation of the circadian clock and photomorphogenesis. XCT is essential for proper clock function: xct mutants display a shortened circadian period in all conditions tested. Interestingly, XCT plays opposite roles in plant responses to light depending both on trait and wavelength. The clock in xct plants is hypersensitive to red but shows normal responses to blue light. By contrast, inhibition of hypocotyl elongation in xct is hyposensitive to red light but hypersensitive to blue light. Finally, XCT is important for ribulose-1,5-bisphosphate carboxylase/oxygenase production and plant greening in response to light. This novel combination of phenotypes suggests XCT may play a global role in coordinating growth in response to the light environment. XCT contains a XAP5 domain and is well conserved across diverse taxa, suggesting it has a common function in higher eukaryotes. Downregulation of the XCT ortholog in Caenorhabditis elegans is lethal, suggesting that studies in Arabidopsis may be instrumental to understanding the biochemical activity of XCT.


The pleiotropic functions of peroxisome proliferator-activated receptor gamma.
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors, initially described as molecular targets for synthetic compounds that induce peroxisome proliferation. PPARgamma is the best characterized of the PPARs. The heterodimer of PPARgamma with the retinoid X receptor (RXR) plays a crucial role in adipogenesis and insulin sensitization. The RXR/PPARgamma heterodimer furthermore has been reported to have important immunomodulatory activities and to affect cell proliferation/differentiation pathways in various malignancies. PPARgamma is activated by a number of naturally occurring fatty acid derivatives and by several synthetic compounds, including the thiazolidinediones and L-tyrosine-based insulin sensitizers. This review gives an overview of the pleiotropic functions of PPARgamma and discusses the wide-ranging medical implications that modulation of PPARgamma activity might have for various diseases, ranging from obesity and type 2 diabetes to cancer and inflammation.


How do we approach thrombocytopenia in critically ill patients?
A low platelet count is a frequently encountered haematological abnormality in patients treated in intensive treatment units (ITUs). Although severe thrombocytopenia (platelet count <20 × 109 /l) can be associated with bleeding, even moderate-degree thrombocytopenia is associated with organ failure and adverse prognosis. The aetiology for thrombocytopenia in ITU is often multifactorial and correcting one aetiology may not normalise the low platelet count. The classical view for thrombocytopenia in this setting is consumption associated with thrombin-mediated platelet activation, but other concepts, including platelet adhesion to endothelial cells and leucocytes, platelet aggregation by increased von Willebrand factor release, red cell damage and histone release, and platelet destruction by the complement system, have recently been described. The management of severe thrombocytopenia is platelet transfusion in the presence of active bleeding or invasive procedure, but the risk-benefit of prophylactic platelet transfusions in this setting is uncertain. In this review, the incidence and mechanisms of thrombocytopenia in patients with ITU, its prognostic significance and the impact on organ function is discussed. A practical approach based on the authors' experience is described to guide management of a critically ill patient who develops thrombocytopenia.


Heritability of blood pressure traits and the genetic contribution to blood pressure variance explained by four blood-pressure-related genes.
To study the heritability of four blood pressure traits and the proportion of variance explained by four blood-pressure-related genes. All participants are members of an extended pedigree from a Dutch genetically isolated population. Heritability and genetic correlations of systolic blood pressure, diastolic blood pressure, mean arterial pressure and pulse pressure were assessed using a variance components approach (SOLAR). Polymorphisms of the alpha-adducin (ADD1), angiotensinogen (AGT), angiotensin II type 1 receptor (AT1R) and G protein beta3 (GNB3) genes were typed. Heritability estimates were significant for all four blood pressure traits, ranging between 0.24 and 0.37. Genetic correlations between systolic blood pressure, diastolic blood pressure and mean arterial pressure were high (0.93-0.98), and those between pulse pressure and diastolic blood pressure were low (0.05). The ADD1 polymorphism explained 0.3% of the variance of pulse pressure (P = 0.07), and the polymorphism of GNB3 explained 0.4% of the variance of systolic blood pressure (P = 0.02), 0.2% of mean arterial pressure (P = 0.05) and 0.3% of pulse pressure (P = 0.06). Genetic factors contribute to a substantial proportion of blood pressure variance. In this study, the effect of polymorphisms of ADD1, AGT, AT1R and GNB3 explained a very small proportion of the heritability of blood pressure traits. As new genes associated with blood pressure are localized in the future, their effect on blood pressure variance should be calculated.


Olfactory groove meningioma: report of 99 cases surgically treated at the Catholic University School of Medicine, Rome.
We reviewed our series of olfactory groove meningiomas (OGMs) with the aim to relate the surgical approach with outcome and to define clinical and pathologic predictors of prognosis. Ninety-nine patients who underwent 113 craniotomies at our Institution between 1984 and 2010 were entered this study. The relationship between surgical approach (bifrontal, fronto-orbito-basal, and pterional) and either tumor diameter, extent of tumor resection, complication rate, need of reoperation, and Karnofsky Performance Status (KPS) was analyzed. The impact of age (≤ 70 vs. > 70 years), sex, tumor diameter (< 6 vs. ≥ 6 cm), pre- and postoperative KPS (< 80 vs. ≥ 80), Simpson grade (I-II vs. III-IV), and World Health Organization (WHO) histologic grade (I vs. II-III) on survival was assessed. Kaplan-Meier survival curves were plotted and differences in survival between groups of patients were compared. A multivariate analysis adjusted for age, pre- and postoperative KPS, Simpson grade, tumor diameter, and WHO histologic grade also was performed. The fronto-orbito-basal approach (n = 22) allowed a significantly greater percentage of Simpson I-II removals than the bifrontal (n = 70) and pterional approach (n = 21) (P = 0.0354 and P = 0.0485, respectively). The risk of life-threatening complications trended to be lower in patients operated upon either via the fronto-orbito-basal and via the pterional approach than in those treated via the bifrontal approach. Retraction-related brain swelling did not occur in any case after the fronto-orbito-basal approach (P = 0.0384); however, this approach was associated with a greater rate of cerebrospinal fluid leak (P = 0.0011). Among prognostic factors, age ≤ 70 years (P = 0.0044), tumor diameter <6 cm (P = 0.0455), pre- and postoperative KPS ≥ 80 (both P < 0.0001), Simpson grade I-II (P = 0.0096), and WHO histologic grade I (P = 0.0112) were significantly associated with longer overall survival. Age (P = 0.0393) and WHO histologic grade (P = 0.0418) emerged as independent prognostic factors for overall survival on multivariate analysis. In the largest series of OGMs published to date, the bifrontal approach was associated with a greater risk of life-threatening complications compared with the lateral pterional and fronto-orbito-basal approaches. The fronto-orbito-basal approach provided greater chances of total tumor removal than the bifrontal and pterional approaches. Two independent factors for overall survival of patients with OGM were identified, namely age and WHO grade.


Genetic marker polymorphisms on chromosome 8q24 and prostate cancer in the Dutch population: DG8S737 may not be the causative variant.
Prostate cancer is the most commonly diagnosed cancer in men in Europe and Northern America. Genome-wide association studies (GWAS) have detected an association with markers on chromosome 8q24. Allele -8 of microsatellite DG8S737 with 22 repeats and allele A of the single-nucleotide polymorphism (SNP) rs1447295 have been found to be significantly associated with prostate cancer. As GWAS are subjected to type 1 error, confirmation studies are required to validate the results. Here, we analysed the same markers in 277 cases and 282 controls from the Netherlands using a nested case-control study. Incident prostate cancer cases and controls selected were identified in the population of the Netherlands Cohort Study. We also investigated clinical features of the disease by stratifying by tumour stage. We did not replicate the association with the SNP rs1447295-A allele (P=0.10), although the effect estimate was in the same direction as previous studies (odds ratio (OR), 1.38). Interestingly a statistically significant decreased risk was observed for DG8S737 allele -8 (OR, 0.62; P=0.03). The apparent protective effect of the DG8S737 -8 allele observed in this study contrasts with the Amundadottir study. This suggests that DG8S737 and rs1447295 might be tightly linked markers flanking the actual causative variant and that there may be potentially more than one high-risk haplotype present in the Caucasian population. This short report highlights the importance of validation, although further confirmation is still needed.


Host races in plant-feeding insects and their importance in sympatric speciation.
The existence of a continuous array of sympatric biotypes - from polymorphisms, through ecological or host races with increasing reproductive isolation, to good species - can provide strong evidence for a continuous route to sympatric speciation via natural selection. Host races in plant-feeding insects, in particular, have often been used as evidence for the probability of sympatric speciation. Here, we provide verifiable criteria to distinguish host races from other biotypes: in brief, host races are genetically differentiated, sympatric populations of parasites that use different hosts and between which there is appreciable gene flow. We recognize host races as kinds of species that regularly exchange genes with other species at a rate of more than ca. 1% per generation, rather than as fundamentally distinct taxa. Host races provide a convenient, although admittedly somewhat arbitrary intermediate stage along the speciation continuum. They are a heuristic device to aid in evaluating the probability of speciation by natural selection, particularly in sympatry. Speciation is thereby envisaged as having two phases: (i) the evolution of host races from within polymorphic, panmictic populations; and (ii) further reduction of gene flow between host races until the diverging populations can become generally accepted as species. We apply this criterion to 21 putative host race systems. Of these, only three are unambiguously classified as host races, but a further eight are strong candidates that merely lack accurate information on rates of hybridization or gene flow. Thus, over one-half of the cases that we review are probably or certainly host races, under our definition. Our review of the data favours the idea of sympatric speciation via host shift for three major reasons: (i) the evolution of assortative mating as a pleiotropic by-product of adaptation to a new host seems likely, even in cases where mating occurs away from the host; (ii) stable genetic differences in half of the cases attest to the power of natural selection to maintain multilocus polymorphisms with substantial linkage disequilibrium, in spite of probable gene flow; and (iii) this linkage disequilibrium should permit additional host adaptation, leading to further reproductive isolation via pleiotropy, and also provides conditions suitable for adaptive evolution of mate choice (reinforcement) to cause still further reductions in gene flow. Current data are too sparse to rule out a cryptic discontinuity in the apparently stable sympatric route from host-associated polymorphism to host-associated species, but such a hiatus seems unlikely on present evidence. Finally, we discuss applications of an understanding of host races in conservation and in managing adaptation by pests to control strategies, including those involving biological control or transgenic parasite-resistant plants.


Assessment of cerebral autoregulation: the quandary of quantification.
We assessed the convergent validity of commonly applied metrics of cerebral autoregulation (CA) to determine the extent to which the metrics can be used interchangeably. To examine between-subject relationships among low-frequency (LF; 0.07-0.2 Hz) and very-low-frequency (VLF; 0.02-0.07 Hz) transfer function coherence, phase, gain, and normalized gain, we performed retrospective transfer function analysis on spontaneous blood pressure and middle cerebral artery blood velocity recordings from 105 individuals. We characterized the relationships (n = 29) among spontaneous transfer function metrics and the rate of regulation index and autoregulatory index derived from bilateral thigh-cuff deflation tests. In addition, we analyzed data from subjects (n = 29) who underwent a repeated squat-to-stand protocol to determine the relationships between transfer function metrics during forced blood pressure fluctuations. Finally, data from subjects (n = 16) who underwent step changes in end-tidal P(CO2) (P(ET)(CO2) were analyzed to determine whether transfer function metrics could reliably track the modulation of CA within individuals. CA metrics were generally unrelated or showed only weak to moderate correlations. Changes in P(ET)(CO2) were positively related to coherence [LF: β = 0.0065 arbitrary units (AU)/mmHg and VLF: β = 0.011 AU/mmHg, both P < 0.01] and inversely related to phase (LF: β = -0.026 rad/mmHg and VLF: β = -0.018 rad/mmHg, both P < 0.01) and normalized gain (LF: β = -0.042%/mmHg(2) and VLF: β = -0.013%/mmHg(2), both P < 0.01). However, Pet(CO(2)) was positively associated with gain (LF: β = 0.0070 cm·s(-1)·mmHg(-2), P < 0.05; and VLF: β = 0.014 cm·s(-1)·mmHg(-2), P < 0.01). Thus, during changes in P(ET)(CO2), LF phase was inversely related to LF gain (β = -0.29 cm·s(-1)·mmHg(-1)·rad(-1), P < 0.01) but positively related to LF normalized gain (β = 1.3% mmHg(-1)/rad, P < 0.01). These findings collectively suggest that only select CA metrics can be used interchangeably and that interpretation of these measures should be done cautiously.


PRAF3 induces apoptosis and inhibits migration and invasion in human esophageal squamous cell carcinoma.
Prenylated Rab acceptor 1 domain family member 3 (PRAF3) is involved in the regulation of many cellular processes including apoptosis, migration and invasion. This study was conducted to investigate the effect of PRAF3 on apoptosis, migration and invasion in human esophageal squamous cell carcinoma (ESCC). The expression of PRAF3 mRNA and protein in primary ESCC and the matched normal tissues (57cases) was determined by quantitative RT-PCR and Western blot. Immunohistochemical analysis of PRAF3 expression was carried out in paraffin-embedded sections of ESCC and correlated with clinical features. The role of PRAF3 in apoptosis, migration and invasion was studied in ESCC cell lines of Eca109 and TE-1 through the adenovirus mediated PRAF3 gene transfer. The effect of PRAF3 on apoptosis was analyzed by annexin V-FITC assay. The regulation of PRAF3 on migration was determined by transwell and wounding healing assay, while the cellular invasion was analyzed by matrigel-coated transwell assay. We found that the expression of PRAF3 was significantly down-regulated in ESCC tissue compared with the matched normal tissue and was correlated with the clinical features of pathological grade, tumor stage and lymph node metastasis. Moreover, overexpression of PRAF3 induced cell apoptosis through both caspase-8 and caspase-9 dependent pathways, and inhibited cell migration and invasion by suppressing the activity of both MMP-2 and MMP-9 in human ESCC cell lines. Our data suggest that PRAF3 plays an important role in the regulation of tumor progression and metastasis and serves as a tumor suppressor in human ESCC. We propose that PRAF3 might be used as a potential therapeutic agent for human ESCC.


The relationship between pain and suicidal vulnerability in adolescence: a systematic review.
Leading suicide theories and research in adults suggest that pain can exacerbate the suicidal risk of an individual. Although pain and suicidality (including suicidal ideation, behaviour, and death by suicide) both increase in prevalence during adolescence, the relationship between these factors remains unclear. We aimed to systematically review the empirical evidence for such an association in adolescence. We included 25 observational studies published between January 1961 and December 2018, exploring the potential association between pain and suicidality in adolescents aged 10-19 years. Across various samples and manifestations of pain and suicidality, we found that pain approximately doubles the suicidal risk in adolescents, with a few studies suggesting that pain can predict suicidality longitudinally. Although depression was an important factor, it did not fully explain the association between pain and suicidality. Evidence for associations between pain characteristics and suicidality is sparse and inconclusive, and potentially hides developmental differences between adolescents and adults. Identification of psychological mediators and moderators is required to develop interventions tailored to the needs of adolescents experiencing pain. This study is registered with the PROSPERO database, number CRD42018097226.


Long-term study of a quadrivalent human papillomavirus vaccine.
We present a long-term safety, immunogenicity, and effectiveness study of a quadrivalent human papillomavirus (HPV4) vaccine. Sexually naive boys and girls aged 9 to 15 years (N = 1781) were assigned (2:1) to receive HPV4 vaccine or saline placebo at day 1 and months 2 and 6. At month 30, the placebo group (n = 482) received HPV4 vaccine following the same regimen and both cohorts were followed through month 96. Subjects ≥ 16 years were eligible for effectiveness evaluations. The primary objective was to evaluate the long-term anti-HPV6/11/16/18 serological levels. The secondary objective was to estimate vaccine effectiveness against HPV6/11/16/18-related persistent infection or disease. For each of the HPV4 vaccine types, vaccination-induced anti-HPV response persisted through month 96. Among 429 subjects who received HPV4 vaccine at a mean age of 12, none developed HPV6/11/16/18-related disease or persistent infection of ≥ 12 months' duration. Acquisition of new sexual partners (among those ≥ 16 years) was ∼1 per year. Subjects receiving HPV4 vaccine at month 30 (mean age 15 years) had a similar baseline rate of seropositivity to ≥ 1 of the 4 HPV types to those vaccinated at day 1 (mean age 12 years; 1.9% [9 of 474] vs 1.7% [20 of 1157]); however, 4 of the 9 subjects vaccinated at the later age were seropositive to 3 vaccine types, indicating previous HPV exposure. No new significant serious adverse events were observed for 8 years postvaccination in both genders. When administered to adolescents, the HPV4 vaccine demonstrated durability in clinically effective protection and sustained antibody titers over 8 years.


Total synthesis of legionaminic acid as basis for serological studies.
Legionaminic acid is a nine-carbon diamino monosaccharide that is found coating the surface of various bacterial human pathogens. Its unique structure makes it a valuable biological probe, but access via isolation is difficult and no practical synthesis has been reported. We describe a stereoselective synthesis that yields a legionaminic acid building block as well as linker-equipped conjugation-ready legionaminic acid starting from cheap d-threonine. To set the desired amino and hydroxyl group pattern of the target, we designed a concise sequence of stereoselective reactions. The key transformations rely on chelation-controlled organometallic additions and a Petasis multicomponent reaction. The legionaminic acid was synthesized in a form that enables attachment to surfaces. Glycan microarray containing legionaminic acid revealed that human antibodies bind the synthetic glycoside. The synthetic bacterial monosaccharide is a valuable probe to detect an immune response to bacterial pathogens such as Legionella pneumophila, the causative agent of Legionnaire's disease.


Is there an association between oral health and severity of COVID-19 complications?
Most patients with severe complications from COVID-19 have underlying conditions such as obesity, diabetes, and hypertension. In parallel, there is growing evidence for a link between periodontitis and non-oral systemic diseases. The oral cavity is also a reservoir for respiratory pathogens, and patients with periodontal disease are more likely to develop hospital-acquired pneumonia than healthy individuals. We therefore hypothesize that improving oral health could decrease the severity of COVID-19 symptoms and reduce the associated morbidity.


Recurrent Hospitalization Among Patients With Atrial Fibrillation Undergoing Intracoronary Stenting Treated With 2 Treatment Strategies of Rivaroxaban or a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy.
Patients with atrial fibrillation who undergo intracoronary stenting traditionally are treated with a vitamin K antagonist (VKA) plus dual antiplatelet therapy (DAPT), yet this treatment leads to high risks of bleeding. We hypothesized that a regimen of rivaroxaban plus a P2Y12 inhibitor monotherapy or rivaroxaban plus DAPT could reduce bleeding and thereby have a favorable impact on all-cause mortality and the need for rehospitalization. Stented subjects with nonvalvular atrial fibrillation (n=2124) were randomized 1:1:1 to administration of reduced-dose rivaroxaban 15 mg daily plus a P2Y12 inhibitor for 12 months (group 1); rivaroxaban 2.5 mg twice daily with stratification to a prespecified duration of DAPT of 1, 6, or 12 months (group 2); or the reference arm of dose-adjusted VKA daily with a similar DAPT stratification (group 3). The present post hoc analysis assessed the end point of all-cause mortality or recurrent hospitalization for an adverse event, which was further classified as the result of bleeding, a cardiovascular cause, or another cause blinded to treatment assignment. The risk of all-cause mortality or recurrent hospitalization was 34.9% in group 1 (hazard ratio=0.79; 95% confidence interval, 0.66-0.94; P=0.008 versus group 3; number needed to treat=15), 31.9% in group 2 (hazard ratio=0.75; 95% confidence interval, 0.62-0.90; P=0.002 versus group 3; number needed to treat=10), and 41.9% in group 3 (VKA+DAPT). Both all-cause death plus hospitalization potentially resulting from bleeding (group 1=8.6% [P=0.032 versus group 3], group 2=8.0% [P=0.012 versus group 3], and group 3=12.4%) and all-cause death plus rehospitalization potentially resulting from a cardiovascular cause (group 1=21.4% [P=0.001 versus group 3], group 2=21.7% [P=0.011 versus group 3], and group 3=29.3%) were reduced in the rivaroxaban arms compared with the VKA arm, but other forms of rehospitalization were not. Among patients with atrial fibrillation undergoing intracoronary stenting, administration of either rivaroxaban 15 mg daily plus P2Y12 inhibitor monotherapy or 2.5 mg rivaroxaban twice daily plus DAPT was associated with a reduced risk of all-cause mortality or recurrent hospitalization for adverse events compared with standard-of-care VKA plus DAPT. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01830543.


The treatment of chronic hepatitis C virus infection in HIV co-infection.
Chronic HCV co-infection is present in up to one third of HIV-positive patients in Europe. In recent years, apart from the traditional transmission route of intravenous drug abuse, outbreaks of sexually transmitted acute HCV infections, mainly among HIV-positive men who have sex with men, have contributed to the overall disease burden. - Because the natural course of HCV infection is substantially accelerated in HIV-co-infection, end-stage liver disease has become the most frequent cause of non-AIDS related death in this population. Therefore every HIV/HCV co-infected patient should be evaluated for possible anti-HCV therapy with the goal of reaching a sustained virological response and thus cure of hepatitis C infection. The standard of care for the treatment of chronic HCV infection in HIV-infected remains a pegylated interferon in combination with weight-adapted ribavirin. - HAART should not be withheld from HCV co-infected patients due to concerns of drug related hepatotoxicity and in patients with reduced CD4-cell counts HAART should be started first. Under pegylated interferon and ribavirin combination therapy drug to drug interactions and cumulated toxicity between nucleoside analogues and anti-HCV therapy may be observed and concomitant didanosine use is contraindicated and zidovudine and stavudine should be avoided if possible. - The development of new drugs for the treatment of chronic hepatitis C represents a promising perspective also for HIV positive patients. However, these substances will probably reach clinical routine for HIV patients later than HCV monoinfected patients. Therefore at present waiting for new drugs is not an alternative to a modern pegylated interferon/ribavirin therapy.


Antiinflammatory and anti-cancer activities of pomegranate and its constituent, ellagic acid: Evidence from cellular, animal, and clinical studies.
Inflammation is commonly characterized as a defensive and protective reaction of the body to various exogenous or endogenous stimuli, which aims to maintain the body health. Punica granatum (pomegranate) and its constituent ellagic acid (EA) are recently more taken into accounts since their promising pharmacological effects. Therefore, we aimed to obtain a comprehensive review regarding antiinflammatory, anticancer, and antioxidant activities of both pomegranate and EA and their possible involved mechanisms. In the procedure, scientific databases, including Web of Science, PubMed, Scopus, and Google Scholar, were searched in the English language, until the end of January 2019. Pomegranate belonging to the Punicaceae has been used for medical purposes from ancient and in different cultures. Several studies have also supported that EA is the major active compound of pomegranate and possesses antimutagenic, antiinflammatory, antifibrosis, anticancer, and antiaging properties. It has been suggested that pomegranate and EA possess promising immunomodulatory effects in preclinical models as well as human studies through regulation of the T-cell function and suppressing humoral immunity. Hopefully, we wish that this review and information could be helpful for designing further experiments to investigate the potential protective effects of pomegranate and EA.


Spo13 facilitates monopolin recruitment to kinetochores and regulates maintenance of centromeric cohesion during yeast meiosis.
Cells undergoing meiosis perform two consecutive divisions after a single round of DNA replication. During the first meiotic division, homologous chromosomes segregate to opposite poles. This is achieved by (1) the pairing of maternal and paternal chromosomes via recombination producing chiasmata, (2) coorientation of homologous chromosomes such that sister chromatids attach to the same spindle pole, and (3) resolution of chiasmata by proteolytic cleavage by separase of the meiotic-specific cohesin Rec8 along chromosome arms. Crucially, cohesin at centromeres is retained to allow sister centromeres to biorient at the second division. Little is known about how these meiosis I-specific events are regulated. Here, we show that Spo13, a centromere-associated protein produced exclusively during meiosis I, is required to prevent sister kinetochore biorientation by facilitating the recruitment of the monopolin complex to kinetochores. Spo13 is also required for the reaccumulation of securin, the persistence of centromeric cohesin during meiosis II, and the maintenance of a metaphase I arrest induced by downregulation of the APC/C activator CDC20. Spo13 is a key regulator of several meiosis I events. The presence of Spo13 at centromere-surrounding regions is consistent with the notion that it plays a direct role in both monopolin recruitment to centromeres during meiosis I and maintenance of centromeric cohesion between the meiotic divisions. Spo13 may also limit separase activity after the first division by ensuring securin reaccumulation and, in doing so, preventing precocious removal from chromatin of centromeric cohesin.


Group B Streptococcus (GBS) colonization is dynamic over time, whilst GBS capsular polysaccharides-specific antibody remains stable.
Group B Streptococcus (GBS) is a leading cause of adverse pregnancy outcomes due to invasive infection. This study investigated longitudinal variation in GBS rectovaginal colonization, serum and vaginal GBS capsular polysaccharide (CPS)-specific antibody levels. Non-pregnant women were recruited in the UK and were sampled every 2 weeks over a 12-week period. GBS isolates were taken from recto-vaginal swabs and serotyped by polymerase chain reaction. Serum and vaginal immunoglobulin G (IgG) and nasal immunoglobulin A (IgA) specific to CPS were measured by Luminex, and total IgG/A by ELISA. Seventy women were enrolled, of median age 26. Out of the 66 participants who completed at least three visits: 14/47 (29.8%) women that were GBS negative at screening became positive in follow-up visits and 16/19 (84.2%) women who were GBS positive at screening became negative. There was 50% probability of becoming negative 36 days after the first positive swab. The rate of detectable GBS carriage fluctuated over time, although serum, vaginal, and nasal CPS-specific antibody levels remained constant. Levels of CPS-specific antibodies were higher in the serum of individuals colonized with GBS than in non-colonized, but similar in the vaginal and nasal mucosa. We found correlations between antibody levels in serum and the vaginal and nasal mucosa. Our study demonstrates the feasibility of elution methods to retrieve vaginal and nasal antibodies, and the optimization of immunoassays to measure GBS-CPS-specific antibodies. The difference between the dynamics of colonization and antibody response is interesting and further investigation is required for vaccine development.


Peak flow rate records in the diagnosis of occupational asthma due to colophony.
Peak expiratory flow rate (PEFR) has been measured hourly from waking to sleeping in 29 workers with respiratory symptoms exposed to the fumes of soft soldering fluxes containing colophony (pine resin). Thirty-nine records of mean length 33 days have been analysed, and the results compared with the occupational history and bronchial provocation testing in the same workers. From plots of daily mean, maximum, and minimum PEFR, recurring physiological patterns of asthma emerge. The most common pattern is for asthma to increase with each successive working day. Some workers have an equivalent deterioration each working day. Regular recovery patterns taking one, two, and three days are described. The combination of a three-day recovery pattern and a late asthmatic reaction on Monday results in Monday being the best day of each week. Assessment of these records has shown them to be specific and sensitive, provided the worker was not taking corticosteroids or sodium cromoglycate during the period of the record and that bronchodilator usage was kept constant on days at home and at work. The results of the PEFR records correlate well with bronchial provocation testing, and provide a suitable alternative to this for the diagnosis of mild to moderate occupational asthma. The records are of particular use for screening symptomatic workers whose symptoms appear unlikely to be related to work.


The effect of activated charcoal on adenine-induced chronic renal failure in rats.
Activated charcoal (AC) is a sorbent that has been shown to remove urinary toxins like urea and indoxyl sulfate. Here, the influence of AC on kidney function of rats with experimental chronic renal failure (CRF) is investigated. CRF was induced in rats by feeding adenine (0.75%) for four weeks. As an intervention, AC was added to the feed at concentrations of 10%, 15% or 20%. Adenine treatment impaired kidney function: it lowered creatinine clearance and increased plasma concentrations of creatinine, urea, neutrophil gelatinase-associated lipocalin and vanin-1. Furthermore, it raised plasma concentrations of the uremic toxins indoxyl sulfate, phosphate and uric acid. Renal morphology was severely damaged and histopathological markers of inflammation and fibrosis were especially increased. In renal homogenates, antioxidant indices, including superoxide dismutase and catalase activity, total antioxidant capacity and reduced glutathione were adversely affected. Most of these changes were significantly ameliorated by dietary administration of AC at a concentration of 20%, while effects induced by lower doses of dietary AC on adenine nephrotoxicity were not statistically significant. The results suggest that charcoal is a useful sorbent agent in dietary adenine-induced CRF in rats and that its usability as a nephroprotective agent in human kidney disease should be studied.


Independence of resistance in Brachiaria spp. to nymphs or to adult spittlebugs (Hemiptera: Cercopidae): implications for breeding for resistance.
Both nymphal and adult spittlebugs (Hemiptera: Cercopidae) cause serious economic damage to susceptible brachiariagrass [genus Brachiaria (Trin.) Griseb], pastures in tropical America. Both life stages are xylem feeders: nymphs feed primarily on roots and stems, whereas the adults feed mainly on foliage. Numerous interspecific brachiariagrass hybrids with high levels of antibiosis resistance to nymphs of several important spittlebug species have been obtained. Recent studies revealed major inconsistencies between reaction to nymphs and reaction to adults on the same host genotype. Because both insect life stages can cause severe economic damage on susceptible brachiariagrass pastures, a cultivar development strategy must take into account resistance to both life stages. To assess the degree of association between resistance to spittlebug nymphs and to adult feeding, we tested 164 hybrids and six check genotypes for resistance to both life stages of three spittlebug species: Aeneolamia varia (F.), Aeneolamia reducta (Lallemand), and Zulia carbonaria (Lallemand). Most hybrids tested were classified as resistant to nymphs. On the contrary, for all three species, the overall mean damage score of the 164 hybrids did not differ from the mean score of the susceptible checks. None of the hybrids was classified as resistant to adult feeding damage. Correlations between percentage nymph survival and adult damage scores were consistently low (r = 0.0104-0.0191). Correlations between nymphal and adult damage scores were also low (0.109-0.271), suggesting that resistances to the different life stages are largely independent. Chi-square analyses comparing frequency distributions of responses of the 164 breeding hybrids to nymphs or adults confirmed essential genetic independence of these two traits. We conclude that attention to improving genetic resistance specifically to adult feeding damage is warranted.


Ultralow surface recombination velocity in InP nanowires probed by terahertz spectroscopy.
Using transient terahertz photoconductivity measurements, we have made noncontact, room temperature measurements of the ultrafast charge carrier dynamics in InP nanowires. InP nanowires exhibited a very long photoconductivity lifetime of over 1 ns, and carrier lifetimes were remarkably insensitive to surface states despite the large nanowire surface area-to-volume ratio. An exceptionally low surface recombination velocity (170 cm/s) was recorded at room temperature. These results suggest that InP nanowires are prime candidates for optoelectronic devices, particularly photovoltaic devices, without the need for surface passivation. We found that the carrier mobility is not limited by nanowire diameter but is strongly limited by the presence of planar crystallographic defects such as stacking faults in these predominantly wurtzite nanowires. These findings show the great potential of very narrow InP nanowires for electronic devices but indicate that improvements in the crystallographic uniformity of InP nanowires will be critical for future nanowire device engineering.


Bacteria from Ips sexdentatus (Coleoptera: Curculionidae) and their biocontrol potential.
Ips sexdentatus (Coleoptera: Curculionidae) is one of the most destructive pests of the spruce trees in Europe. In this study, we have isolated and characterized culturable bacteria from I. sexdentatus and tested their insecticidal activity against the last instar larvae of the pest as a possible biocontrol agent. A total of eight bacterial isolates was determined and four of them were identified at species level, and the others were identified at genus level. Isolates were identified as Stenotrophomonas maltophilia (Is1), Rahnella sp. (Is2), Pseudomonas sp. (Is3), Bacillus sp. (Is4), Alcaligenes faecalis (Is5), Panteoea agglomerans (Is6), Pseudomonas fluorescens (Is7) and Serratia sp. (Is8) based on their morphological, biochemical and molecular characteristics. Insecticidal effects of bacterial isolates were performed on the last instar larvae of the pest. The highest insecticidal activity was obtained from P. fluorescens (Is7) with 73% mortality within 10 days after inoculation (p < 0.05). Mortality values of the other isolates ranged from 20 to 53%. This study suggests that Pseudomonas fluorescens (Is7) seems to be a good candidate as a possible biocontrol agent against I. sexdentatus, and provides suitable strains that can be modified to express insecticidal toxins and/or other detrimental substances to develop new control methods for I. sexdentatus.


Hospitalist Perceptions of Barriers to Lung Ultrasound Adoption in Diverse Hospital Environments.
Despite the many advantages of lung ultrasound (LUS) in the diagnosis and management of patients with dyspnea, its adoption among hospitalists has been slow. We performed semi-structured interviews of hospitals from four diverse health systems in the United States to understand determinants of adoption within a range of clinical settings. We used the diffusion of innovation theory to guide a framework analysis of the data. Of the 27 hospitalists invited, we performed 22 interviews from four hospitals of diverse types. Median years post-residency of interviewees was 10.5 [IQR:5-15]. Four main themes emerged: (1) There are important clinical advantages to LUS despite operator dependence, (2) LUS enhances patient and clinician experience, (3) Investment of clinician time to learn and perform LUS is a barrier to adoption but yields improved efficiency for the health system and (4) Mandated training and use may be necessary to achieve broad adoption as monetary incentives are less effective. Despite the perceived benefits of LUS for patients, clinicians and health systems, a significant barrier to broad LUS adoption is the experience of time scarcity by hospitalists. Future implementation strategies should focus on changes to the clinical environment that address clinician barriers to learning and adoption of new skills.


Predicting malignancy: subsolid nodules detected on LDCT in a surgical cohort of East Asian patients.
Due to widespread use of low-dose computed tomography (LDCT) screening, increasing number of patients are found to have subsolid nodules (SSNs). The management of SSNs is a clinical challenge and primarily depends on CT imaging. We seek to identify risk factors that may help clinicians determine an optimal course of management. We retrospectively reviewed the characteristics of 83 SSN lesions, including 48 pure ground-glass nodules and 35 part-solid nodules, collected from 83 patients who underwent surgical resection. Of the 83 SSNs, 16 (19.28%) were benign and 67 (80.72%) were malignant, including 23 adenocarcinomas in situ (AIS), 16 minimally invasive adenocarcinomas (MIA), and 28 invasive adenocarcinomas (IA). Malignant lesions were found to have significantly larger diameters (P<0.05) with an optimal cut-off point of 9.24 mm. Significant indicators of malignancy include female sex (P<0.05), air bronchograms (P<0.001), spiculation (P<0.05), pleural tail sign (P<0.05), and lobulation (P<0.05). When compared with AIS/MIA combined, IA lesions were found to be larger (P<0.05) with an optimal cut-off of 12 mm, and have a higher percentage of part-solid nodules (P<0.001), pleural tail sign (P<0.001), air bronchograms (P<0.05), and lobulation (P<0.05). Further multivariate analysis found that lesion size and spiculation were independent factors for malignancy while part-solid nodules were associated with IA histology. East Asian females are at risk of presenting with a malignant lesion even without history of heavy smoking or old age. Nodule features associated with malignancy include larger size, air bronchograms, lobulation, pleural tail sign, spiculation, and solid components. A combination of patient characteristic and LDCT features can be effectively used to guide management of patients with SSNs.


A phylogenetic analysis using full-length viral genomes of South American dengue serotype 3 in consecutive Venezuelan outbreaks reveals a novel NS5 mutation.
Dengue virus currently causes 50-100 million infections annually. Comprehensive knowledge about the evolution of Dengue in response to selection pressure is currently unavailable, but would greatly enhance vaccine design efforts. In the current study, we sequenced 187 new dengue virus serotype 3 (DENV-3) genotype III whole genomes isolated from Asia and the Americas. We analyzed them together with previously-sequenced isolates to gain a more detailed understanding of the evolutionary adaptations existing in this prevalent American serotype. In order to analyze the phylogenetic dynamics of DENV-3 during outbreak periods; we incorporated datasets of 48 and 11 sequences spanning two major outbreaks in Venezuela during 2001 and 2007-2008, respectively. Our phylogenetic analysis of newly sequenced viruses shows that subsets of genomes cluster primarily by geographic location, and secondarily by time of virus isolation. DENV-3 genotype III sequences from Asia are significantly divergent from those from the Americas due to their geographical separation and subsequent speciation. We measured amino acid variation for the E protein by calculating the Shannon entropy at each position between Asian and American genomes. We found a cluster of seven amino acid substitutions having high variability within E protein domain III, which has previously been implicated in serotype-specific neutralization escape mutants. No novel mutations were found in the E protein of sequences isolated during either Venezuelan outbreak. Shannon entropy analysis of the NS5 polymerase mature protein revealed that a G374E mutation, in a region that contributes to interferon resistance in other flaviviruses by interfering with JAK-STAT signaling was present in both the Asian and American sequences from the 2007-2008 Venezuelan outbreak, but was absent in the sequences from the 2001 Venezuelan outbreak. In addition to E, several NS5 amino acid changes were unique to the 2007-2008 epidemic in Venezuela and may give additional insight into the adaptive response of DENV-3 at the population level.


Seagrass proliferation precedes mortality during hypo-salinity events: a stress-induced morphometric response.
Halophytes, such as seagrasses, predominantly form habitats in coastal and estuarine areas. These habitats can be seasonally exposed to hypo-salinity events during watershed runoff exposing them to dramatic salinity shifts and osmotic shock. The manifestation of this osmotic shock on seagrass morphology and phenology was tested in three Indo-Pacific seagrass species, Halophila ovalis, Halodule uninervis and Zostera muelleri, to hypo-salinity ranging from 3 to 36 PSU at 3 PSU increments for 10 weeks. All three species had broad salinity tolerance but demonstrated a moderate hypo-salinity stress response--analogous to a stress induced morphometric response (SIMR). Shoot proliferation occurred at salinities <30 PSU, with the largest increases, up to 400% increase in shoot density, occurring at the sub-lethal salinities <15 PSU, with the specific salinity associated with peak shoot density being variable among species. Resources were not diverted away from leaf growth or shoot development to support the new shoot production. However, at sub-lethal salinities where shoots proliferated, flowering was severely reduced for H. ovalis, the only species to flower during this experiment, demonstrating a diversion of resources away from sexual reproduction to support the investment in new shoots. This SIMR response preceded mortality, which occurred at 3 PSU for H. ovalis and 6 PSU for H. uninervis, while complete mortality was not reached for Z. muelleri. This is the first study to identify a SIMR in seagrasses, being detectable due to the fine resolution of salinity treatments tested. The detection of SIMR demonstrates the need for caution in interpreting in-situ changes in shoot density as shoot proliferation could be interpreted as a healthy or positive plant response to environmental conditions, when in fact it could signal pre-mortality stress.