What are the clinical outcome and cost-effectiveness of endoscopy undertaken by nurses when compared with doctors? A Multi-Institution Nurse Endoscopy Trial (MINuET).
To compare the clinical outcome and cost-effectiveness of doctors and nurses undertaking upper and lower gastrointestinal endoscopy. The study was a pragmatic randomised controlled trial. Zelen's randomisation before consent was used to minimise distortion of existing practice in the participating sites. An economic evaluation was conducted alongside the trial, assessing the relative cost-effectiveness of nurses and doctors. The study was undertaken in 23 hospitals in England, Scotland and Wales. In six hospitals nurses undertook both upper and lower gastrointestinal endoscopy, yielding a total of 29 'centres'. The study was coordinated and managed from Swansea. Randomisation, data management and analysis were undertaken at York. Analysis was by intention-to-scope. Sixty-seven doctors and 30 nurses took part in the study. Of 4964 potentially eligible patients, 4128 (83%) were randomised. Of these, 1888 (45%) were recruited to the study from 29 July 2002 to 30 June 2003. The procedures under study were diagnostic upper gastrointestinal endoscopy and flexible sigmoidoscopy undertaken by nurses or doctors, with or without sedation, using the preparation, techniques and protocols of participating hospitals. Primary outcome measure was the Gastrointestinal Symptom Rating Questionnaire (GSRQ). The secondary outcome measures were EuroQol (EQ5D), Gastrointestinal Endoscopy Satisfaction Questionnaire (GESQ), State-Trait Anxiety Inventory (STAI), cost-effectiveness, immediate and delayed complications, quality of examination by blinded assessment of endoscopic video recordings, quality of procedure reports, patients' preferences for operator 1 year after endoscopy, and new diagnoses at 1 year. The two groups were well matched at baseline for demographic and clinical characteristics. Significantly more patients changed from a planned endoscopy by a doctor to a nurse than vice versa, mainly for staffing reasons. There was no significant difference between the two groups in the primary or secondary outcome measures at 1 day, 1 month or 1 year after endoscopy, with the exception of patient satisfaction at 1 day, which favoured nurses. Nurses were significantly more thorough in the examination of stomach and oesophagus, but no different from doctors in the examination of duodenum and colon. There was no significant difference in costs to the NHS or patients, although doctors cost slightly more. Although quality of life measures showed improvement in some scores in the doctor group, this did not reach traditional levels of statistical significance. Even so, the economic evaluation, taking account of uncertainty in both costs and quality of life, suggests that endoscopy by doctors has an 87% chance of being more cost-effective than endoscopy by nurses. There is no statistically significant difference between doctors and nurses in their clinical effectiveness in diagnostic endoscopy. However, nurses are significantly more thorough in the examination of oesophagus and stomach, and patients are significantly more satisfied after endoscopy by a nurse. Endoscopy by doctors is associated with better outcome at 1 year at higher cost, but overall is likely to be cost-effective. Further research is needed to evaluate the clinical outcome and cost-effectiveness of nurses undertaking a greater role in other settings, to monitor the cost-effectiveness of nurse endoscopists as they become more experienced and to assess, the effect of increasing the number of nurse endoscopists on waiting times for patients, and the career implications and opportunities for nurses who become trained endoscopists. Evaluation of the clinical outcome and cost-effectiveness of diagnostic endoscopy for all current indications is also needed.


Childhood asthma, can admissions be avoided?
Since admissions with asthma continue to increase and account for considerable morbidity, we chose to prospectively study asthma admissions over a one year period to assess the severity of patients' asthma, their need for treatment available only in hospital, and to assess the adequacy of their prehospital treatment. A study proforma was completed soon after the admission of each child. Data gathered between the 1st January and 31st December 1990 are presented. There were 105 children admitted, two-thirds of those were boys and just over half were aged less than 5 years. Eighty-seven children had a previous diagnosis of asthma. Overall the attacks were not severe, only 10 patients were treated with intravenous medication and 18 children required continuous oxygen. Sixteen patients required hospitalisation for more than 48 hours, the remainder were discharged within 2 days. Suboptimal prehospital care was identified in a third of patients, inappropriate management of the acute attack, failure of adequate prophylactic medication and non-compliance with prescribed regimes were common. In our hospital, admissions with acute severe asthma have declined in 1990, attention to simple treatment schedules may further reduce hospitalisation.


Effect of Exposure Dose on Ichthyophonus Prevalence and Infection Intensity in Experimentally Infected Rainbow Trout, Oncorhynchus mykiss.
This study describes the effect of increasing exposure dose on Ichthyophonus prevalence and infection intensity in experimentally infected rainbow trout, Oncorhynchus mykiss. Specific-pathogen free trout were exposed per os to increasing numbers of Ichthyophonus schizonts obtained from naturally infected donor fish, then sampled after 30 and 60 days post-exposure. Both in vitro explant culture and histology revealed that as the number of schizonts per dose increased there was a proportionate increase in the number of infected fish, as well as an increase in the number of infected organs; parasite density in individual infected organs also increased with dose. Explant culture revealed that all fish exposed to the highest dose (≥2,080 schizonts) became infected, while only 67% of those exposed to the intermediate dose (1,040-1,153 schizonts) were Ichthyophonus-positive after 60 days; Ichthyophonus was not detected in fish exposed to the 2 lowest doses (≤280 schizonts). Histologic examination of individual infected organs also revealed increasing infection prevalence and parasite density in response to exposure to increasing numbers of Ichthyophonus schizonts.


Age changes of human serum polyreactive immunoglobulins (PRIG) activity.
It has been determined that activity of serum polyreactive immunoglobulins (PRIG) changes with age in practically healthy people at the age from twenty five to seventy. Therewith, the activity of serum IgG PRIG increases most of all (about 3-4 times), while IgM PRIG activity, on the contrary, does not increase, but sometimes even decreases with age. IgA PRIG activity varies significantly more than IgG PRIG activity and, besides, IgA PRIG significantly less depends on age than IgG PRIG. The age changes in the activity of human serum PRIG, belonging to different types of immunoglobulins, may evidence for the important functional role of these immunoglobulins that has to be clarified.


2-Hydroxyethyl-alpha-D-glucopyranoside-2,3',4'-trisphosphate, a novel, metabolically resistant, adenophostin A and myo-inositol-1,4,5-trisphosphate analogue, potently interacts with the myo-inositol-1,4,5-trisphosphate receptor.
The novel, synthetic, adenophostin A analogue 2-hydroxyethyl-alpha-D-glucopyranoside-2,3',4'-trisphosphate [Glu(2,3',4')P3] was synthesized to probe the structure-activity relationship at the D-myo-inositol-1,4,5-trisphosphate [Ins(1,4,5)P3] receptor [Ins(1,4,5)P3R]. This study was stimulated by the recent observation that the fungal isolates adenophostins A and B were very potent, metabolically resistant, Ins(1,4,5)P3R agonists [J. Biol. Chem. 269:369-372 (1994)]. Gluc(2,3',4')P3 can be visualized as a truncated version of adenophostin A, in which the 2'- and 3'-carbons of the ribose ring, with their terminal phosphate groups, are retained and the remainder of the adenosine residue is excised. Gluc(2,3',4')P3 specifically displaced [3H]Ins(1,4,5)P3 from pig cerebellar Ins(1,4,5)P3 binding sites, with an affinity (IC50 = 130 nM) only 5-fold weaker than that of Ins(1,4,5)P3 (IC50 = 27 nM). Gluc(2,3',4')P3 was also a full agonist for Ca2+ release, being only 10-12-fold less potent than Ins(1,4,5)P3 in saponin-permeabilized SH-SY5Y neuroblastoma cells [EC50 = 647 nM; Ins(1,4,5)P3 EC50 = 52 nM] and Madin-Darby canine kidney cells [EC50 = 2484 nM; Ins(1,4,5)P3 EC50 = 247 nM]. Gluc(2,3',4')P3 did not significantly interact with recombinant Ins(1,4,5)P3 3-kinase and 5-phosphatase enzymes and was also poorly metabolized by saponin-permeabilized SH-SY5Y cells. However, Gluc(2,3',4')P3 was a considerably weaker ligand (approximately 500-fold) and agonist (approximately 1000-fold) than adenophostin A, suggesting that the partial excision of the adenosine residue compromised structural motifs that have favorable interactions with the Ins(1,4,5)P3R. Indeed, molecular dynamics simulations revealed that the potencies of the three compounds show a correlation with the relative distance of the two vicinal ring phosphates from the remaining phosphate. Gluc(2,3',4')P3, with its alpha-glucoside ring, is the first synthetic Ins(1,4,5)P3 analogue that is not structurally based on a phosphorylated inositol isomer and that exhibits potent activity at the Ins(1,4,5)P3R. This, combined with the metabolic resistance of Gluc(2,3',4')P3, thus affords a novel approach for the investigation of the cellular role of Ins(1,4,5)P3 and its receptor.


When radiologists perform best: the learning curve in screening mammogram interpretation.
To examine changes in screening mammogram interpretation as radiologists with and radiologists without fellowship training in breast imaging gain clinical experience. In an institutional review board-approved HIPAA-compliant study, the performance of 231 radiologists who interpreted screen-film screening mammograms from 1996 to 2005 at 280 facilities that contribute data to the Breast Cancer Surveillance Consortium was examined. Radiologists' demographic data and clinical experience levels were collected by means of a mailed survey. Mammograms were grouped on the basis of how many years the interpreting radiologist had been practicing mammography, and the influence of increasing experience on performance was examined separately for radiologists with and those without fellowship training in breast imaging, taking into account case-mix and radiologist-level differences. A total of 1 599 610 mammograms were interpreted during the study period. Performance for radiologists without fellowship training improved most during their 1st 3 years of clinical practice, when the odds of a false-positive reading dropped 11%-15% per year (P < .015) with no associated decrease in sensitivity (P > .89). The number of women recalled per breast cancer detected decreased from 33 for radiologists in their 1st year of practice to 24 for radiologists with 3 years of experience to 19 for radiologists with 20 years of experience. Radiologists with fellowship training in breast imaging experienced no learning curve and reached desirable goals during their 1st year of practice. Radiologists' interpretations of screening mammograms improve during their first few years of practice and continue to improve throughout much of their careers. Additional residency training and targeted continuing medical education may help reduce the number of work-ups of benign lesions while maintaining high cancer detection rates.


Asian society of gynecologic oncology workshop 2010.
This workshop was held on July 31-August 1, 2010 and was organized to promote the academic environment and to enhance the communication among Asian countries prior to the 2nd biennial meeting of Australian Society of Gynaecologic Oncologists (ASGO), which will be held on November 3-5, 2011. We summarized the whole contents presented at the workshop. Regarding cervical cancer screening in Asia, particularly in low resource settings, and an update on human papillomavirus (HPV) vaccination was described for prevention and radical surgery overview, fertility sparing and less radical surgery, nerve sparing radical surgery and primary chemoradiotherapy in locally advanced cervical cancer, were discussed for management. As to surgical techniques, nerve sparing radical hysterectomy, optimal staging in early ovarian cancer, laparoscopic radical hysterectomy, one-port surgery and robotic surgery were introduced. After three topics of endometrial cancer, laparoscopic surgery versus open surgery, role of lymphadenectomy and fertility sparing treatment, there was a special additional time for clinical trials in Asia. Finally, chemotherapy including neo-adjuvant chemotherapy, optimal surgical management, and the basis of targeted therapy in ovarian cancer were presented.


Superatom chemistry: promising properties of near-spherical noble metal clusters.
Properties of near-spherical metal clusters are best understood on the basis of the concept of conventional atoms. Their conduction electrons occupy cluster orbitals that remind of hydrogen-like orbitals since they have the same angular dependence. When populated with electrons, maxima in their ionization potentials and minima in electron affinities reveal the closing of shells in the same sense as for noble gases. This suggests that the periodic table of elements should be amended by a third dimension reflecting the number of atoms in a cluster of the element. In a bonded situation the symmetry of cluster atoms is broken, and the atomic orbital momentum is quenched to a large extent. However, if superatoms are axially symmetric, there are superatomic orbital angular moments that are locked along this symmetry axis. If their z-component is non-zero, this leads to large magnetic moments and to significant spin-orbit interactions, which greatly complicate spectroscopic observation. This magnetic interaction is anisotropic and may lead to hysteresis loops with corresponding blocking temperatures up to room temperature. The number of unpaired electrons in such a system is crucial, and it may be influenced by doping with different atoms or by chemical bonds to capping ligands. Stable superatom clusters with size-tuned, tailored band gaps and band edge energies may be attractive replacements for toxic or rare elements in photovoltaic cells or batteries; they form chemically inert and well-defined stoichiometric complexes with various ligands. This reminds of the established transition metal complexes and may lead to a novel branch of chemistry in which the central ion of organometallic complexes is replaced by a metal superatom.


Neurokinin-1 receptor antagonism attenuates neuronal activity triggered by stress-induced reinstatement of alcohol seeking.
Substance P (SP) and its cognate neurokinin-1 receptor (NK1R) are involved in alcohol-related behaviors. We have previously reported that NK1R antagonism attenuates stress-induced reinstatement of alcohol seeking and suppresses escalated alcohol self-administration, but does not affect primary reinforcement or cue-induced reinstatement. Here, we administered an NK1R antagonist or vehicle prior to footshock-induced reinstatement of alcohol seeking, and mapped the resulting neuronal activation using Fos immunohistochemistry. As expected, vehicle treated animals exposed to footshock showed induction of Fos immunoreactivity in several regions of the brain stress circuitry, including the amygdala (AMG), nucleus accumbens (NAC), dorsal raphe nucleus (DR), prefrontal cortex (PFC), and bed nucleus of the stria terminalis (BNST). NK1R antagonism selectively suppressed the stress-induced increase in Fos in the DR and NAC shell. In the DR, Fos-induction by stress largely overlapped with tryptophan hydroxylase (TrpH), indicating activation of serotonergic neurons. Of NAC shell neurons activated during stress-induced reinstatement of alcohol seeking, about 30% co-expressed dynorphin (DYN), while 70% co-expressed enkephalin (ENK). Few (<1%) activated NAC shell neurons coexpressed choline acetyltransferase (ChAT), which labels the cholinergic interneurons of this region. Infusion of the NK1R antagonist L822429 into the NAC shell blocked stress-induced reinstatement of alcohol seeking. In contrast, L822429 infusion into the DR had no effect, suggesting that the influence of NK1R signaling on neuronal activity in the DR is indirect. Taken together, our results outline a potential pathway through which endogenous NK1R activation mediates stress-induced alcohol seeking.


Strategies to mitigate peanut allergy: production, processing, utilization, and immunotherapy considerations.
Peanut (Arachis hypogaea L.) is an important crop grown worldwide for food and edible oil. The surge of peanut allergy in the past 25 years has profoundly impacted both affected individuals and the peanut and related food industries. In response, several strategies to mitigate peanut allergy have emerged to reduce/eliminate the allergenicity of peanuts or to better treat peanut-allergic individuals. In this review, we give an overview of peanut allergy, with a focus on peanut proteins, including the impact of thermal processing on peanut protein structure and detection in food matrices. We discuss several strategies currently being investigated to mitigate peanut allergy, including genetic engineering, novel processing strategies, and immunotherapy in terms of mechanisms, recent research, and limitations. All strategies are discussed with considerations for both peanut-allergic individuals and the numerous industries/government agencies involved throughout peanut production and utilization.


Virus-Based Immuno-Oncology Models.
Immunotherapy has been extensively explored in recent years with encouraging results in selected types of cancer. Such success aroused interest in the expansion of such indications, requiring a deep understanding of the complex role of the immune system in carcinogenesis. The definition of hot vs. cold tumors and the role of the tumor microenvironment enlightened the once obscure understanding of low response rates of solid tumors to immune check point inhibitors. Although the major scope found in the literature focuses on the T cell modulation, the innate immune system is also a promising oncolytic tool. The unveiling of the tumor immunosuppressive pathways, lead to the development of combined targeted therapies in an attempt to increase immune infiltration capability. Oncolytic viruses have been explored in different scenarios, in combination with various chemotherapeutic drugs and, more recently, with immune check point inhibitors. Moreover, oncolytic viruses may be engineered to express tumor specific pro-inflammatory cytokines, antibodies, and antigens to enhance immunologic response or block immunosuppressive mechanisms. Development of preclinical models capable to replicate the human immunologic response is one of the major challenges faced by these studies. A thorough understanding of immunotherapy and oncolytic viruses' mechanics is paramount to develop reliable preclinical models with higher chances of successful clinical therapy application. Thus, in this article, we review current concepts in cancer immunotherapy including the inherent and synthetic mechanisms of immunologic enhancement utilizing oncolytic viruses, immune targeting, and available preclinical animal models, their advantages, and limitations.


Design of an adenosine phosphorylase by active-site modification of murine purine nucleoside phosphorylase. Enzyme kinetics and molecular dynamics simulation of Asn-243 and Lys-244 substitutions of purine nucleoside phosphorylase.
Our objective was to alter the substrate specificity of purine nucleoside phosphorylase such that it would catalyse the phosphorolysis of 6-aminopurine nucleosides. We modified both Asn-243 and Lys-244 in order to promote the acceptance of the C6-amino group of adenosine. The Asn-243-Asp substitution resulted in an 8-fold increase in K(m) for inosine from 58 to 484 microM and a 1000-fold decrease in k(cat)/K(m). The Asn-243-Asp construct catalysed the phosphorolysis of adenosine with a K(m) of 45 microM and a k(cat)/K(m) 8-fold that with inosine. The Lys-244-Gln construct showed only marginal reduction in k(cat)/K(m), 83% of wild type, but had no activity with adenosine. The Asn-243-Asp;Lys-244-Gln construct had a 14-fold increase in K(m) with inosine and 7-fold decrease in k(cat)/K(m) as compared to wild type. This double substitution catalysed the phosphorolysis of adenosine with a K(m) of 42 microM and a k(cat)/K(m) twice that of the single Asn-243-Asp substitution. Molecular dynamics simulation of the engineered proteins with adenine as substrate revealed favourable hydrogen bond distances between N7 of the purine ring and the Asp-243 carboxylate at 2.93 and 2.88 A, for Asn-243-Asp and the Asn-243-Asp;Lys-244-Gln constructs respectively. Simulation also supported a favourable hydrogen bond distance between the purine C6-amino group and Asp-243 at 2.83 and 2.88 A for each construct respectively. The Asn-243-Thr substitution did not yield activity with adenosine and simulation gave unfavourable hydrogen bond distances between Thr-243 and both the C6-amino group and N7 of the purine ring. The substitutions were not in the region of phosphate binding and the apparent S(0.5) for phosphate with wild type and the Asn-243-Asp enzymes were 1.35+/-0.01 and 1.84+/-0.06 mM, respectively. Both proteins exhibited positive co-operativity with phosphate giving Hill coefficients of 7.9 and 3.8 respectively.


An outbreak of hepatitis A associated with an infected foodhandler.
The recommended criteria for public notification of a hepatitis A virus (HAV)-infected foodhandler include assessment of the foodhandler's hygiene and symptoms. In October 1994, a Kentucky health department received a report of a catering company foodhandler with hepatitis A. Patrons were not offered immune globulin because the foodhandler's hygiene was assessed to be good and he denied having diarrhea. During early November, 29 cases of hepatitis A were reported among people who had attended an event catered by this company. Two local health departments and the Centers for Disease Control and Prevention, in collaboration with two state health departments, undertook an investigation to determine the extent of the outbreak, to identify the foods and event characteristics associated with illness, and to investigate the apparent failure of the criteria for determining when immune globulin (IG) should be offered to exposed members of the public. Cases were IgM anti-HAV-positive people with onset of symptoms during October or November who had eaten foods prepared by the catering company. To determine the outbreak's extent and factors associated with illness, the authors interviewed all case patients and the infected foodhandler and collected information on menus and other event characteristics. To investigate characteristics of events associated with transmission, the authors conducted a retrospective analysis comparing the risk of illness by selected event characteristics. To evaluate what foods were associated with illness, they conducted a retrospective cohort study of attendees of four events with high attack rates. A total of 91 cases were identified. At least one case was reported from 21 (51%) of the 41 catered events. The overall attack rate was 7% among the 1318 people who attended these events (range 0 to 75% per event). Attending an event at which there was no on-site sink (relative risk [RR] = 2.3, 95% confidence interval [CI] 1.4, 3.8) or no on-site kitchen (RR = 1.9, 95% Cl 1.1, 2.9) was associated with illness. For three events with high attack rates, eating at least one of several uncooked foods was associated with illness, with RRs ranging from 8 to undefined. A large hepatitis A outbreak resulted from an infected foodhandler with apparent good hygiene and no reported diarrhea who prepared many uncooked foods served at catered events. Assessing hygiene and symptoms s subjective, and may be difficult to accomplish. The effectiveness of the recommended criteria for determining when IG should be provided to exposed members of the public needs to be evaluated.


Prognostic factors for surgical outcome and survival in 447 women treated for advanced (FIGO-stages III-IV) epithelial ovarian carcinoma.
The objectives of this population-based, retrospective study, was to find predictive factors for surgical outcome and long-term survival in 447 patients with epithelial ovarian cancer in FIGO-stages III-IV treated during 1975-1993. The median overall survival rate of this series was 18 months, the 5-year cancer-specific survival rate was 18%, and the 5-year overall survival rate, 16%. In a logistic regression analysis, type of surgeon was the strongest (P=0.006) predictive factor for surgical outcome after the age of the patient. The optimal debulking rate was 36% for gynecologic oncologists, 29% for general gynecologists, 24% for combined gynecologist and obstetrician with the third level of specialization, and 4% for general surgeons. Optimal debulking (no visible tumor or residual tumor <2 cm) was achieved in 26% of the cases. Predictive factors of the outcome of cytoreduction were FIGO-stage (P=0.007), histological subtype (P=0.016), and tumor grade (P=0.046) in univariate analyses. In a Cox multivariate analysis the most important prognostic factor for overall survival was the amount of residual cancer (P=0.000001) before age, grade and stage. Therefore, to achieve optimal surgical outcome and optimal overall survival rate the primary surgery of advanced ovarian cancer should be performed by gynecologic oncologists or by gynecologists specially trained in gynecologic cancer surgery.


The fibre-folate debate in colo-rectal cancer.
Intervention and prospective studies showing no effect of fibre in protection against colo-rectal cancer have challenged consensus recommendations that population intakes of fibre should be increased to reduce the risk of colo-rectal cancer. The European Prospective Investigation of Cancer and Nutrition (EPIC) of 519 978 individuals aged 25-70 years is the largest prospective study of diet and cancer to date worldwide. It incorporates ten different European countries in order to increase heterogeneity in dietary habits and calibration procedures to reduce measurement error. Data for 1065 reported cases of colo-rectal cancer were reported in 2003. There was a 40% reduction in risk for the highest quintile v. lowest quintile of fibre in food after calibration. It has been suggested that these effects were a result of confounding by folate and other factors. Although there are a number of hypotheses to explain why folate should be protective in colo-rectal cancer, a meta-analysis has shown that folate in food may be protective but there is no effect of total folate (i.e. food plus supplements). In a further analysis of 1826 cases in EPIC, identified in the latest follow-up, the inclusion of an additional 761 cases has confirmed the previously published results, with a strong and significant reduction in colo-rectal cancer of approximately 9% reduction in risk for each uncalibrated quintile increase in fibre (P<0.001 for linear trend) compared with an 8% reduction in the previous report, which had not been adjusted for folate. Inclusion of the other covariates (physical activity, alcohol, smoking and red and processed meat) with folate has confirmed this significant inverse association for colon cancer and strengthened the association with left-sided colon cancer (P < 0.001).


Excessive synchronization of basal ganglia neurons at 20 Hz slows movement in Parkinson's disease.
Excessive synchronization of neuronal activity at around 20 Hz is a common finding in the basal ganglia of patients with untreated Parkinson's disease (PD). Correlative evidence suggests, but does not prove, that this spontaneous activity may contribute to slowness of movement in this condition. Here we investigate whether externally imposed synchronization through direct stimulation of the region of the subthalamic nucleus at 20 Hz can slow motor performance in a simple unimanual tapping task and whether this effect is frequency selective. Tapping rates were recorded on 42 sides in 22 patients with PD after overnight withdrawal of medication. Tapping was performed without stimulation and during bilateral stimulation at 20 Hz, 50 Hz and 130 Hz. We found that tapping rates were slowed by 8.2+/-3.2% (p=0.014) during 20-Hz stimulation in subjects with relatively preserved baseline function in the task. This effect was frequency selective. The current data provide proof of the principle that excessive beta synchrony within the basal ganglia-cortical loop may contribute to the slowing of movements in Parkinson's disease.


Scanning MscL Channels with Targeted Post-Translational Modifications for Functional Alterations.
Mechanosensitive channels are present in all living organisms and are thought to underlie the senses of touch and hearing as well as various important physiological functions like osmoregulation and vasoregulation. The mechanosensitive channel of large conductance (MscL) from Escherichia coli was the first protein shown to encode mechanosensitive channel activity and serves as a paradigm for how a channel senses and responds to mechanical stimuli. MscL plays a role in osmoprotection in E. coli, acting as an emergency release valve that is activated by membrane tension due to cell swelling after an osmotic down-shock. Using an osmotically fragile strain in an osmotic down-shock assay, channel functionality can be directly determined in vivo. In addition, using thiol reagents and expressed MscL proteins with a single cysteine substitution, we have shown that targeted post-translational modifications can be performed, and that any alterations that lead to dysfunctional proteins can be identified by this in vivo assay. Here, we present the results of such a scan performed on 113 MscL cysteine mutants using five different sulfhydryl-reacting probes to confer different charges or hydrophobicity to each site. We assessed which of these targeted modifications affected channel function and the top candidates were further studied using patch clamp to directly determine how channel activity was affected. This comprehensive screen has identified many residues that are critical for channel function as well as highlighted MscL domains and residues that undergo the most drastic environmental changes upon gating.


Mavacamten Treatment for Obstructive Hypertrophic Cardiomyopathy: A Clinical Trial.
Mavacamten, an orally administered, small-molecule modulator of cardiac myosin, targets underlying biomechanical abnormalities in obstructive hypertrophic cardiomyopathy (oHCM). To characterize the effect of mavacamten on left ventricular outflow tract (LVOT) gradient. Open-label, nonrandomized, phase 2 trial. (ClinicalTrials.gov: NCT02842242). 5 academic centers. 21 symptomatic patients with oHCM. Patients in cohort A received mavacamten, 10 to 20 mg/d, without background medications. Those in cohort B received mavacamten, 2 to 5 mg/d, with β-blockers allowed. The primary end point was change in postexercise LVOT gradient at 12 weeks. Secondary end points included changes in peak oxygen consumption (pVO2), resting and Valsalva LVOT gradients, left ventricular ejection fraction (LVEF), and numerical rating scale dyspnea score. In cohort A, mavacamten reduced mean postexercise LVOT gradient from 103 mm Hg (SD, 50) at baseline to 19 mm Hg (SD, 13) at 12 weeks (mean change, -89.5 mm Hg [95% CI, -138.3 to -40.7 mm Hg]; P = 0.008). Resting LVEF was also reduced (mean change, -15% [CI, -23% to -6%]). Peak VO2 increased by a mean of 3.5 mL/kg/min (CI, 1.2 to 5.9 mL/kg/min). In cohort B, the mean postexercise LVOT gradient decreased from 86 mm Hg (SD, 43) to 64 mm Hg (SD, 26) (mean change, -25.0 mm Hg [CI, -47.1 to -3.0 mm Hg]; P = 0.020), and mean change in resting LVEF was -6% (CI, -10% to -1%). Peak VO2 increased by a mean of 1.7 mL/kg/min (SD, 2.3) (CI, 0.03 to 3.3 mL/kg/min). Dyspnea scores improved in both cohorts. Mavacamten was well tolerated, with mostly mild (80%), moderate (19%), and unrelated (79%) adverse events. The most common adverse events definitely or possibly related to mavacamten were decreased LVEF at higher plasma concentrations and atrial fibrillation. Small size; open-label design. Mavacamten can reduce LVOT obstruction and improve exercise capacity and symptoms in patients with oHCM. MyoKardia.


Measured, opportunistic, unexpected and naïve quitting: a qualitative grounded theory study of the process of quitting from the ex-smokers' perspective.
To better understand the process of quitting from the ex-smokers' perspective, and to explore the role spontaneity and planning play in quitting. Qualitative grounded theory study using in-depth interviews with 37 Australian adult ex-smokers (24-68 years; 15 males, 22 females) who quit smoking in the past 6-24 months (26 quit unassisted; 11 used assistance). Based on participants' accounts of quitting, we propose a typology of quitting experiences: measured, opportunistic, unexpected and naïve. Two key features integral to participants' accounts of their quitting experiences were used as the basis of the typology: (1) the apparent onset of quitting (gradual through to sudden); and (2) the degree to which the smoker appeared to have prepared for quitting (no evidence through to clear evidence of preparation). The resulting 2 × 2 matrix of quitting experiences took into consideration three additional characteristics: (1) the presence or absence of a clearly identifiable trigger; (2) the amount of effort (cognitive and practical) involved in quitting; and (3) the type of cognitive process that characterised the quitting experience (reflective; impulsive; reflective and impulsive). Quitting typically included elements of spontaneity (impulsive behaviour) and preparation (reflective behaviour), and, importantly, the investment of time and cognitive effort by participants prior to quitting. Remarkably few participants quit completely out-of-the-blue with little or no preparation. Findings are discussed in relation to stages-of-change theory, catastrophe theory, and dual process theories, focusing on how dual process theories may provide a way of conceptualising how quitting can include elements of both spontaneity and preparation.


Absorption of 1.5% glycine after percutaneous ultrasonic lithotripsy for renal stone disease.
An elderly normotensive man underwent percutaneous ultrasonic lithotripsy for renal stone disease, the procedure lasting three hours and the fragments being washed out with 20 l 1.5% glycine. After two hours the inflation pressure had risen to 25 cm H2O and his blood pressure to 150 mm Hg. Inflation pressure continued to rise until drainage tubes were inserted into the retroperitoneal space, releasing a large volume of fluid, some of which appeared to be from the peritoneal cavity. Shortly after transfer to the recovery area the patient showed signs of the transurethral resection syndrome, with hyponatraemia, hyperkalaemia, and hypertension. He was treated appropriately and survived. Low infusion pressures should be used for irrigation during lithotripsy and 0.9% saline instead of 1.5% glycine. In patients given a general anaesthetic any rise in inflation pressure suggests extravasation of fluid and warrants emergency estimation of the plasma sodium concentration.


The Native American adolescent: social network structure and perceptions of alcohol induced social problems.
Race/ethnicity and the structure of an adolescent's social network are both important factors in the etiology of delinquent behavior. Yet, much of the minority-group delinquency literature overlooks the Native American youth population that traditionally exhibits high rates of alcohol use and abuse. Utilizing data from the National Longitudinal Study of Adolescent Health, we compare the structural characteristics of school-based friendship networks of American Indian youth and other racial/ethnic groups. Our core sample for the descriptive analysis consists of 70,841 youth (Caucasian = 42,096; Black = 13,554; Asian = 4,758; Hispanic = 4,464; American Indian = 3,426; Other = 2,543; Female = 50%). We find that Native American youth generally occupy similar social positions within school hierarchies compared to other minority groups. However, American Indian youth have fewer ties at the school level than Caucasian youth, including reports of fewer reciprocated friendships, a smaller number of in-school friends, and membership in less cohesive personal networks. We also focus on the detrimental social and physical consequences of alcohol use during adolescence and offer an extended consequences model (n = 5,841) that includes the interactive effects of race/ethnicity, age, and drinking influences on relationships with friends (Caucasian = 59%; Black = 19%; Asian = 7%; Hispanic = 7%; American Indian = 5%; Other = 3%; Female = 54%). American Indian youth are no more likely than other youth to report personal drinking as being detrimental to social relationships with parents, peers, and romantic partners. We address ties between our findings and criminal justice policies and practices, as well as the implications for similar network analyses involving other racial/ethnic groups.


Advantages of Single-Molecule Real-Time Sequencing in High-GC Content Genomes.
Next-generation sequencing has become the most widely used sequencing technology in genomics research, but it has inherent drawbacks when dealing with high-GC content genomes. Recently, single-molecule real-time sequencing technology (SMRT) was introduced as a third-generation sequencing strategy to compensate for this drawback. Here, we report that the unbiased and longer read length of SMRT sequencing markedly improved genome assembly with high GC content via gap filling and repeat resolution.


Synthetic lethality: general principles, utility and detection using genetic screens in human cells.
Synthetic lethality occurs when the simultaneous perturbation of two genes results in cellular or organismal death. Synthetic lethality also occurs between genes and small molecules, and can be used to elucidate the mechanism of action of drugs. This area has recently attracted attention because of the prospect of a new generation of anti-cancer drugs. Based on studies ranging from yeast to human cells, this review provides an overview of the general principles that underlie synthetic lethality and relates them to its utility for identifying gene function, drug action and cancer therapy. It also identifies the latest strategies for the large-scale mapping of synthetic lethalities in human cells which bring us closer to the generation of comprehensive human genetic interaction maps.


National Randomized Controlled Trial of Virtual House Calls for People with Parkinson's Disease: Interest and Barriers.
Delivering specialty care remotely directly into people's homes can enhance access for and improve the healthcare of individuals with chronic conditions. However, evidence supporting this approach is limited. Connect.Parkinson is a randomized comparative effectiveness study that compares usual care of individuals with Parkinson's disease in the community with usual care augmented by virtual house calls with a Parkinson's disease specialist from 1 of 18 centers nationally. Individuals in the intervention arm receive four virtual visits from a Parkinson's disease specialist over 1 year via secure, Web-based videoconferencing directly into their homes. All study activities, including recruitment, enrollment, and assessments, are conducted remotely. Here we report on interest, feasibility, and barriers to enrollment in this ongoing study. During recruitment, 11,734 individuals visited the study's Web site, and 927 unique individuals submitted electronic interest forms. Two hundred ten individuals from 18 states enrolled in the study from March 2014 to June 2015, and 195 were randomized. Most participants were white (96%) and college educated (73%). Of the randomized participants, 73% had seen a Parkinson's disease specialist within the previous year. Among individuals with Parkinson's disease, national interest in receiving remote specialty care directly into the home is high. Remote enrollment in this care model is feasible but is likely affected by differential access to the Internet.


Explorative learning and functional inferences on a five-step means-means-end problem in Goffin's cockatoos (Cacatuagoffini).
To investigate cognitive operations underlying sequential problem solving, we confronted ten Goffin's cockatoos with a baited box locked by five different inter-locking devices. Subjects were either naïve or had watched a conspecific demonstration, and either faced all devices at once or incrementally. One naïve subject solved the problem without demonstration and with all locks present within the first five sessions (each consisting of one trial of up to 20 minutes), while five others did so after social demonstrations or incremental experience. Performance was aided by species-specific traits including neophilia, a haptic modality and persistence. Most birds showed a ratchet-like progress, rarely failing to solve a stage once they had done it once. In most transfer tests subjects reacted flexibly and sensitively to alterations of the locks' sequencing and functionality, as expected from the presence of predictive inferences about mechanical interactions between the locks.


Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata.
Alopecia areata (AA) is an autoimmune disease characterized by hair loss mediated by CD8+ T cells. There are no reliably effective therapies for AA. Based on recent developments in the understanding of the pathomechanism of AA, JAK inhibitors appear to be a therapeutic option; however, their efficacy for the treatment of AA has not been systematically examined. This was a 2-center, open-label, single-arm trial using the pan-JAK inhibitor, tofacitinib citrate, for AA with >50% scalp hair loss, alopecia totalis (AT), and alopecia universalis (AU). Tofacitinib (5 mg) was given twice daily for 3 months. Endpoints included regrowth of scalp hair, as assessed by the severity of alopecia tool (SALT), duration of hair growth after completion of therapy, and disease transcriptome. Of 66 subjects treated, 32% experienced 50% or greater improvement in SALT score. AA and ophiasis subtypes were more responsive than AT and AU subtypes. Shorter duration of disease and histological peribulbar inflammation on pretreatment scalp biopsies were associated with improvement in SALT score. Drug cessation resulted in disease relapse in 8.5 weeks. Adverse events were limited to grade I and II infections. An AA responsiveness to JAK/STAT inhibitors score was developed to segregate responders and nonresponders, and the previously developed AA disease activity index score tracked response to treatment. At the dose and duration studied, tofacitinib is a safe and effective treatment for severe AA, though it does not result in a durable response. Transcriptome changes reveal unexpected molecular complexity within the disease. ClinicalTrials.gov NCT02197455 and NCT02312882. This work was supported by the US Department of Veterans Affairs Office of Research and Development, National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health grant R01 AR47223 and U01 AR67173, the National Psoriasis Foundation, the Swedish Society of Medicine, the Fernström Foundation, the Locks of Love Foundation, the National Alopecia Areata Foundation, and the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research.


Minimal hepatic encephalopathy: consensus statement of a working party of the Indian National Association for Study of the Liver.
Hepatic encephalopathy (HE) is a major complication that develops in some form and at some stage in a majority of patients with liver cirrhosis. Overt HE occurs in approximately 30-45% of cirrhotic patients. Minimal HE (MHE), the mildest form of HE, is characterized by subtle motor and cognitive deficits and impairs health-related quality of life. The Indian National Association for Study of the Liver (INASL) set up a Working Party on MHE in 2008 with a mandate to develop consensus guidelines on various aspects of MHE relevant to clinical practice. Questions related to the definition of MHE, its prevalence, diagnosis, clinical characteristics, pathogenesis, natural history and treatment were addressed by the members of the Working Party.


Existing data sources for clinical epidemiology: the Danish National Pathology Registry and Data Bank.
Diagnostic histological and cytological specimens are routinely stored in pathology department archives. These biobanks are a valuable research resource for many diseases, particularly if they can be linked to high quality population-based health registries, allowing large retrospective epidemiological studies to be carried out. Such studies are of significant importance, for example in the search for novel prognostic and predictive biomarkers in the era of personalized medicine. Denmark has a wealth of highly-regarded population-based registries that are ideally suited to conduct this type of epidemiological research. We describe two recent additions to these databases: the Danish National Pathology Registry (DNPR) and its underlying national online registration database, the Danish Pathology Data Bank (DPDB). The DNPR and the DPDB contain detailed nationwide records of all pathology specimens analyzed in Denmark since 1997, and an incomplete but nonetheless valuable record of specimens from some pathology departments dating back to the 1970s. The data are of high quality and completeness and are sufficient to allow precise and efficient localization of the specimens. We describe the relatively uncomplicated procedures required to use these pathology databases in clinical research and to gain access to the archived specimens.


Dynamics of White Matter Plasticity Underlying Working Memory Training: Multimodal Evidence from Diffusion MRI and Relaxometry.
Adaptive working memory (WM) training may lead to cognitive benefits that are associated with white matter plasticity in parietofrontal networks, but the underlying mechanisms remain poorly understood. We investigated white matter microstructural changes after adaptive WM training relative to a nonadaptive comparison group. Microstructural changes were studied in the superior longitudinal fasciculus, the main parietofrontal connection, and the cingulum bundle as a comparison pathway. MRI-based metrics were the myelin water fraction and longitudinal relaxation rate R1 from multicomponent relaxometry (captured with the mcDESPOT approach) as proxy metrics of myelin, the restricted volume fraction from the composite hindered and restricted model of diffusion as an estimate of axon morphology, and fractional anisotropy and radial diffusivity from diffusion tensor imaging. PCA was used for dimensionality reduction. Adaptive training was associated with benefits in a "WM capacity" component and increases in a microstructural component (increases in R1, restricted volume fraction, fractional anisotropy, and reduced radial diffusivity) that predominantly loaded on changes in the right dorsolateral superior longitudinal fasciculus and the left parahippocampal cingulum. In contrast, nonadaptive comparison activities were associated with the opposite pattern of reductions in WM capacity and microstructure. No group differences were observed for the myelin water fraction metric suggesting that R1 was a more sensitive "myelin" index. These results demonstrate task complexity and location-specific white matter microstructural changes that are consistent with tissue alterations underlying myelination in response to training.


Human CTL-based functional analysis shows the reliability of a munc13-4 protein expression assay for FHL3 diagnosis.
Familial hemophagocytic lymphohistiocytosis (FHL) is the major form of hereditary hemophagocytic lymphohistiocytosis (HLH); as such, it requires prompt and accurate diagnosis. We previously reported that FHL type 3 (FHL3) can be rapidly screened by detecting munc13-4 expression in platelets using flow cytometry; however, the reliability of the munc13-4 expression assay for FHL3 diagnosis is unclear. Regardless of the type of UNC13D mutation, all reported FHL3 cases examined for the munc13-4 protein showed significantly reduced expression. However, the translated munc13-4 protein of some reportedly disease-causing UNC13D missense variants has not been assessed in terms of expression or function; therefore, their clinical significance remains unclear. The aim of this study was to determine the reliability of a munc13-4 expression assay for screening FHL3. Between 2011 and 2016, 108 HLH patients were screened by this method in our laboratory, and all 15 FHL3 patients were diagnosed accurately. To further elucidate whether munc13-4 expression analysis can reliably identify FHL3 patients harboring missense mutations in UNC13D, we developed an alloantigen-specific cytotoxic T lymphocyte (CTL) line and a CTL line immortalized by Herpesvirus saimiri derived from FHL3 patients. We then performed a comprehensive functional analysis of UNC13D variants. Transient expression of UNC13D complementary DNA constructs in these cell lines enabled us to determine the pathogenicity of the reported UNC13D missense variants according to expression levels of their translated munc13-4 proteins. Taken together with previous findings, the results presented herein show that the munc13-4 protein expression assay is a reliable tool for FHL3 screening.


Intrinsic differences between the catalytic properties of the oncogenic NUP214-ABL1 and BCR-ABL1 fusion protein kinases.
The NUP214-ABL1 fusion kinase has recently been identified in 6% of patients with T-cell acute lymphoblastic leukemia. In contrast to the more common oncogenic ABL1 fusion BCR-ABL1, NUP214-ABL1 localizes to the nuclear pore complexes and has attenuated transforming properties in hematopoietic cells and in mouse bone marrow transplant models. We have performed a thorough biochemical comparative analysis of NUP214-ABL1 and BCR-ABL1 and show that, despite their common tyrosine kinase domain, the two fusion proteins differ in many critical catalytic properties. NUP214-ABL1 has lower in vitro tyrosine kinase activity, which is in agreement with the absence of phosphorylation on its activation loop. NUP214-ABL1 was more sensitive to imatinib (Glivec) than BCR-ABL1 in vitro and in cells, indicating a different activation state and conformation of the two ABL1 fusion kinases. Using a peptide array, we identified differences in the spectrum and efficiency of substrate peptide phosphorylation and a differential involvement of Src kinases in downstream signaling. These results clearly indicate that different fusion partners of the same kinase can determine not only localization, but also critical functional properties of the enzyme such as inhibitor sensitivity and substrate preference, with subsequent differences in downstream signaling effectors and likely consequences in disease pathogenesis.


Development of Ly-1+ B cells in immunodeficient CBA/N mice.
Spleen cells from CBA/N mice developing a systemic autoimmune disease after daily injection of CsA during an autologous bone marrow reconstitution were transferred into unmanipulated syngeneic recipients. Adoptive transfer allowed the development of Ly-1+ B cells, which shared Mac-1 differentiation antigen expression with the myelomonocytic lineage. Interestingly, expansion of formerly absent Ly-1+ B cells was paralleled by a severe reduction in common, Ly-1-, B cell development in the recipient. We conclude that precursors for Ly-1+ B lineage do exist in CBA/N mice.


Fetuin, an inhibitor of lymphocyte transformation. The interaction of fetuin with phytomitogens and a possible role for fetuin in fetal development.
Fetuin, the bovine alpha-fetoprotein, contains glycopeptide sequences similar to those found on red cells. As a result, it is capable of strong physical interaction with the phytohemagglutinin isomitogens (H-PHAP) which possess two or more R (red cell binding) subunits as part of their tetrameric structures. Fetuin shows little or no interaction with L-PHAP, a phytohemagglutinin made up of four L subunits which also lack red cell affinity. Despite these differences fetuin is able to inhibit both H- and L-PHAP-induced lymphocyte transformation and is also capable of inhibiting the mitogenic effects of pokeweed mitogen, concanavalin A, antithymocyte antiserum, and the one-way mixed lymphocyte culture. In the case of L-PHAP, the inhibitory effect of fetuin is proportional to the intensity of the mitogenic stimulus. The inhibitory effects of fetuin upon lymphocyte transformation may result from perturbation or "blindfolding" of the cell membrane in a manner analogous to other immunosuppressive serum alpha-globulins. Alpha-Fetoproteins may play an immunoregulatory role during fetal development.


EPR Imaging Spin Probe Trityl Radical OX063: A Method for Its Isolation from Animal Effluent, Redox Chemistry of Its Quinone Methide Oxidation Product, and in Vivo Application in a Mouse.
We report herein a method for the recovery, purification, and application of OX063, a costly, commercially available nontoxic spin probe widely used for electron paramagnetic resonance (EPR) imaging, as well as its corresponding quinone methide (QM) form. This precious probe can be successfully recovered after use in animal model experiments (25-47% recovery from crude lyophilizate with 98.5% purity), even from samples that are >2 years old. Significantly, the recovered trityl can be reused in further animal model EPR imaging experiments. The work also describes support for the observed formation of an air-sensitive radical derived from the QM under reducing conditions.


Inhibiting the Priming for Cancer in Li-Fraumeni Syndrome.
The concept of the pre-cancerous niche applies the 'seed and soil' theory of metastasis to the initial process of carcinogenesis. TP53 is at the nexus of this process and, in the context of Li-Fraumeni Syndrome (LFS), is a key determinant of the conditions in which cancers are formed and progress. Important factors in the creation of the pre-cancerous niche include disrupted tissue homeostasis, cellular metabolism and chronic inflammation. While druggability of TP53 remains a challenge, there is evidence that drug re-purposing may be able to address aspects of pre-cancerous niche formation and thereby reduce the risk of cancer in individuals with LFS.


Role of the murine reprogramming factors in the induction of pluripotency.
Induced pluripotent stem (iPS) cells can be obtained from fibroblasts upon expression of Oct4, Sox2, Klf4, and c-Myc. To understand how these factors induce pluripotency, we carried out genome-wide analyses of their promoter binding and expression in iPS and partially reprogrammed cells. We find that target genes of the four factors strongly overlap in iPS and embryonic stem (ES) cells. In partially reprogrammed cells, many genes co-occupied by c-Myc and any of the other three factors already show an ES cell-like binding and expression pattern. In contrast, genes that are specifically co-bound by Oct4, Sox2, and Klf4 in ES cells and encode pluripotency regulators severely lack binding and transcriptional activation. Among the four factors, c-Myc promotes the most ES cell-like transcription pattern when expressed individually in fibroblasts. These data uncover temporal and separable contributions of the four factors during the reprogramming process and indicate that ectopic c-Myc predominantly acts before pluripotency regulators are activated.


GAD-alum treatment induces GAD65-specific CD4+CD25highFOXP3+ cells in type 1 diabetic patients.
Type 1 diabetes results from autoimmune destruction of insulin producing pancreatic β-cells. We have shown that treatment with alum-formulated glutamic acid decarboxylase 65 (GAD-alum) preserved residual insulin secretion and induced antigen-specific responses in children with recent onset type 1 diabetes. The aim of this study was to further investigate the immunomodulatory effect of GAD-alum, focusing on CD4(+)CD25(high) cells and their association to cytokine secretion. Samples obtained 21 and 30months after the initial injection of GAD-alum or placebo were included in the present study. GAD(65)-stimulation enhanced the percentage of CD4(+)CD25(high)FOXP3(+) cells, but reduced the percentage of CD4(+)CD25(+) cells, in samples from the GAD-alum treated group. Further, the GAD(65)-induced secretion of IL-5, -10, and -13 correlated with the expression of CD4(+)CD25(high)FOXP3(+) cells, but inversely with CD4(+)CD25(+) cells. These new data suggest that GAD-alum treatment induced GAD(65)-specific T cells with regulatory features.


Should outbreak response immunization be recommended for measles outbreaks in middle- and low-income countries? An update.
Measles caused mortality in >164,000 children in 2008, with most deaths occurring during outbreaks. Nonetheless, the impact and desirability of conducting measles outbreak response immunization (ORI) in middle- and low-income countries has been controversial. World Health Organization guidelines published in 1999 recommended against ORI in such settings, although recently these guidelines have been reversed for countries with measles mortality reduction goals. We searched literature published during 1995-2009 for papers reporting on measles outbreaks. Papers identified were reviewed by 2 reviewers to select those that mentioned ORI. World Bank classification of country income was used to identify reports of outbreaks in middle- and low-income countries. We identified a total of 485 articles, of which 461 (95%) were available. Thirty-eight of these papers reported on a total of 38 outbreaks in which ORI was used. ORI had a clear impact in 16 (42%) of these outbreaks. In the remaining outbreaks, we were unable to independently assess the impact of ORI. These findings generally support ORI in middle- and low-income countries. However, the decision to conduct ORI and the nature and extent of the vaccination response need to be made on a case-by-case basis.


Effects of rising amyloidβ levels on hippocampal synaptic transmission, microglial response and cognition in APPSwe/PSEN1M146V transgenic mice.
Progression of Alzheimer's disease is thought initially to depend on rising amyloidβ and its synaptic interactions. Transgenic mice (TASTPM; APPSwe/PSEN1M146V) show altered synaptic transmission, compatible with increased physiological function of amyloidβ, before plaques are detected. Recently, the importance of microglia has become apparent in the human disease. Similarly, TASTPM show a close association of plaque load with upregulated microglial genes. CA1 synaptic transmission and plasticity were investigated using in vitro electrophysiology. Microglial relationship to plaques was examined with immunohistochemistry. Behaviour was assessed with a forced-alternation T-maze, open field, light/dark box and elevated plus maze. The most striking finding is the increase in microglial numbers in TASTPM, which, like synaptic changes, begins before plaques are detected. Further increases and a reactive phenotype occur later, concurrent with development of larger plaques. Long-term potentiation is initially enhanced at pre-plaque stages but decrements with the initial appearance of plaques. Finally, despite altered plasticity, TASTPM have little cognitive deficit, even with a heavy plaque load, although they show altered non-cognitive behaviours. The pre-plaque synaptic changes and microglial proliferation are presumably related to low, non-toxic amyloidβ levels in the general neuropil and not directly associated with plaques. However, as plaques grow, microglia proliferate further, clustering around plaques and becoming phagocytic. Like in humans, even when plaque load is heavy, without development of neurofibrillary tangles and neurodegeneration, these alterations do not result in cognitive deficits. Behaviours are seen that could be consistent with pre-diagnosis changes in the human condition. GlaxoSmithKline; BBSRC; UCL; ARUK; MRC.


Systematic evaluation of machine learning methods for identifying human-pathogen protein-protein interactions.
In recent years, high-throughput experimental techniques have significantly enhanced the accuracy and coverage of protein-protein interaction identification, including human-pathogen protein-protein interactions (HP-PPIs). Despite this progress, experimental methods are, in general, expensive in terms of both time and labour costs, especially considering that there are enormous amounts of potential protein-interacting partners. Developing computational methods to predict interactions between human and bacteria pathogen has thus become critical and meaningful, in both facilitating the detection of interactions and mining incomplete interaction maps. In this paper, we present a systematic evaluation of machine learning-based computational methods for human-bacterium protein-protein interactions (HB-PPIs). We first reviewed a vast number of publicly available databases of HP-PPIs and then critically evaluate the availability of these databases. Benefitting from its well-structured nature, we subsequently preprocess the data and identified six bacterium pathogens that could be used to study bacterium subjects in which a human was the host. Additionally, we thoroughly reviewed the literature on 'host-pathogen interactions' whereby existing models were summarized that we used to jointly study the impact of different feature representation algorithms and evaluate the performance of existing machine learning computational models. Owing to the abundance of sequence information and the limited scale of other protein-related information, we adopted the primary protocol from the literature and dedicated our analysis to a comprehensive assessment of sequence information and machine learning models. A systematic evaluation of machine learning models and a wide range of feature representation algorithms based on sequence information are presented as a comparison survey towards the prediction performance evaluation of HB-PPIs.


The characteristics of people with mental illness who are under treatment in traditional healer centres in Sudan.
To determine the general characteristics of people with mental disorders in traditional healers centres in Sudan in terms of sociodemographic profile, common clinical presentations and diagnostic features, and to look at the treatment methods and intervention procedures used in these centres for treating people with mental illness. This is a descriptive cross-sectional study using both quantitative and qualitative research methods. All inpatients with mental illness (405) from 10 selected traditional healers centres in Sudan who gave consent were interviewed, using a specially designed questionnaire and the Mini International Neuropsychiatric Interview (MINI). Most of the visitors to the centres were from central Sudan with a mean age of 31 years, illiterate or with only a primary basic education, male and jobless. The average mean duration of stay in the traditional healer centre was five months and the mean duration of untreated illness before coming to the centre was 13 months. Only 17% reported a history of alcohol abuse and only 11% of drug abuse. The most common prevalent diagnosis was psychotic disorder. This study improves the understanding about what types of people with mental illness are treated at these traditional healer centres and gives recommendations that can help in improving the quality of services in these centres. It can probably be used in building bridges of collaboration between these centres and the available mental health and psychiatric services in Sudan, especially at primary healthcare level.


Investigation of phase composition and nanoscale microstructure of high-energy ball-milled MgCu sample.
The ball milling technique has been successfully applied to the synthesis of various materials such as equilibrium intermetallic phases, amorphous compounds, nanocrystalline materials, or metastable crystalline phases. However, how the phase composition and nanoscale microstructure evolute during ball milling in various materials is still controversial due to the complex mechanism of ball milling, especially in the field of solid-state amorphization caused by ball milling. In the present work, the phase evolution during the high-energy ball milling process of the Mg and Cu (atomic ratio is 1:1) mixed powder was investigated. It was found that Mg firstly reacts with Cu, forming the Mg2Cu alloy in the primary stage of ball milling. As the milling time increases, the diffracted peaks of Mg2Cu and Cu gradually disappear, and only a broad halo peak can be observed in the X-ray diffraction pattern of the final 18-h milled sample. As for this halo peak, lots of previous studies suggested that it originated from the amorphous phase formed during the ball milling. Here, a different opinion that this halo peak results from the very small size of crystals is proposed: As the ball milling time increases, the sizes of Mg2Cu and Cu crystals become smaller and smaller, so the diffracted peaks of Mg2Cu and Cu become broader and broader and result in their overlap between 39° and 45°, at last forming the amorphous-like halo peak. In order to determine the origin of this halo peak, microstructure observation and annealing experiment on the milled sample were carried out. In the transmission electron microscopy dark-field image of the milled sample, lots of very small nanocrystals (below 20 nm) identified as Mg2Cu and Cu were found. Moreover, in the differential scanning calorimetry curve of the milled sample during the annealing process, no obvious exothermic peak corresponding to the crystallization of amorphous phase is observed. All the above results confirm that the broad halo diffracted peak in the milled MgCu sample is attributed to the overlap of the broadened peaks of the very small Mg2Cu and Cu nanocrystalline phase, not the MgCu amorphous phase. The whole milling process of MgCu can be described as follows: Mg+Cu→Mg2Cu+Cu→Mg2Cunanocrystal+Cunanocrystal.


Separating the scattering and absorption coefficients using the real and imaginary parts of the refractive index with low-coherence interferometry.
We present an analytical method that yields the real and imaginary parts of the refractive index (RI) from low-coherence interferometry measurements, leading to the separation of the scattering and absorption coefficients of turbid samples. The imaginary RI is measured using time-frequency analysis, with the real part obtained by analyzing the nonlinear phase induced by a sample. A derivation relating the real part of the RI to the nonlinear phase term of the signal is presented, along with measurements from scattering and nonscattering samples that exhibit absorption due to hemoglobin.


Population-wide administration of single dose rifampicin for leprosy prevention in isolated communities: a three year follow-up feasibility study in Indonesia.
Indonesia ranking third in the world, regarding leprosy burden. Chemoprophylaxis is effective in reducing risk of developing leprosy among contacts. 'Blanket approach' is an operational strategy for leprosy post-exposure prophylaxis in which all members of an isolated community, high endemic for leprosy are screened and given a single dose of rifampicin (SDR) in the absence of signs and symptoms of leprosy. The objective is to assess the operational feasibility of a population-wide 'blanket' administration of SDR for leprosy prevention in isolated communities in a remote island. A prospective follow-up study was conducted in the year 2014, 2015 and 2016 in Lingat village of Selaru Island, Indonesia. During the first two visits, screening and SDR were provided, whereas only screening was conducted during the third visit. The demographic and clinical data were used for a descriptive analysis of the project coverage and leprosy epidemiology. During the first two visits, 1671 persons (88%) were screened, 1499 (79%) received SDR, and 213 (11%) were excluded based on the exclusion criteria. During the first two visits, 43 (2.6%) cases were diagnosed with leprosy with a rate of 2263 per 100,000 population. The prevalence was highest in the age groups 15-24 and 25-49 years. Total, 14 (33%) cases had MB and 29 (67%) PB leprosy. Two cases (5%) had grade 2 disability. During the third visit, 10 new leprosy cases, with no grade 2 disability, were detected out of 1481 screened persons at the rate of 484 cases per 100,000 population (n = 2065 population in 2016). Among those screened during the third visit, there was a 50% reduction of leprosy among those who had previously received SDR compared to those who had not. With adequate planning and some additional investment, it is feasible to implement a blanket approach of chemoprophylaxis in a remote island of Indonesia, although effort needs to be made to cover as many people as possible in the first visit. Contingency plans need to be made to actively follow this village closely in the coming years and continue leprosy elimination efforts until no new cases are found any more.


Predicting demographically sustainable rates of adaptation: can great tit breeding time keep pace with climate change?
Populations need to adapt to sustained climate change, which requires micro-evolutionary change in the long term. A key question is how the rate of this micro-evolutionary change compares with the rate of environmental change, given that theoretically there is a 'critical rate of environmental change' beyond which increased maladaptation leads to population extinction. Here, we parametrize two closely related models to predict this critical rate using data from a long-term study of great tits (Parus major). We used stochastic dynamic programming to predict changes in optimal breeding time under three different climate scenarios. Using these results we parametrized two theoretical models to predict critical rates. Results from both models agreed qualitatively in that even 'mild' rates of climate change would be close to these critical rates with respect to great tit breeding time, while for scenarios close to the upper limit of IPCC climate projections the calculated critical rates would be clearly exceeded with possible consequences for population persistence. We therefore tentatively conclude that micro-evolution, together with plasticity, would rescue only the population from mild rates of climate change, although the models make many simplifying assumptions that remain to be tested.


HIV and symptoms of depression are independently associated with impaired glucocorticoid signaling.
Chronic inflammation caused by HIV infection may lead to deficient glucocorticoid (GC) signaling predisposing people living with HIV to depression and other psychiatric disorders linked to GC resistance. We hypothesized that comorbid HIV and depressive symptoms in women would synergistically associate with deficits in GC signaling. This cross-sectional study used samples obtained from the Women's Interagency HIV Study (WIHS). The Centers for Epidemiological Studies (CES-D) was used to define depression in four groups of women from the Women's Interagency HIV Study (WIHS): 1) HIV-negative, non-depressed (n = 37); 2) HIV-negative, depressed (n = 34); 3) HIV-positive, non-depressed (n = 38); and 4) HIV-positive, depressed (n = 38). To assess changes in GC signaling from peripheral blood mononuclear cells (PBMCs), we examined baseline and dexamethasone (Dex)-stimulated changes in the expression of the GC receptor (GR, gene: Nr3c1) and its negative regulator Fkbp5 via quantitative RT-PCR. GR sensitivity was evaluated in vitro by assessing the Dex inhibition of lipopolysaccharide (LPS)-stimulated IL-6 and TNF-α levels. Depressive symptoms and HIV serostatus were independently associated with elevated baseline expression of Fkbp5 and Nr3c1. Depressive symptoms, but not HIV status, was independently associated with reduced LPS-induced release of IL-6. Counter to predictions, there was no interactive association of depressive symptoms and HIV on any outcome. Comorbid depressive symptoms with HIV infection were associated with a gene expression and cytokine profile similar to that of healthy control women, a finding that may indicate further disruptions in disease adaptation.


Parkin interacts with LIM Kinase 1 and reduces its cofilin-phosphorylation activity via ubiquitination.
Mutations in the PARKIN (PARK2) gene have been found in the majority of early-onset familial Parkinson's disease (PD) patients with autosomal recessive juvenile parkinsonism (ARJP). Parkin protein functions as an ubiquitin (E3) ligase that targets specific proteins for degradation in the 26S proteasome. Here, based on a mass spectrometry analysis of the human dopaminergic neuroblastoma-derived cell line SH-SY5Y that over-expresses parkin, we found that parkin may suppress cofilin phosphorylation. LIM Kinase 1 (LIMK1) is the upstream protein that phosphorylates cofilin, an actin depolymerizing protein. Thus, we postulated a possible connection between parkin and LIMK1. Our studies in other cell lines, using co-transfection assays, demonstrated that LIMK1 and parkin bind each other. LIMK1 also interacted with previously known parkin interactors Hsp70 and CHIP. Parkin enhanced LIMK1-ubiquitination in the human neuroblastoma-derived BE(2)-M17 cell line, but not in the human embryonic kidney-derived HEK293 cell line. In fact, parkin-over-expression reduced the level of LIMK1-induced phosphocofilin in the BE(2)-M17 cells but not in the HEK293 cells. Additionally, in simian kidney-derived COS-7 cells, parkin-over-expression reduced LIMK1-induced actin filament accumulation. LIMK1 in cultured cells regulates parkin reversibly: LIMK1 did not phosphorylate parkin but LIMK1 overexpression reduced parkin self-ubiquitination in vitro and in HEK293 cells. Furthermore, in the cells co-transfected with parkin and p38, LIMK1 significantly decreased p38-ubiquitination by parkin. These findings demonstrate a cell-type dependent functional interaction between parkin and LIMK1 and provide new evidence that links parkin and LIMK1 in the pathogenesis of familial PD.


Comparison of Simulated Workplace Protection Factors Offered by N95 and P100 Filtering Facepiece and Elastomeric Half-Mask Respirators against Particles of 10 to 400 nm.
This study compared the simulated workplace protection factors (SWPFs) between NIOSH-approved N95 respirators and P100 respirators, including two models of filtering facepiece respirator (FFR) and two models of elastomeric half-mask respirator (EHR), against sodium chloride particles (NaCl) in a range of 10 to 400 nm. Twenty-five human test subjects performed modified OSHA fit test exercises in a controlled laboratory environment with the N95 respirators (two FFR models and two EHR models) and the P100 respirators (two FFRs and two EHRs). Two Scanning Mobility Particle Sizers (SMPS) were used to measure aerosol concentrations (in the 10-400 nm size range) inside (Cin) and outside (Cout) of the respirator, simultaneously. SWPF was calculated as the ratio of Cout to Cin. The SWPF values obtained from the N95 respirators were then compared to those of the P100 respirators. SWPFs were found to be significantly different (P<0.05) between N95 and P100 class respirators. The 10th, 25th, 50th, 75th and 90th percentiles of the SWPFs for the N95 respirators were much lower than those for the P100 models. The N95 respirators had 5th percentiles of the SWPFs > 10. In contrast, the P100 class was able to generate 5th percentiles SWPFs > 100. No significant difference was found in the SWPFs when tested against nano-size (10 to 100 nm) and large-size (100 to 400 nm) particles. Overall, the findings suggest that the two FFRs and two EHRs with P100 class filters provide better performance than those with N95 filters against particles from 10 to 400 nm, supporting current OSHA and NIOSH recommendations.


Codelivery of a cytotoxin and photosensitiser via a liposomal nanocarrier: a novel strategy for light-triggered cytosolic release.
Endosomal entrapment is a key issue for the intracellular delivery of many nano-sized biotherapeutics to their cytosolic or nuclear targets. Photochemical internalisation (PCI) is a novel light-based solution that can be used to trigger the endosomal escape of a range of bioactive agents into the cytosol leading to improved efficacy in pre-clinical and clinical studies. PCI typically depends upon the endolysosomal colocalisation of the bioactive agent with a suitable photosensitiser that is administered separately. In this study we demonstrate that both these components may be combined for codelivery via a novel multifunctional liposomal nanocarrier, with a corresponding increase in the biological efficacy of the encapsulated agent. As proof of concept, we show here that the cytotoxicity of the 30 kDa protein toxin, saporin, in MC28 fibrosarcoma cells is significantly enhanced when delivered via a cell penetrating peptide (CPP)-modified liposome, with the CPP additionally functionalised with a photosensitiser that is targeted to endolysosomal membranes. This innovation opens the way for the efficient delivery of a range of biotherapeutics by the PCI approach, incorporating a clinically proven liposome delivery platform and using bioorthogonal ligation chemistries to append photosensitisers and peptides of choice.


Measuring Person-centered Care: A Critical Comparative Review of Published Tools.
to present a critical comparative review of published tools measuring the person-centeredness of care for older people and people with dementia. included tools were identified by searches of PubMed, Cinahl, the Bradford Dementia Group database, and authors' files. The terms "Person-centered," "Patient-centered" and "individualized" (US and UK spelling), were paired with "Alzheimer's disease," "older people," and "dementia" in various combinations. The tools were compared in terms of conceptual influences, perspectives studied and intended use, applicability, psychometric properties, and credibility. twelve tools eligible for review were identified. Eight tools were developed for evaluating long-term aged care, three for hospital-based care, and one for home care. One tool, Dementia Care Mapping, was dementia specific. A common limitation of the tools reviewed is that they are yet to be used and validated beyond the development period; thus, their validity, reliability, and applicability needs further exploration. Also, the perspective of people with dementia remains absent. the review demonstrates the availability of a multitude of tools for measurement of person-centered care in different settings and from different perspectives, even if further testing of the tools is needed. The conceptual underpinnings of the tools are rarely explicit, which makes it difficult to ascertain the conceptual comparability of the tools.


Recursive Mahalanobis separability measure for gene subset selection.
Mahalanobis class separability measure provides an effective evaluation of the discriminative power of a feature subset, and is widely used in feature selection. However, this measure is computationally intensive or even prohibitive when it is applied to gene expression data. In this study, a recursive approach to Mahalanobis measure evaluation is proposed, with the goal of reducing computational overhead. Instead of evaluating Mahalanobis measure directly in high-dimensional space, the recursive approach evaluates the measure through successive evaluations in 2D space. Because of its recursive nature, this approach is extremely efficient when it is combined with a forward search procedure. In addition, it is noted that gene subsets selected by Mahalanobis measure tend to overfit training data and generalize unsatisfactorily on unseen test data, due to small sample size in gene expression problems. To alleviate the overfitting problem, a regularized recursive Mahalanobis measure is proposed in this study, and guidelines on determination of regularization parameters are provided. Experimental studies on five gene expression problems show that the regularized recursive Mahalanobis measure substantially outperforms the nonregularized Mahalanobis measures and the benchmark recursive feature elimination (RFE) algorithm in all five problems.


Perioperative cardiac complications and 30-day mortality in patients undergoing intracranial aneurysmal surgery with adenosine-induced flow arrest: a retrospective comparative study.
Adenosine-induced flow arrest is a technique used to assist in the surgical clipping of complex aneurysms. To assess the safety associated with adenosine-assisted intracranial aneurysm surgery. Medical records of all patients presenting between January 1, 2009, and December 31, 2012, for intracranial aneurysm surgery were analyzed. Patients were divided into 2 groups based on the intraoperative administration of adenosine: the nonadenosine group (n = 262) and the adenosine group (n = 64). The primary outcome compared between groups included a composite of 30-day mortality and incidences of perioperative cardiac complications (perioperative myocardial infarction or perioperative cardiac arrhythmias). The study groups were statistically similar except for a difference in the size and location of cerebral aneurysms and the incidence of coronary artery disease. The primary composite outcome occurred in 4.6% and 9.4% of patients in the nonadenosine and adenosine groups, respectively (P = .13). After adjustment for differences in the incidence of coronary artery disease between the 2 groups, the odds of the primary outcome were not significantly different between the groups (adjusted odds ratio = 2.12; 95% confidence interval, 0.76-5.93; P = .15). There were also no significant differences in the durations of hospital and intensive care unit stay between the study groups. Our results suggest that adenosine-assisted intracranial aneurysm surgery is not associated with an increase in perioperative cardiac complications or mortality in patients with low risk of coronary artery disease and may be considered a safe technique to assist clipping of complex aneurysms.


Systemic energy management by strategically located functional components within molecular frameworks, determined by systems chemistry.
A novel concept and, therefore, a novel discipline is defined, wherein molecules are described as frameworks of strategically located functional components within molecular structures, acting in unison to effect efficient energy management. The term "systems chemistry" effectively serves to define the phenomenon of an assembly of atoms and functional groups within a molecule having systemic properties "valued" at more than their component sum. The reduction of NAD+ and FAD is complimented by an enthalpy transfer between organic functional components (aromatic ring, amide and olefinic functionalities), yet the sum of the overall energy values (the total system) remains nearly constant, irrespective of which direction the redox reaction proceeds. From this aspect, both NAD+ and FAD operate as real chemical systems of atoms and functional groups, working together within the individual molecules to store the reaction enthalpy as resonance enthalpy, rather than manifesting it as emitted or absorbed heat. In this way, the thermoneutral reaction of the wet combustion occurring in all living cells is made possible by an internal "cooling process".


Multidisciplinary Treatment for Hypermobile Adolescents with Chronic Musculoskeletal Pain.
To determine whether adolescents with generalized hypermobility spectrum disorder/ hypermobile Ehlers-Danlos syndrome (G-HSD/ hEDS) show changes in the level of disability, physical functioning, perceived harmfulness and pain intensity after completing multidisciplinary rehabilitation treatment. Pre-test post-test design. Fourteen adolescents with G-HSD/hEDS participated. The multidisciplinary rehabilitation treatment consisted of a combination of physical training and exposure in vivo. Physical training aims to improve aerobic capacity, muscle strength and propriocepsis for compensating hypermobility. Exposure in vivo aims to decrease disability and pain-related fear. Pre- and post-treatment assessments were conducted to assess the level of disability, physical functioning (motor performance, muscle strength and physical activity level), perceived harmfulness and pain intensity. After completing multidisciplinary rehabilitation treatment, the adolescents showed a significant and clinically relevant improvement (improvement of 67%, p<0.01) in functional disability. Furthermore, significant improvements were found in motor performance (p < 0.01), muscle strength (p < 0.05), perceived harmfulness (p < 0.01) and pain intensity (p <0.01) after completing multidisciplinary rehabilitation treatment. Multidisciplinary rehabilitation treatment leads to a significantly and clinically relevant improvement in the level of disability for adolescents with G-HSD/hEDS. Positive effects were also found in physical functioning, perceived harmfulness and pain intensity. Although the results of this multidisciplinary rehabilitation treatment for adolescents with G-HSD/hEDS are promising, further study is needed to confirm these findings in a randomized design.


Safety and Efficacy of Flow Reversal in Acute and Elective Carotid Angioplasty and Stenting Using the Mo.Ma Device with Short-Term Follow-Up.
To determine the safety and efficacy of flow reversal following proximal flow arrest as an embolic protection strategy for carotid angioplasty and stenting (CAS) with short-term follow-up. We performed a retrospective review of our CAS database for patients who underwent stent-supported carotid revascularization in the setting of acute/subacute stroke or TIA. We reviewed clinical and radiographic data during a 36-month period. Primary outcome was clinical evidence of ipsilateral stroke in the first 30 days. Secondary outcomes include clinical outcomes and sonographic and/or angiographic follow-up over 6 months, 6-month functional scale, and all-cause mortality. Fifty-five patients underwent CAS using flow reversal: 26 females and 29 males with a mean age of 69.7 years. Median time to treatment from index event was 3 days. 11% underwent stenting as part of hyperacute stroke therapy. Average luminal stenosis was 86%. The 9-Fr Mo.Ma device was used in combination with Penumbra aspiration in all cases. There were no ipsilateral strokes. Incidence of any ischemic event was 3.64%, but only 1 (1.82%) patient had a postoperative stroke. Clinical follow-up was available for 94.5%, while lesion follow-up was available for 73% of patients. Three patients had evidence of restenosis, but none were symptomatic. Luminal restenosis was ≤30% in all three. Median pre- and post-NIHSS were 1 and 1, respectively. Flow reversal using the Mo.Ma device is a safe and effective strategy in preventing distal embolization during carotid artery revascularization.


Diagnosis of varicocele and postoperative evaluation using inguinal ultrasonography.
Ultrasonographic real-time imaging and measurements of spermatic veins in the inguinal canal were evaluated in two groups of patients: 20 young men with varicocele and 18 controls. Examinations were performed with the patient in an upright relaxed position, and performing the Valsalva maneuver. The increase in diameter of the main vein during Valsalva maneuver was considered to quantitatively represent venous reflux. The data obtained were correlated with pre- and postoperative clinical findings. This method of evaluation proved to be a useful noninvasive diagnostic modality for detecting varicocele and for assessing treatment results. On the basis of venous diameters and reflux values, a classification of varicocele is proposed. Such an objective method of grading would eliminate the subjective impression and interpretation factors of the examiner.


The use of visual information in the recognition of posed and spontaneous facial expressions.
Recognizing facial expressions is crucial for the success of social interactions, and the visual processes underlying this ability have been the subject of many studies in the field of face perception. Nevertheless, the stimuli used in the majority of these studies consist of facial expressions that were produced on request rather than spontaneously induced. In the present study, we directly compared the visual strategies underlying the recognition of posed and spontaneous expressions of happiness, disgust, surprise, and sadness. We used the Bubbles method with pictures of the same individuals spontaneously expressing an emotion or posing with an expression on request. Two key findings were obtained: Visual strategies were less systematic with spontaneous than with posed expressions, suggesting a higher heterogeneity in the useful facial cues across identities; and with spontaneous expressions, the relative reliance on the mouth and eyes areas was more evenly distributed, contrasting with the higher reliance on the mouth compared to the eyes area observed with posed expressions.


How beneficiaries fare under the new Medicare drug bill.
The Medicare Prescription Drug Improvement and Modernization Act (MMA) provides the largest benefit expansion in Medicare's history while enacting major changes to the program's structure. Offering $410 billion in new drug benefits will certainly help many beneficiaries now struggling with the costs of prescriptions, particularly those with low incomes. It is difficult to determine, however, whether beneficiaries will be better off in the long run. The drug benefits will not grow with the needs of beneficiaries, and other changes that prove to be unworkable or that place some beneficiaries at risk will create added costs. In the meantime, favorable treatment of private plans will create new inequities. Additional legislation and carefully crafted regulations could mitigate a number of these issues; in the meantime, they will require close scrutiny.


Exercise, training, and neutrophil function.
Although neutrophils are critical to host defense, they are also involved in the pathology of various inflammatory diseases. Neutrophils, representing 60% of circulating leukocytes in human subjects, are readily accessible to experimental investigation. Discrete aspects of, neutrophil function can be quickly and accurately assessed in vitro using a variety of techniques that involve assessment of intracellular and extracellular functional activities. Moderate exercise has variable effects on neutrophil function, but intense exercise is potentially immunosuppressive. Endurance training also suppresses most neutrophil functions chronically. A greater understanding of some fundamental aspects of neutrophil function and the uncovering of newly defined roles underlines potential applications in general and sports medicine. However, the practical value of this knowledge for monitoring the health and training programs of elite athletes requires further clarification. The current knowledge of neutrophil and immune functional measurements has not progressed to an extent that routine profiling in athletes can be used diagnostically.


Gradient nonlinearity effects on upper cervical spinal cord area measurement from 3D T1 -weighted brain MRI acquisitions.
To explore (i) the variability of upper cervical cord area (UCCA) measurements from volumetric brain 3D T1 -weighted scans related to gradient nonlinearity (GNL) and subject positioning; (ii) the effect of vendor-implemented GNL corrections; and (iii) easily applicable methods that can be used to retrospectively correct data. A multiple sclerosis patient was scanned at seven sites using 3T MRI scanners with the same 3D T1 -weighted protocol without GNL-distortion correction. Two healthy subjects and a phantom were additionally scanned at a single site with varying table positions. The 2D and 3D vendor-implemented GNL-correction algorithms and retrospective methods based on (i) phantom data fit, (ii) normalization with C2 vertebral body diameters, and (iii) the Jacobian determinant of nonlinear registrations to a template were tested. Depending on the positioning of the subject, GNL introduced up to 15% variability in UCCA measurements from volumetric brain T1 -weighted scans when no distortion corrections were used. The 3D vendor-implemented correction methods and the three proposed methods reduced this variability to less than 3%. Our results raise awareness of the significant impact that GNL can have on quantitative UCCA studies, and point the way to prospectively and retrospectively managing GNL distortions in a variety of settings, including clinical environments. Magn Reson Med 79:1595-1601, 2018. © 2017 International Society for Magnetic Resonance in Medicine.


Frequency of elevated hepatocellular carcinoma (HCC) biomarkers in patients with advanced hepatitis C.
Prospective studies of serum hepatocellular carcinoma (HCC) biomarkers in patients with advanced hepatitis C are lacking. The aim of this study was to determine the frequencies and performance of elevated α-fetoprotein (AFP), AFP-L3, and des-γ-carboxy prothrombin (DCP) levels as HCC biomarkers in advanced hepatitis C. Patients in the HALT-C Trial were tested every 3 months for 42 months. Screening ultrasound was performed every 12 months. Levels of biomarkers were compared in patients in whom HCC did or did not develop. In all, 855 patients were evaluated; HCC developed in 46. Among patients without HCC, 73.2% had AFP consistently <20, 24.5% had at least one AFP between 20 and 199, and 2.3% had at least one AFP value ≥200 ng/ml; 73.7% had DCP consistently <90, 11.6% had at least one DCP between 90 and 149, and 14.7% had at least one DCP value ≥150 mAU/ml. AFP-L3 ≥10% was present at least once in 9.0% and in 17.1% of those with AFP ≥20 ng/ml. Among all patients with elevated biomarkers, a diagnosis of HCC was made in 0-31.6% (depending on the biomarker and cutoff) during the subsequent 24 months. AFP ≥200 ng/ml had the highest specificity (99%), but sensitivity was ≤20%. DCP ≥40 mAU/ml had the highest sensitivity (76%), but specificity was ≤58%. Independent predictors of elevated AFP were gender (female), race (Black), more advanced disease, and HCC. Elevated DCP was associated with more advanced disease and HCC. Mild-moderate elevations in total AFP and DCP but not in AFP-L3 occur frequently in patients with chronic hepatitis C and advanced fibrosis, are related to factors other than HCC, and are poor predictors of HCC.


Severity of renal vascular disease predicts mortality in patients undergoing coronary angiography.
Renal artery stenosis (RAS) is a relatively uncommon but potentially reversible cause of renal failure. In a previous report, we demonstrated that the presence of RAS is independently associated with mortality in a group of patients undergoing coronary angiography. Our current study expands on this cohort, investigating the effect of the severity of RAS on all-cause mortality. A total of 3987 patients underwent abdominal aortography immediately following coronary angiography. For the purpose of survival analysis, significant RAS was defined as > or =75% narrowing in the luminal diameter. Significant RAS was present in 4.8% of patients studied and was bilateral in 0.8%. Factors associated with the presence of RAS included female gender, older age, hypertension, congestive heart failure, elevated serum creatinine, and congestive heart failure. The four-year unadjusted survivals for patients with and without significant RAS were 57 and 89%, respectively (P < 0.001). Using the Cox proportional hazards model, the factors independently associated with decreased survival were the presence of RAS, increased age, the severity of coronary artery disease, the presence of comorbid disease, reduced ejection fraction, symptoms of congestive cardiac failure, and the mode of treatment of coronary artery disease. In the multivariate model, the presence of RAS conferred a hazard ratio of 2.01 (95% CI, 1.51 to 2.67, P < 0.001). We demonstrated an incremental effect on mortality according to the severity of RAS at baseline. Four-year adjusted survival for patients with 50%, 75%, and > or =95% stenosis was 70%, 68%, and 48%, respectively. In addition, bilateral disease was associated with four-year survival of 47% as compared with 59% for patients with unilateral disease (P < 0.001). The impact of RAS on survival remained robust regardless of the manner of treatment of coronary artery disease [that is, medical, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass graft (CABG)]. In this patient population, the presence of RAS is a strong independent predictor of mortality. Increasing severity of RAS has an incremental effect on survival probability.


The Combination of Gastroschisis, Jejunal Atresia, and Colonic Atresia in a Newborn.
We encountered a rare case of gastroschisis associated with jejunal atresia and colonic atresia. In our case, the jejunal atresia was not discovered for 27 days after the initial abdominal wall closure. The colonic atresia was not discovered for 48 days after initial repair of the gastroschisis secondary to the rarity of the disorder. Both types of atresia were repaired with primary hand-sewn anastomoses. Other than the prolonged parenteral nutrition and hyperbilirubinemia, our patient did very well throughout his hospital course. Based on our case presentation, small bowel atresia and colonic atresia must be considered in patients who undergo abdominal wall closure for gastroschisis with prolonged symptoms suggestive of bowel obstruction. Our case report also demonstrates primary enteric anastomosis as a safe, well-tolerated surgical option for patients with types of intestinal atresia.