Smoking among adolescents in substance abuse treatment: a study of programs, policy, and prevalence.
The study was designed to: (1) identify smoking policies and interventions in adolescent residential treatment settings; (2) examine the prevalence of smoking among adolescents in these settings; and (3) assess relationships between program-level smoking policies and client-level smoking. The Center for Substance Abuse Treatment funded 17 sites to evaluate the effectiveness of Adolescent Residential Treatment (ART) programs for substance abuse. To describe program smoking policies and interventions, we conducted phone interviews with one key informant at each program (N=12). To describe client smoking behaviors, we conducted a secondary data analysis of baseline data for adolescents (N=912) entering ART programs. All sites had no smoking indoors and 75% of the site had tobacco-free grounds for adolescents. Forty-two percent provided their youth with nicotine replacement therapy, and 42% provided counseling for smoking cessation. Also, 33% did not allow staff smoking on and off campus. The prevalence of any smoking in the past month was 66%, and 22% of current smokers were daily smokers at admission. Where smoking was allowed on grounds, adolescents more often reported recent smoking. Smoking behavior is prevalent among adolescents in residential drug treatment, and should be addressed in all such programs through policy implementation and client-level smoking cessation intervention.


Whole-body vibration versus proprioceptive training on postural control in post-menopausal osteopenic women.
To prevent falls in the elderly, especially those with low bone density, is it necessary to maintain muscle coordination and balance. The aim of this study was to examine the effect of classical balance training (BAL) and whole-body vibration training (VIB) on postural control in post-menopausal women with low bone density. Sixty-eight subjects began the study and 57 completed the nine-month intervention program. All subjects performed resistive exercise and were randomized to either the BAL- (N=31) or VIB-group (N=26). The BAL-group performed progressive balance and coordination training and the VIB-group underwent, in total, four minutes of vibration (depending on exercise; 24-26Hz and 4-8mm range) on the Galileo Fitness. Every month, the performance of a single leg stance task on a standard unstable surface (Posturomed) was tested. At baseline and end of the study only, single leg stance, Romberg-stance, semi-tandem-stance and tandem-stance were tested on a ground reaction force platform (Leonardo). The velocity of movement on the Posturomed improved by 28.3 (36.1%) (p<0.001) in the VIB-group and 18.5 (31.5%) (p<0.001) in the BAL-group by the end of the nine-month intervention period, but no differences were seen between the two groups (p=0.45). Balance tests performed on the Leonardo device did not show any significantly different responses between the two groups after nine months (p≥0.09). Strength training combined with either proprioceptive training or whole-body vibration was associated with improvements in some, but not all, measures of postural control in post-menopausal women with low bone density. The current study could not provide evidence for a significantly different impact of whole-body vibration or balance training on postural control.


Reduction of the time-to-full-brightness in solid-state lasers using intra-cavity adaptive optics.
Several adaptive-optics techniques, based on the active modification of the optical properties of the laser cavity, were used to significantly reduce the time-to-full-brightness of solid-state lasers. Resonator re-configuration was achieved using a mechanical translation stage and both multi- and single-element deformable bimorph mirrors. Using these techniques the effects of thermally induced distortion in Nd:YLF and Nd:YAG lasers can be minimized and the warm-up time reduced by a factor of 3-6.


Clinical response and outcome of infection with Salmonella enterica serotype Typhi with decreased susceptibility to fluoroquinolones: a United States foodnet multicenter retrospective cohort study.
Patients with typhoid fever due to Salmonella enterica serotype Typhi strains for which fluoroquinolones MICs are elevated yet that are classified as susceptible by the current interpretive criteria of the Clinical and Laboratory Standards Institute may not respond adequately to fluoroquinolone therapy. Patients from seven U.S. states with invasive Salmonella serotype Typhi infection between 1999 and 2002 were enrolled in a multicenter retrospective cohort study. Patients infected with Salmonella serotype Typhi isolates with ciprofloxacin MICs of 0.12 to 1 microg/ml (decreased ciprofloxacin susceptibility but not resistant to ciprofloxacin [DCS]) were compared with patients infected with isolates with ciprofloxacin MICs <0.12 microg/ml for fever clearance time and treatment failure. Of 71 patients, 30 (43%) were female and 24 (34%) were infected with Salmonella serotype Typhi with DCS; the median age was 14 years (range, 1 to 51 years). Twenty-one (88%) of 24 isolates with DCS were resistant to nalidixic acid. The median antimicrobial-related fever clearance times in the DCS and non-DCS groups were 92 h (range, 21 to 373 h) and 72 h (range, 19 to 264 h) (P = 0.010), respectively, and the fluoroquinolone-related fever clearance times in the DCS and non-DCS groups were 90 h (range, 9 to 373 h) and 64 h (range, 34 to 204 h) (P = 0.153), respectively. Four (17%) of 24 patients in the DCS group and 2 (4%) of 46 patients in the non-DCS group (relative risk, 2.5; 95% confidence interval, 1.2 to 5.1) experienced treatment failure. Associations persisted after adjustment for potential confounders. We demonstrate that patients infected with Salmonella serotype Typhi isolates with DCS show evidence of a longer time to fever clearance and more frequent treatment failure. Nalidixic acid screening does not detect all isolates with DCS.


Study of differential cross-polarization modulation in a semiconductor optical amplifier.
Differential cross-polarization modulation (DXPoM) wavelength conversion using a semiconductor optical amplifier has been proposed to outperform substantially traditional cross-polarization modulation (XPoM). This work presents analytical small-signal models of XPoM and DXPoM. The transfer function of DXPoM is used to elucidate the significant improvement in bandwidth and the relationships among the modulation bandwidth, the delay, the operating points and other device parameters of a semiconductor optical amplifier (SOA).


A new cryomacroscope device (Type III) for visualization of physical events in cryopreservation with applications to vitrification and synthetic ice modulators.
The objective of the current study is to develop a new cryomacroscope prototype for the study of vitrification in large-size specimens. The unique contribution in the current study is in developing a cryomacroscope setup as an add-on device to a commercial controlled-rate cooler and in demonstration of physical events in cryoprotective cocktails containing synthetic ice modulators (SIM)-compounds which hinder ice crystal growth. Cryopreservation by vitrification is a highly complex application, where the likelihood of crystallization, fracture formation, degradation of the biomaterial quality, and other physical events are dependent not only upon the instantaneous cryogenic conditions, but more significantly upon the evolution of conditions along the cryogenic protocol. Nevertheless, cryopreservation success is most frequently assessed by evaluating the cryopreserved product at its end states-either at the cryogenic storage temperature or room temperature. The cryomacroscope is the only available device for visualization of large-size specimens along the thermal protocol, in an effort to correlate the quality of the cryopreserved product with physical events. Compared with earlier cryomacroscope prototypes, the new Cryomacroscope-III evaluated here benefits from a higher resolution color camera, improved illumination, digital recording capabilities, and high repeatability in tested thermal conditions via a commercial controlled-rate cooler. A specialized software package was developed in the current study, having two modes of operation: (a) experimentation mode to control the operation of the camera, record camera frames sequentially, log thermal data from sensors, and save case-specific information; and (b) post-processing mode to generate a compact file integrating images, elapsed time, and thermal data for each experiment. The benefits of the Cryomacroscope-III are demonstrated using various tested mixtures of SIMs with the cryoprotective cocktail DP6, which were found effective in preventing ice growth, even at significantly subcritical cooling rates with reference to the pure DP6.


AAV Vectors for FRET-Based Analysis of Protein-Protein Interactions in Photoreceptor Outer Segments.
Fluorescence resonance energy transfer (FRET) is a powerful method for the detection and quantification of stationary and dynamic protein-protein interactions. Technical limitations have hampered systematic in vivo FRET experiments to study protein-protein interactions in their native environment. Here, we describe a rapid and robust protocol that combines adeno-associated virus (AAV) vector-mediated in vivo delivery of genetically encoded FRET partners with ex vivo FRET measurements. The method was established on acutely isolated outer segments of murine rod and cone photoreceptors and relies on the high co-transduction efficiency of retinal photoreceptors by co-delivered AAV vectors. The procedure can be used for the systematic analysis of protein-protein interactions of wild type or mutant outer segment proteins in their native environment. Conclusively, our protocol can help to characterize the physiological and pathophysiological relevance of photoreceptor specific proteins and, in principle, should also be transferable to other cell types.


Transfer printing techniques for materials assembly and micro/nanodevice fabrication.
Transfer printing represents a set of techniques for deterministic assembly of micro-and nanomaterials into spatially organized, functional arrangements with two and three-dimensional layouts. Such processes provide versatile routes not only to test structures and vehicles for scientific studies but also to high-performance, heterogeneously integrated functional systems, including those in flexible electronics, three-dimensional and/or curvilinear optoelectronics, and bio-integrated sensing and therapeutic devices. This article summarizes recent advances in a variety of transfer printing techniques, ranging from the mechanics and materials aspects that govern their operation to engineering features of their use in systems with varying levels of complexity. A concluding section presents perspectives on opportunities for basic and applied research, and on emerging use of these methods in high throughput, industrial-scale manufacturing.


PLK1 inhibitors as a new targeted treatment for adrenocortical carcinoma.
Adrenocortical carcinoma (ACC) is an aggressive malignancy with limited treatment options. Polo-like kinase 1 (PLK1) is a promising drug target; PLK1 inhibitors (PLK1i) have been investigated in solid cancers and are more effective in TP53-mutated cases. We evaluated PLK1 expression in ACC samples and the efficacy of two PLK1i in ACC cell lines with different genetic backgrounds. PLK1 protein expression was investigated by immunohistochemistry in tissue samples and correlated with clinical data. The efficacy of rigosertib (RGS), targeting RAS/PI3K, CDKs and PLKs, and poloxin (Pol), specifically targeting the PLK1 polo-box domain, was tested in TP53-mutated NCI-H295R, MUC-1, and CU-ACC2 cells and in TP53 wild-type CU-ACC1. Effects on proliferation, apoptosis, and viability were determined. PLK1 immunostaining was stronger in TP53-mutated ACC samples vs wild-type (P = 0.0017). High PLK1 expression together with TP53 mutations correlated with shorter progression-free survival (P= 0.041). NCI-H295R showed a time- and dose-dependent reduction in proliferation with both PLK1i (P< 0.05at 100 nM RGS and 30 µM Pol). In MUC-1, a less pronounced decrease was observed (P< 0.05at 1000 nM RGS and 100 µM Pol). 100 nM RGS increased apoptosis in NCI-H295R (P< 0.001), with no effect on MUC-1. CU-ACC2 apoptosis was induced only at high concentrations (P < 0.05 at 3000 nM RGS and 100 µM Pol), while proliferation decreased at 1000 nM RGS and 30 µM Pol. CU-ACC1 proliferation reduced, and apoptosis increased, only at 100 µM Pol. TP53-mutated ACC cell lines demonstrated better response to PLK1i than wild-type CU-ACC1. These data suggest PLK1i may be a promising targeted treatment of a subset of ACC patients, pre-selected according to tumour genetic signature.


A mindful model of sexual health: A review and implications of the model for the treatment of individuals with compulsive sexual behavior disorder.
Mindfulness-based approaches, derived from centuries of eastern philosophy and practice, have been increasingly incorporated into western medicine. For example, data support the efficacy of mindfulness-based therapies to reduce stress and promote mental health. In this study, we briefly review models and approaches to sexual health in the context of considering compulsive sexual behavior disorder, describe mindfulness-based approaches to stress, addiction, and compulsive sexual behaviors, and present a Mindful Model of Sexual Health (MMSH) that incorporates elements of eastern and western philosophies. We further illustrate the clinical utility of the MMSH in a clinical case description. We propose the MMSH as a holistic and integrative model that honors and acknowledges individual differences and provides mindfulness-based tools and practices to support individuals to proactively manage, balance, and promote sexual and mental health. The MMSH may be used as a framework to organize information regarding physical, mental, emotional, sexual, and relational health, as well as a conceptual map offering navigational skills to access information within one's mind/body to make informed decisions to promote well-being regarding sexual satisfaction and health. In its organizational structure, the MMSH is divided into eight domains that are theoretically linked to biological functions and may be used to identify and overcome barriers to sexual health through mindful inquiries in clinical practice or educational settings. Given its focus on awareness of interoceptive processes through mind/body connectedness, the MMSH may resonate with a wide range of individuals, including those with compulsive sexual behavior disorder.


The impact of cigarette excise taxes on smoking cessation rates from 1994 to 2010 in Poland, Russia, and Ukraine.
We studied the impact of cigarette excise taxes on the rates of smoking cessation with data from 3 neighboring Eastern European countries (Russia, Poland, and Ukraine) during the post-transitional period of the 1990s and 2000s. Using Global Adult Tobacco Survey data from 11,106 former and current smokers, we estimated the impact of cigarette taxes on the smokers' likelihood of quitting over time. We first transformed the survey's cross-sectional data into a pseudo-longitudinal format in which the average observation period for individual subjects was 12 years and then employed duration analysis. We estimated that a 10% increase in cigarette taxes during the observation period increased the probability of smoking cessation among smokers in these countries by 1.6% to 2.3%. Cigarette tax increases have played a significant role in driving smoking cessation in Poland, Russia, and Ukraine. Further increases in cigarette excise taxes are likely to encourage further cessation and thus impact the prevalence of smoking in the region.


The MRA-DWI mismatch identifies patients with stroke who are likely to benefit from reperfusion.
The aim of this exploratory analysis was to evaluate if a combination of MR angiography (MRA) and diffusion-weighted imaging (DWI) selection criteria can be used to identify patients with acute stroke who are likely to benefit from early reperfusion. Data from DEFUSE, a study of 74 patients with stroke who received intravenous tissue plasminogen activator in the 3- to 6-hour time window and underwent MRIs before and approximately 4 hours after treatment were analyzed. The MRA-DWI mismatch model was defined as (1) a DWI lesion volume less than 25 mL in patients with a proximal vessel occlusion; or (2) a DWI lesion volume less than 15 mL in patients with proximal vessel stenosis or an abnormal finding of a distal vessel. Favorable clinical response was defined as an improvement on the National Institutes of Health Stroke Scale score of at least 8 points between baseline and 30 days or a National Institutes of Health Stroke Scale score </=1 at 30 days. Twenty-seven of 62 patients (44%) had an MRA-DWI mismatch. There was a differential response to early reperfusion based on MRA-DWI mismatch status. Reperfusion was associated with an increased rate of a favorable clinical response in patients with an MRA-DWI mismatch (OR, 12.5; 95% CI, 1.8 to 83.9) and a lower rate in patients without mismatch (OR, 0.2; 95% CI, 0.0 to 0.8). The MRA-DWI mismatch model appears to identify patients with stroke who are likely to benefit from reperfusion therapy administered in the 3- to 6-hour time window after symptom onset. The criteria established for the MRA-DWI mismatch model in this study require validation in an independent cohort.


Symmetry breaking in smectics and surface models of their singularities.
The homotopy theory of topological defects in ordered media fails to completely characterize systems with broken translational symmetry. We argue that the problem can be understood in terms of the lack of rotational Goldstone modes in such systems and provide an alternate approach that correctly accounts for the interaction between translations and rotations. Dislocations are associated, as usual, with branch points in a phase field, whereas disclinations arise as critical points and singularities in the phase field. We introduce a three-dimensional model for two-dimensional smectics that clarifies the topology of disclinations and geometrically captures known results without the need to add compatibility conditions. Our work suggests natural generalizations of the two-dimensional smectic theory to higher dimensions and to crystals.


Reduced levels of oestrogen receptor beta mRNA in Swedish patients with chronic fatigue syndrome.
Chronic fatigue syndrome (CFS) is an illness with unknown aetiology and pathophysiology. The difference in incidence by sex observed for CFS indicates a role for oestrogen and oestrogen receptors in disease development. Furthermore, an immunomediated pathogenesis has been suggested for CFS, providing an additional connection to oestrogen, which displays immunomodular functions. To investigate a possible association of oestrogen receptor (ER) mRNAs and two ERbeta single-nucleotide polymorphisms (SNPs) with CFS. Messenger RNA levels of ERalpha, ERbeta wt and ERbeta cx were investigated in peripheral blood mononuclear cells from 30 patients with CFS and 36 healthy controls by quantitative real-time polymerase chain reaction. Two ERbeta SNPs were scored in the same material. The CFS group showed significantly lower mRNA expression levels of ERbeta wt compared with the healthy control group. No differences were observed for ERalpha or ERbeta cx between patients and controls. There were no significant differences in frequency for the investigated ERbeta SNPs between cases and controls. The reduced ERbeta wt expression level observed in this study is consistent with an immune-mediated pathogenesis of CFS. Additionally, the observation that ERbeta wt expression is decreased in CFS could provide an entry point to identify interesting, potentially disease-causing, candidate molecules for further study. A possible connection between oestrogen, oestrogen receptors and CFS should be evaluated further.


Oat bran, but not its isolated bioactive β-glucans or polyphenols, have a bifidogenic effect in an in vitro fermentation model of the gut microbiota.
Wholegrain oats are known to modulate the human gut microbiota and have prebiotic properties (increase the growth of some health-promoting bacterial genera within the colon). Research to date mainly attributes these effects to the fibre content; however, oat is also a rich dietary source of polyphenols, which may contribute to the positive modulation of gut microbiota. In vitro anaerobic batch-culture experiments were performed over 24 h to evaluate the impact of two different doses (1 and 3 % (w/v)) of oat bran, matched concentrations of β-glucan extract or polyphenol mix, on the human faecal microbiota composition using 16S RNA gene sequencing and SCFA analysis. Supplementation with oats increased the abundance of Proteobacteria (P <0·01) at 10 h, Bacteroidetes (P <0·05) at 24 h and concentrations of acetic and propionic acid increased at 10 and 24 h compared with the NC. Fermentation of the 1 % (w/v) oat bran resulted in significant increase in SCFA production at 24 h (86 (sd 27) v. 28 (sd 5) mm; P <0·05) and a bifidogenic effect, increasing the relative abundance of Bifidobacterium unassigned at 10 h and Bifidobacterium adolescentis (P <0·05) at 10 and 24 h compared with NC. Considering the β-glucan treatment induced an increase in the phylum Bacteroidetes at 24 h, it explains the Bacteriodetes effects of oats as a food matrix. The polyphenol mix induced an increase in Enterobacteriaceae family at 24 h. In conclusion, in this study, we found that oats increased bifidobacteria, acetic acid and propionic acid, and this is mediated by the synergy of all oat compounds within the complex food matrix, rather than its main bioactive β-glucan or polyphenols. Thus, oats as a whole food led to the greatest impact on the microbiota.


Gender differences in mental health problems among adolescents and the role of social support: results from the Belgian health interview surveys 2008 and 2013.
To investigate how social support relates to mental health problems for Belgian late adolescents and young adults 15-25 years of age. Additionally, we examine changes in mental health problems between 2008 and 2013 and investigate gender differences. Multivariate analysis of variance was used to investigate (1) psychological distress, (2) anxiety and (3) depression among 713 boys and 720 girls taken from two successive waves (2008 and 2013) of a representative sample of the Belgian population (Belgian Health Interview survey). Psychological distress was measured by the General Health Questionnaire, anxiety and depression by the Symptom Check-List-90-Revised. Gender differences were found for psychological distress, anxiety and depression with girls reporting significantly higher scores than boys. Multivariate analysis of variance (MANOVA) revealed that adolescents who are dissatisfied with their social contacts and experience poor social support reported more psychological distress, anxiety and depression. In addition, young adult boys (20-25 years of age) were more likely to experience psychological distress when compared to late adolescent boys (15-19 years of age). Finally, the prevalence of anxiety and depression increased substantially between 2008 and 2013 for girls and to a lesser extent for boys. Especially girls and young people with poor social support experience mental health problems more frequently than boys and those with strong social support. Improving social support among young people may serve as a protective buffer to mental health problems.


Subnanometer structure and function from ion beams through complex fluidics to fluorescent particles.
The vertical dimensions of complex nanostructures determine the functions of diverse nanotechnologies. In this paper, we investigate the unknown limits of such structure-function relationships at subnanometer scales. We begin with a quantitative evaluation of measurement uncertainty from atomic force microscopy, which propagates through our investigation from ion beam fabrication to fluorescent particle characterization. We use a focused beam of gallium ions to subtractively pattern silicon surfaces, and silicon nitride and silicon dioxide films. Our study of material responses quantifies the atomic limits of forming complex topographies with subnanometer resolution of vertical features over a wide range of vertical and lateral dimensions. Our results demonstrate the underutilized capability of this standard system for rapid prototyping of subnanometer structures in hard materials. We directly apply this unprecedented dimensional control to fabricate nanofluidic devices for the analytical separation of colloidal nanoparticles by size exclusion. Optical microscopy of single nanoparticles within such reference materials establishes a subnanometer limit of the fluidic manipulation of particulate matter and enables critical-dimension particle tracking with subnanometer accuracy. After calibrating for optical interference within our multifunctional devices, which also enables device metrology and integrated spectroscopy, we reveal an unexpected relationship between nanoparticle size and emission intensity for common fluorescent probes. Emission intensity increases supervolumetrically with nanoparticle diameter and then decreases as nanoparticles with different diameters photobleach to similar values of terminal intensity. We propose a simple model to empirically interpret these surprising results. Our investigation enables new control and study of structure-function relationships at subnanometer scales.


Compensatory responses to pyruvate carboxylase suppression in islet beta-cells. Preservation of glucose-stimulated insulin secretion.
We have previously reported that glucose-stimulated insulin secretion (GSIS) is tightly correlated with pyruvate carboxylase (PC)-catalyzed anaplerotic flux into the tricarboxylic acid cycle and stimulation of pyruvate cycling activity. To further evaluate the role of PC in beta-cell function, we constructed a recombinant adenovirus containing a small interfering RNA (siRNA) specific to PC (Ad-siPC). Ad-siPC reduced PC mRNA levels by 83 and 64% and PC protein by 56 and 35% in INS-1-derived 832/13 cells and primary rat islets, respectively. Surprisingly, this manipulation did not impair GSIS in rat islets. In Ad-siPC-treated 832/13 cells, GSIS was slightly increased, whereas glycolytic rate and glucose oxidation were unaffected. Flux through PC at high glucose was decreased by only 20%, suggesting an increase in PC-specific activity. Acetyl carnitine, a surrogate for acetyl-CoA, an allosteric activator of PC, was increased by 36% in Ad-siPC-treated cells, suggesting a mechanism by which PC enzymatic activity is maintained with suppressed PC protein levels. In addition, the NADPH:NADP ratio, a proposed coupling factor for GSIS, was unaffected in Ad-siPC-treated cells. We conclude that beta-cells activate compensatory mechanisms in response to suppression of PC expression that prevent impairment of anaplerosis, pyruvate cycling, NAPDH production, and GSIS.


Treating male sexual dysfunction after traumatic brain injury: Two case reports.
Sexual dysfunction is common after traumatic brain injury (TBI) but evaluation of treatment interventions have been sparse. To report on the treatment of sexual dysfunction for two males with severe TBI. Case one was treated for erectile dysfunction (ED). After a medical examination which found no underlying physiological problems, Sildenafil was prescribed. Scores on the Golombok Rust Inventory of Sexual Satisfaction Impotence subscale found that scores had improved from the dysfunction range at baseline to the functional range at 6 weeks follow-up. There was some reduction in this improvement at 3 months follow-up, maybe associated with a co-morbid deterioration of emotional state. Case two was treated for idiopathic delayed ejaculation (DE). A standard sex therapy intervention was employed that resulted in the resolution of the problem, documented on the Sex Behavior sub-scale of the Derogatis Inventory for Sexual Functioning-Self Report (comparing baseline to post intervention and follow-up scores). The case reports show promise for the treatment of sexual dysfunction after severe TBI using standard medical and sex therapy treatments. In the future, controlled evaluations are required to demonstrate the efficacy of such interventions.


Gradenigo's Syndrome in a Patient with Chronic Suppurative Otitis Media, Petrous Apicitis, and Meningitis.
BACKGROUND Gradenigo's syndrome includes the triad of suppurative otitis media, ipsilateral sixth (abducens) cranial nerve palsy and facial pain in the distribution of the fifth (trigeminal) cranial nerve. Gradenigo's syndrome is rare, and the diagnosis is easily overlooked. This case is the first to report Gradenigo's syndrome presenting with meningitis on a background of chronic suppurative otitis media (CSOM) and petrous apicitis (apical petrositis). CASE REPORT A 58-year-old male African American presented with headaches and confusion. Magnetic resonance imaging (MRI) of the head showed petrous apicitis with mastoiditis and abscess formation in the cerebellomedullary cistern (cisterna magna). The case was complicated by the development of palsy of the fourth (trochlear) cranial nerve, fifth (trigeminal) cranial nerve, and sixth (abducens) cranial nerve, with radiological changes indicating infection involving the seventh (facial) cranial nerve, and eighth (vestibulocochlear) cranial nerve. Cerebrospinal fluid (CSF) culture results were positive for Klebsiella pneumoniae, sensitive to ceftriaxone. The patient improved with surgery that included a left mastoidectomy and debridement of the petrous apex, followed by a ten-week course of antibiotics. Follow-up MRI showed resolution of the infection. CONCLUSIONS This report is of an atypical case of Gradenigo's syndrome. It is important to recognize that the classical triad of Gradenigo's syndrome, suppurative otitis media, ipsilateral sixth (abducens) cranial nerve palsy and facial pain in the distribution of the fifth (trigeminal) cranial nerve, may also involve chronic suppurative otitis media (CSOM), which may lead to involvement of other cranial nerves, petrous apicitis (apical petrositis), and bacterial meningitis.


Consultations for clinical features of possible cancer and associated urgent referrals before and during the COVID-19 pandemic: an observational cohort study from English primary care.
It remains unclear to what extent reductions in urgent referrals for suspected cancer during the COVID-19 pandemic were the result of fewer patients attending primary care compared to GPs referring fewer patients. Cohort study including electronic health records data from 8,192,069 patients from 663 English practices. Weekly consultation rates, cumulative consultations and referrals were calculated for 28 clinical features from the NICE suspected cancer guidelines. Clinical feature consultation rate ratios (CRR) and urgent referral rate ratios (RRR) compared time periods in 2020 with 2019. Consultations for cancer clinical features decreased by 24.19% (95% CI: 24.04-24.34%) between 2019 and 2020, particularly in the 6-12 weeks following the first national lockdown. Urgent referrals for clinical features decreased by 10.47% (95% CI: 9.82-11.12%) between 2019 and 2020. Overall, once patients consulted with primary care, GPs urgently referred a similar or greater proportion of patients compared to previous years. Due to the significant fall in patients consulting with clinical features of cancer there was a lower than expected number of urgent referrals in 2020. Sustained efforts should be made throughout the pandemic to encourage the public to consult their GP with cancer clinical features.


Trends in Clinical Severity of Hospitalized Patients With Coronavirus Disease 2019-Premier Hospital Dataset, April 2020-April 2021.
Clinical severity of coronavirus disease 2019 (COVID-19) may vary over time; trends in clinical severity at admission during the pandemic among hospitalized patients in the United States have been incompletely described, so a historical record of severity over time is lacking. We classified 466677 hospital admissions for COVID-19 from April 2020 to April 2021 into 4 mutually exclusive severity grades based on indicators present on admission (from most to least severe): Grade 4 included intensive care unit (ICU) admission and invasive mechanical ventilation (IMV); grade 3 included non-IMV ICU and/or noninvasive positive pressure ventilation; grade 2 included diagnosis of acute respiratory failure; and grade 1 included none of the above indicators. Trends were stratified by sex, age, race/ethnicity, and comorbid conditions. We also examined severity in states with high vs low Alpha (B.1.1.7) variant burden. Severity tended to be lower among women, younger adults, and those with fewer comorbidities compared to their counterparts. The proportion of admissions classified as grade 1 or 2 fluctuated over time, but these less-severe grades comprised a majority (75%-85%) of admissions every month. Grades 3 and 4 consistently made up a minority of admissions (15%-25%), and grade 4 showed consistent decreases in all subgroups, including states with high Alpha variant burden. Clinical severity among hospitalized patients with COVID-19 has varied over time but has not consistently or markedly worsened over time. The proportion of admissions classified as grade 4 decreased in all subgroups. There was no consistent evidence of worsening severity in states with higher vs lower Alpha prevalence.


A systematic review of studies on socioeconomic inequalities in dietary intakes associated with weight gain and overweight/obesity conducted among European adults.
This Review examined socioeconomic inequalities in intakes of dietary factors associated with weight gain, overweight/obesity among adults in Europe. Literature searches of studies published between 1990 and 2007 examining socioeconomic position (SEP) and the consumption of energy, fat, fibre, fruit, vegetables, energy-rich drinks and meal patterns were conducted. Forty-seven articles met the inclusion criteria. The direction of associations between SEP and energy intakes were inconsistent. Approximately half the associations examined between SEP and fat intakes showed higher total fat intakes among socioeconomically disadvantaged groups. There was some evidence that these groups consume a diet lower in fibre. The most consistent evidence of dietary inequalities was for fruit and vegetable consumption; lower socioeconomic groups were less likely to consume fruit and vegetables. Differences in energy, fat and fibre intakes (when found) were small-to-moderate in magnitude; however, differences were moderate-to-large for fruit and vegetable intakes. Socioeconomic inequalities in the consumption of energy-rich drinks and meal patterns were relatively under-studied compared with other dietary factors. There were no regional or gender differences in the direction and magnitude of the inequalities in the dietary factors examined. The findings suggest that dietary behaviours may contribute to socioeconomic inequalities in overweight/obesity in Europe. However, there is only consistent evidence that fruit and vegetables may make an important contribution to inequalities in weight status across European regions.


Vascular metallomics: copper in the vasculature.
Owing to recent progress in analytical techniques, metallomics are evolving from detecting distinct trace metals in a defined state to monitor the dynamic changes in the abundance and location of trace metals in vitro and in vivo. Vascular metallomics is an emerging field that studies the role of trace metals in vasculature. This review will introduce common metallomics techniques including atomic absorption spectrometry, inductively coupled plasma-atomic emission spectrometry, inductively coupled plasma-mass spectrometry and X-ray fluorescence spectrometry with a summary table to compare these techniques. Moreover, we will summarize recent research findings that have applied these techniques to human population studies in cardiovascular diseases, with a particular emphasis on the role of copper in these diseases. In order to address the issue of interdisciplinary studies between metallomics and vascular biology, we will review the progress of efforts to understand the role of copper in neovascularization. This recent advance in the metallomics field may be a powerful tool to elucidate the signaling pathways and specific biological functions of these trace metals. Finally, we summarize the evidence to support the notion that copper is a dynamic signaling molecule. As a future direction, vascular metallomics studies may lead to the identification of targets for diagnosis and therapy in cardiovascular disease.


lnCeDB: database of human long noncoding RNA acting as competing endogenous RNA.
Long noncoding RNA (lncRNA) influences post-transcriptional regulation by interfering with the microRNA (miRNA) pathways, acting as competing endogenous RNA (ceRNA). These lncRNAs have miRNA responsive elements (MRE) in them, and control endogenous miRNAs available for binding with their target mRNAs, thus reducing the repression of these mRNAs. lnCeDB provides a database of human lncRNAs (from GENCODE 19 version) that can potentially act as ceRNAs. The putative mRNA targets of human miRNAs and the targets mapped to AGO clipped regions are collected from TargetScan and StarBase respectively. The lncRNA targets of human miRNAs (up to GENCODE 11) are downloaded from miRCode database. miRNA targets on the rest of the GENCODE 19 lncRNAs are predicted by our algorithm for finding seed-matched target sites. These putative miRNA-lncRNA interactions are mapped to the Ago interacting regions within lncRNAs. To find out the likelihood of an lncRNA-mRNA pair for actually being ceRNA we take recourse to two methods. First, a ceRNA score is calculated from the ratio of the number of shared MREs between the pair with the total number of MREs of the individual candidate gene. Second, the P-value for each ceRNA pair is determined by hypergeometric test using the number of shared miRNAs between the ceRNA pair against the number of miRNAs interacting with the individual RNAs. Typically, in a pair of RNAs being targeted by common miRNA(s), there should be a correlation of expression so that the increase in level of one ceRNA results in the increased level of the other ceRNA. Near-equimolar concentration of the competing RNAs is associated with more profound ceRNA effect. In lnCeDB one can not only browse for lncRNA-mRNA pairs having common targeting miRNAs, but also compare the expression of the pair in 22 human tissues to estimate the chances of the pair for actually being ceRNAs. Downloadable freely from http://gyanxet-beta.com/lncedb/.


Treatment preference for weekly versus daily DPP-4 inhibitors in patients with type 2 diabetes mellitus: outcomes from the TRINITY trial.
Objective: To examine patient preference for treatment with the oral once-weekly dipeptidyl peptidase-4 inhibitor (DPP-4i), trelagliptin, and oral once-daily DPP-4i, alogliptin, administered for 8 weeks each in patients with type 2 diabetes mellitus prescribed a daily DPP-4i.Methods: In this randomized, open-label, two-way crossover study, patients received trelagliptin followed by alogliptin (T-A group) or alogliptin followed by trelagliptin (A-T group), for 8 weeks each (NCT03231709, JapicCTI-173662). Treatment preference was assessed using a standardized questionnaire in the overall population and by baseline characteristics. Other outcomes included patient satisfaction with diabetes treatment (assessed using the Diabetes Treatment Satisfaction Questionnaire [DTSQ]), hemoglobin A1c (HbA1c) levels after 8 weeks of treatment with each agent, and safety.Results: Sixty patients from two clinical sites were randomized 1:1 to T-A and A-T groups (each n = 30); baseline characteristics were similar between groups. After 16 weeks of treatment, 51.7% of patients preferred treatment with alogliptin compared with 30.0% selecting trelagliptin (p = .014); preference for alogliptin was consistently greater than for trelagliptin in the secondary analyses by baseline characteristics. DTSQ score and HbA1c levels were similar between treatments after 8 weeks of therapy. Both treatments demonstrated favorable safety and tolerability profiles.Conclusions: Patients expressed a significantly greater treatment preference for once-daily alogliptin than once-weekly trelagliptin, although patient satisfaction and HbA1c levels were similar across treatments. The decision to administer a once-weekly or once-daily DPP-4i is likely to depend on patient preference, patient-physician discussions, and treatment practices of the prescribing physician.


Non-traumatic coma in paediatric patients: etiology and predictors of outcome.
To determine the common etiological features of non-traumatic coma in children and evaluate possible predictors of morbidity and mortality in these patients. A cross sectional study was carried out at the Paediatric Department of Civil Hospital Karachi from February 2008 to February 2009. In total 100 children, up to 14 years of age having history of non-traumatic coma were included. At the time of enrolment demographic data, clinical features, laboratory parameters and radiological workup were recorded. Data was entered and analyzed with SPSS version 16. Descriptive statistics were generated for all variables. Relationships between categorical variables were evaluated by examining cross-tabulations, chi2 test and Fisher's exact tests. P-values < 0.05 were considered statistically significant. Mean age of the patients in months were 45 months. Male female ratio was 1.45:1. Among 65 survivors 38 (58%) showed no disability and 27 (41%) showed disability. Infections emerged as major cause of mortality (n=23, 79%). Clinical features that showed association with mortality included hypothermia (P = 0.032), hypotension (P = 0.002), altered breathing pattern (P = 0.0001), non reactive pupils (P = 0.001), low Glasgow coma scale (GCS) (P = 0.038), hypotonia (P = 0.002), hyporeflexia (P = 0.0001) and muscle power score of two (P = 0.043). Infections were the leading cause of non-traumatic coma as well as the leading cause of mortality in our study. Hypothermia, hypotension, altered breathing pattern, non reactive pupils, low GCS, hypotonia, hyporeflexia and low muscle power score were significantly associated with mortality in children presenting with non-traumatic coma.


Effects of axial, transverse, and oblique sample motion in FD OCT in systems with global or rolling shutter line detector.
This study deals with effects on the interference signal caused by axial, transverse, and oblique motion in spectrometer-based Fourier-domain optical coherence tomography (FD OCT). Two different systems are compared-one with a global shutter line detector and the other with a rolling shutter. We present theoretical and experimental investigations of motion artifacts. Regarding axial motion, fringe washout is observed in both systems, and an additional Doppler frequency shift is seen in the system using a rolling shutter. In addition, both systems show the same SNR decrease as a result of a transversely and obliquely moving sample. The possibility of flow measurement by using the decrease in signal power was demonstrated by imaging 1% Intralipid emulsion flowing through a glass capillary. This research provides an understanding of the SNR degradation caused by sample motion and demonstrates the importance of fast data acquisition in medical imaging.


Direct detection and characterization of foot-and-mouth disease virus in East Africa using a field-ready real-time PCR platform.
Effective control and monitoring of foot-and-mouth disease (FMD) relies upon rapid and accurate disease confirmation. Currently, clinical samples are usually tested in reference laboratories using standardized assays recommended by The World Organisation for Animal Health (OIE). However, the requirements for prompt and serotype-specific diagnosis during FMD outbreaks, and the need to establish robust laboratory testing capacity in FMD-endemic countries have motivated the development of simple diagnostic platforms to support local decision-making. Using a portable thermocycler, the T-COR™ 8, this study describes the laboratory and field evaluation of a commercially available, lyophilized pan-serotype-specific real-time RT-PCR (rRT-PCR) assay and a newly available FMD virus (FMDV) typing assay (East Africa-specific for serotypes: O, A, Southern African Territories [SAT] 1 and 2). Analytical sensitivity, diagnostic sensitivity and specificity of the pan-serotype-specific lyophilized assay were comparable to that of an OIE-recommended laboratory-based rRT-PCR (determined using a panel of 57 FMDV-positive samples and six non-FMDV vesicular disease samples for differential diagnosis). The FMDV-typing assay was able to correctly identify the serotype of 33/36 FMDV-positive samples (no cross-reactivity between serotypes was evident). Furthermore, the assays were able to accurately detect and type FMDV RNA in multiple sample types, including epithelial tissue suspensions, serum, oesophageal-pharyngeal (OP) fluid and oral swabs, both with and without the use of nucleic acid extraction. When deployed in laboratory and field settings in Tanzania, Kenya and Ethiopia, both assays reliably detected and serotyped FMDV RNA in samples (n = 144) collected from pre-clinical, clinical and clinically recovered cattle. These data support the use of field-ready rRT-PCR platforms in endemic settings for simple, highly sensitive and rapid detection and/or characterization of FMDV.


Relative indexes of cutaneous blood perfusion measured by real-time laser Doppler imaging (LDI) in healthy volunteers.
We used real-time LDI to study regional variations in microcirculatory perfusion in healthy candidates to establish a new methodology for global perfusion body mapping that is based on intra-individual perfusion index ratios. Our study included 74 (37 female) healthy volunteers aged between 22 and 30 years (mean 24.49). Imaging was performed using a recent microcirculation-imaging camera (EasyLDI) for different body regions of each volunteer. The perfusion values were reported in Arbitrary Perfusion Units (APU). The relative perfusion indexes for each candidate's body region were then obtained by normalization with the perfusion value of the forehead. Basic parameters such as weight, height, and blood pressure were also measured and analyzed. The highest mean perfusion value was reported in the forehead area (259.21APU). Mean perfusion in the measured parts of the body correlated positively with mean forehead value, while there was no significant correlation between forehead blood perfusion values and room temperature, BMI, systolic blood pressure and diastolic blood pressure (p=0.420, 0.623, 0.488, 0.099, respectively). Analysis of the data showed that perfusion indexes were not significantly different between male and female volunteers except for the ventral upper arm area (p=.001). LDI is a non-invasive, fast technique that opens several avenues for clinical applications. The mean perfusion indexes are useful in clinical practice for monitoring patients before and after surgical interventions. Perfusion values can be predicted for different body parts for patients only by taking the forehead perfusion value and using the perfusion index ratios to obtain expected normative perfusion values.


Association of Cancer Incidence and Duration of Residence in Geothermal Heating Area in Iceland: An Extended Follow-Up.
Residents of geothermal areas have higher incidence of non-Hodgkin's lymphoma, breast cancer, prostate cancer, and kidney cancers than others. These populations are exposed to chronic low-level ground gas emissions and various pollutants from geothermal water. The aim was to assess whether habitation in geothermal areas and utilisation of geothermal water is associated with risk of cancer according to duration of residence. The cohort obtained from the census 1981 was followed to the end of 2013. Personal identifier was used in record linkage with nation-wide emigration, death, and cancer registries. The exposed population, defined by community codes, was located on young bedrock and had utilised geothermal water supply systems since 1972. Two reference populations were located by community codes on older bedrock or had not utilised geothermal water supply systems for as long a period as had the exposed population. Adjusted hazard ratio (HR), 95% confidence intervals (CI) non-stratified and stratified on cumulative years of residence were estimated in Cox-model. The HR for all cancer was 1.21 (95% CI 1.12-1.30) as compared with the first reference area. The HR for pancreatic cancer was 1.93 (1.22-3.06), breast cancer, 1.48 (1.23-1.80), prostate cancer 1.47 (1.22-1.77), kidney cancer 1.46 (1.03-2.05), lymphoid and haematopoietic tissue 1.54 (1.21-1.97), non-Hodgkin´s lymphoma 2.08 (1.38-3.15) and basal cell carcinoma of the skin 1.62 (1.35-1.94). Positive dose-response relationship was observed between incidence of cancers and duration of residence, and between incidence of cancer and degree of geothermal/volcanic activity in the comparison areas. The higher cancer incidence in geothermal areas than in reference areas is consistent with previous findings. As the dose-response relationships were positive between incidence of cancers and duration of residence, it is now more urgent than before to investigate the chemical and physical content of the geothermal water and of the ambient air of the areas to detect recognized or new carcinogens.


Synthetic and isolation studies related to the marine natural products (+)-elisabethadione and (+)-elisabethamine.
These studies were conducted to determine the discrepancies between the spectroscopic data of the isolated and synthetic samples of the marine natural product (+)-elisabethadione. Attempts at the re-isolation of (+)-elisabethadione from Pseudopterogorgia elisabethae were unsuccessful, but during these efforts, two related natural products of O-methylelisabethadione (8) and O-methyl-nor-elisabethadione (9) were discovered. The total syntheses of these new natural products were accomplished by using the combined C-H activation/Cope rearrangement as the key step and the previously synthesized elisabethadione was converted to O-methylelisabethadione. These studies confirmed that the synthetic sample of (+)-elisabthadione was assigned the correct structure. The considerable differences in the data between the synthetic and natural samples of (+)-elisabethadione lead to the conclusion that the structure of the natural material was either miss-assigned or the published spectral data were incorrect. During the course of these studies, questions arose about the assigned structure of another natural product, elisabethamine, which was proposed to be an aminohydroquinone. Attempts at the synthesis of this compound revealed that the aminohydroquinone structure was unstable in air as it was readily oxidized to the quinone.


Patterns of care and referral in children with atopic dermatitis and concern for food allergy.
Although many providers believe that up to 30% of atopic dermatitis (AD) is food induced, food challenge studies show that food-induced eczematous reactions are rare. When food allergy is suggested to cause AD, it often leads to allergy testing with a high false-positivity rate, in turn further focusing parents on food allergy. Study subjects were children less than 11 years old with AD and food allergy suspicion. Prior diagnoses, provider, and testing patterns were assessed by questionnaire given to the parents. Thirty-eight patients with AD were enrolled. Most subject's parents suspected food allergy induced AD. Initial skin diagnoses were made by pediatricians (79%) and family practitioners (18%) as eczema. Allergy was suggested by providers as cause for AD in 63% of the present study's patients. Seventy-nine percent had allergy testing. Greater than 90% of parents claimed their children had food allergy and food-induced AD. Sixty-six percent had positive food allergy tests and 37% had definite history of immediate IgE reactions to food. The majority of this population had allergy suggested as causative for eczema by their primary care provider and were subsequently evaluated by allergist and allergy testing. Consensus about the role of food allergy between the different providers of AD in children would result in more effective, efficient, and less costly health care.


Prediction of violent crime on discharge from secure psychiatric hospitals: A clinical prediction rule (FoVOx).
Current approaches to assess violence risk in secure hospitals are resource intensive, limited by accuracy and authorship bias and may have reached a performance ceiling. This study seeks to develop scalable predictive models for violent offending following discharge from secure psychiatric hospitals. We identified all patients discharged from secure hospitals in Sweden between January 1, 1992 and December 31, 2013. Using multiple Cox regression, pre-specified criminal, sociodemographic, and clinical risk factors were included in a model that was tested for discrimination and calibration in the prediction of violent crime at 12 and 24 months post-discharge. Risk cut-offs were pre-specified at 5% (low vs. medium) and 20% (medium vs. high). We identified 2248 patients with 2933 discharges into community settings. We developed a 12-item model with good measures of calibration and discrimination (area under the curve=0.77 at 12 and 24 months). At 24 months post-discharge, using the 5% cut-off, sensitivity was 96% and specificity was 21%. Positive and negative predictive values were 19% and 97%, respectively. Using the 20% cut-off, sensitivity was 55%, specificity 83% and the positive and negative predictive values were 37% and 91%, respectively. The model was used to develop a free online tool (FoVOx). We have developed a prediction score in a Swedish cohort of patients discharged from secure hospitals that can assist in clinical decision-making. Scalable predictive models for violence risk are possible in specific patient groups and can free up clinical time for treatment and management. Further evaluation in other countries is needed. Wellcome Trust (202836/Z/16/Z) and the Swedish Research Council. The funding sources had no involvement in writing of the manuscript or decision to submit or in data collection, analysis or interpretation or any aspect pertinent to the study.


Human interleukin-5 expressed in Escherichia coli: assignment of the disulfide bridges of the purified unglycosylated protein.
Human interleukin-5 is a homodimer; each subunit contains two cysteine residues that form two inter-subunit disulfide bonds. The topology of the disulfides in recombinant human interleukin-5 produced in Escherichia coli was studied by proteolytic digestion and peptide mapping. Disulfide linked peptides containing cysteine 42 linked to cysteine 84 were isolated. This indicated that cysteines 42 and 84 of one subunit were linked in an antiparallel manner to cysteines 84 and 42 of the other subunit.


Auditory perceptual processing in people with reading and oral language impairments: current issues and recommendations.
A popular hypothesis holds that specific reading disability (SRD) and specific language impairment (SLI) result from an impaired ability to process rapid and brief sounds. However, the results of experiments that have tested this hypothesis are incongruous. A number of factors could explain these contradictory findings, including the questionable reliability and validity of rapid auditory processing tasks, individual differences in the auditory processing abilities of SRD and SLI populations, the age of listeners, the quality of control groups, and the relationship between verbal and non-verbal auditory processing abilities. These issues highlight the need for future studies to (1) establish the reliability and validity of psychophysical tasks used to assess rapid auditory processing; (2) report the rapid auditory processing scores of individuals rather than just group means; (3) include a wide range of reading and spoken language tests to determine the literacy and oral language profile of people who demonstrate an auditory processing deficit; (4) include clinical comparison groups to determine whether a rapid auditory processing deficit is related specifically to written and spoken language impairments; and (5) examine the relationship between low-level non-verbal, verbal, and phonological processing abilities.


Simple HPLC Method with Internal Standard for Evaluation of Vitamin B1 Status By Use of Whole Blood.
Two primary assays are routinely used for evaluating a patient's vitamin B1 status: plasma free thiamine and whole blood thiamine diphosphate (TDP). TDP is the bioactive form of vitamin B1 and best reflects body stores. Plasma free thiamine levels are driven by recent dietary intake. The objective of this study was to develop a simple HPLC method with an internal standard (IS) that simultaneously measures TDP and thiamine in whole blood, and to assess the use of this single-tube assay to provide comprehensive evaluation of vitamin B1 status. The final assay used amprolium thiochrome as an IS, and the sample preparation procedure takes approximately 1 h. Whole blood thiamine and plasma thiamine were concurrently measured for 126 subjects. The analytical measurement range was 1.7 to 442.3 nmol/L (TDP) and 1.7 to 375.4 nmol/L (thiamine), with interassay precisions of 4.0% to 4.8% (TDP) and 2.9% to 8.0% (thiamine), respectively. Method comparison with a reference laboratory HPLC method showed r = 0.9625, slope = 1.021, and intercept = 0.982 (n = 53) for TDP quantification. Whole blood thiamine correlated closely with plasma thiamine levels but were slightly higher with a mean difference of 1.0 nmol/L (range: -3.0 to 5.0 nmol/L). The reference interval for whole blood TDP and thiamine was 84.3 to 213.3 nmol/L and 1.7 to 21.9 nmol/L, respectively. This assay provides a simple and reliable HPLC method with a suitable IS for quantification of both TDP and thiamine from whole blood. It also eliminates the need for separate samples for TDP and thiamine measurement, which will allow both short-term and long-term vitamin B1 status to be assessed from a single sample.


Differential association between HERG and KCNE1 or KCNE2.
The small proteins encoded by KCNE1 and KCNE2 have both been proposed as accessory subunits for the HERG channel. Here we report our investigation into the cell biology of the KCNE-HERG interaction. In a co-expression system, KCNE1 was more readily co-precipitated with co-expressed HERG than was KCNE2. When forward protein trafficking was prevented (either by Brefeldin A or engineering an ER-retention/retrieval signal onto KCNE cDNA) the intracellular abundance of KCNE2 and its association with HERG markedly increased relative to KCNE1. HERG co-localized more completely with KCNE1 than with KCNE2 in all the membrane-processing compartments of the cell (ER, Golgi and plasma membrane). By surface labeling and confocal immunofluorescence, KCNE2 appeared more abundant at the cell surface compared to KCNE1, which exhibited greater co-localization with the ER-marker calnexin. Examination of the extracellular culture media showed that a significant amount of KCNE2 was extracellular (both soluble and membrane-vesicle-associated). Taken together, these results suggest that during biogenesis of channels HERG is more likely to assemble with KCNE1 than KCNE2 due to distinctly different trafficking rates and retention in the cell rather than differences in relative affinity. The final channel subunit constitution, in vivo, is likely to be determined by a combination of relative cell-to-cell expression rates and differential protein processing and trafficking.


Postoperative IMRT in head and neck cancer.
Aim of this work was to assess loco-regional disease control in head and neck cancer (HNC) patients treated with postoperative intensity modulated radiation therapy (pIMRT). For comparative purposes, risk features of our series have been analysed with respect to histopathologic adverse factors. Results were compared with an own historic conventional radiation (3DCRT) series, and with 3DCRT and pIMRT data from other centres.Between January 2002 and August 2006, 71 patients were consecutively treated with pIMRT for a squamous cell carcinoma (SCC) of the oropharynx (32), oral cavity (22), hypopharynx (7), larynx (6), paranasal sinus (3), and an unknown primary, respectively. Mean and median follow up was 19 months (2-48), and 17.6 months. 83% were treated with IMRT-chemotherapy. Mean prescribed dose was 66.3 Gy (60-70), delivered with doses per fraction of 2-2.3 Gy, respectively. 2-year local, nodal, and distant control rates were 95%, 91%, and 96%, disease free and overall survival 90% and 83%, respectively. The corresponding survival rates for the subgroup of patients with a follow up time >12 months (n = 43) were 98%, 95%, 98%, 93%, and 88%, respectively. Distribution according to histopathologic risk features revealed 15% and 85% patients with intermediate and high risk, respectively. All loco-regional events occurred in the high risk subgroup. Surgery followed by postoperative IMRT in patients with substantial risk for recurrence resulted in high loco-regional tumor control rates compared with large prospective 3DCRT trials.


A trigger tool to detect harm in pediatric inpatient settings.
An efficient and reliable process for measuring harm due to medical care is needed to advance pediatric patient safety. Several pediatric studies have assessed the use of trigger tools in varying inpatient environments. Using the Institute for Healthcare Improvement's adult-focused Global Trigger Tool as a model, we developed and pilot tested a trigger tool that would identify the most common causes of harm in pediatric inpatient environments. After formal training, 6 academic children's hospitals used this novel pediatric trigger tool to review 100 randomly selected inpatient records per site from patients discharged during the month of February 2012. From the 600 patient charts evaluated, 240 harmful events ("harms") were identified, resulting in a rate of 40 harms per 100 patients admitted and 54.9 harms per 1000 patient days across the 6 hospitals. At least 1 harm was identified in 146 patients (24.3% of patients). Of the 240 total events, 108 (45.0%) were assessed to have been potentially or definitely preventable. The most common patient harms were intravenous catheter infiltrations/burns, respiratory distress, constipation, pain, and surgical complications. Consistent with earlier rates of all-cause harm in adult hospitals, harm occurs at high rates in hospitalized children. Availability and use of an all-cause harm identification tool will establish the epidemiology of harm and will provide a consistent approach to assessing the effect of interventions on harms in hospitalized children.


Effective Rat Lung Tumor Model for Stereotactic Body Radiation Therapy.
Stereotactic body radiation therapy (SBRT) has found an important role in the treatment of patients with non-small cell lung cancer, demonstrating improvements in dose distribution and even tumor cure rates, particularly for early-stage disease. Despite its emerging clinical efficacy, SBRT has primarily evolved due to advances in medical imaging and more accurate dose delivery, leaving a void in knowledge of the fundamental biological mechanisms underlying its activity. Thus, there is a critical need for the development of orthotropic animal models to further probe the biology associated with high-dose-per-fraction treatment typical of SBRT. We report here on an improved surgically based methodology for generating solitary intrapulmonary nodule tumors, which can be treated with simulated SBRT using the X-RAD 225Cx small animal irradiator and Small Animal RadioTherapy (SmART) Plan treatment system. Over 90% of rats developed solitary tumors in the right lung. Furthermore, the tumor response to radiation was monitored noninvasively via bioluminescence imaging (BLI), and complete ablation of tumor growth was achieved with 36 Gy (3 fractions of 12 Gy each). We report a reproducible, orthotopic, clinically relevant lung tumor model, which better mimics patient treatment regimens. This system can be utilized to further explore the underlying biological mechanisms relevant to SBRT and high-dose-per-fraction radiation exposure and to provide a useful model to explore the efficacy of radiation modifiers in the treatment of non-small cell lung cancer.


Modeling toxicity of binary metal mixtures (Cu(2+) -Ag(+) , Cu(2+) -Zn(2+) ) to lettuce, Lactuca sativa, with the biotic ligand model.
The biotic ligand model (BLM) was applied to predict metal toxicity to lettuce, Lactuca sativa. Cu(2+) had the lowest median effective activity (EA50(M) ), compared with Ag(+) and Zn(2+) (EA50(Cu) = 2.60 × 10(-8) M, EA50(Ag) = 1.34 × 10(-7) M, EA50(Zn) = 1.06 × 10(-4) M). At the 50% response level, the fraction of the total number of biotic ligands occupied by ions (f50(M) ) was lowest for Ag(+) among the metals (f50(Ag) = 0.22, f50(Cu) = 0.36, f50(Zn) = 0.42). Cu(2+) had the highest affinity for biotic ligands compared with Ag(+) and Zn(2+) , as shown by stability constants of the cation-biotic ligand binding, expressed as log K(MBL) (log K(CuBL) = 7.40, log K(AgBL) = 6.39, log K(ZnBL) = 4.00). Furthermore, the BLM was combined with the toxic equivalency factor approach in predicting toxicity of mixtures of Cu(2+) -Zn(2+) and Cu(2+) -Ag(+) . The fraction of biotic ligands occupied by ions was used to determine the relative toxic potency of metals and the toxic equivalency quotient (TEQ) of mixtures. This approach allowed for including interactions in estimating mixture toxicity and showed good predictive power (r(2) = 0.64-0.84). The TEQ at the 50% response level (TEQ50, Cu(2+) equivalents) for Cu(2+) -Zn(2+) mixtures was significantly lower than the value for Cu(2+) -Ag(+) mixtures. Joint toxicity depended on both TEQ and specific composition of the mixture. The present study supports the use of the accumulation of metal ions at the biotic ligands as a predictor of toxicity of single metals and mixtures.


Molecular rheometry: direct determination of viscosity in Lo and Ld lipid phases via fluorescence lifetime imaging.
Understanding of cellular regulatory pathways that involve lipid membranes requires the detailed knowledge of their physical state and structure. However, mapping the viscosity and diffusion in the membranes of complex composition is currently a non-trivial technical challenge. We report fluorescence lifetime spectroscopy and imaging (FLIM) of a meso-substituted BODIPY molecular rotor localised in the leaflet of model membranes of various lipid compositions. We prepare large and giant unilamellar vesicles (LUVs and GUVs) containing phosphatidylcholine (PC) lipids and demonstrate that recording the fluorescence lifetime of the rotor allows us to directly detect the viscosity of the membrane leaflet and to monitor the influence of cholesterol on membrane viscosity in binary and ternary lipid mixtures. In phase-separated 1,2-dioleoyl-sn-glycero-3-phosphocholine-cholesterol-sphingomyelin GUVs we visualise individual liquid ordered (Lo) and liquid disordered (Ld) domains using FLIM and assign specific microscopic viscosities to each domain. Our study showcases the power of FLIM with molecular rotors to image microviscosity of heterogeneous microenvironments in complex biological systems, including membrane-localised lipid rafts.


Efficient meltwater drainage through supraglacial streams and rivers on the southwest Greenland ice sheet.
Thermally incised meltwater channels that flow each summer across melt-prone surfaces of the Greenland ice sheet have received little direct study. We use high-resolution WorldView-1/2 satellite mapping and in situ measurements to characterize supraglacial water storage, drainage pattern, and discharge across 6,812 km(2) of southwest Greenland in July 2012, after a record melt event. Efficient surface drainage was routed through 523 high-order stream/river channel networks, all of which terminated in moulins before reaching the ice edge. Low surface water storage (3.6 ± 0.9 cm), negligible impoundment by supraglacial lakes or topographic depressions, and high discharge to moulins (2.54-2.81 cm⋅d(-1)) indicate that the surface drainage system conveyed its own storage volume every <2 d to the bed. Moulin discharges mapped inside ∼52% of the source ice watershed for Isortoq, a major proglacial river, totaled ∼41-98% of observed proglacial discharge, highlighting the importance of supraglacial river drainage to true outflow from the ice edge. However, Isortoq discharges tended lower than runoff simulations from the Modèle Atmosphérique Régional (MAR) regional climate model (0.056-0.112 km(3)⋅d(-1) vs. ∼0.103 km(3)⋅d(-1)), and when integrated over the melt season, totaled just 37-75% of MAR, suggesting nontrivial subglacial water storage even in this melt-prone region of the ice sheet. We conclude that (i) the interior surface of the ice sheet can be efficiently drained under optimal conditions, (ii) that digital elevation models alone cannot fully describe supraglacial drainage and its connection to subglacial systems, and (iii) that predicting outflow from climate models alone, without recognition of subglacial processes, may overestimate true meltwater export from the ice sheet to the ocean.


Interferon-Tau has Antiproliferative effects, Represses the Expression of E6 and E7 Oncogenes, Induces Apoptosis in Cell Lines Transformed with HPV16 and Inhibits Tumor Growth In Vivo.
Interferon tau (IFN-τ) is a promising alternative antiviral and immunotherapeutic agent in a wide variety of diseases including infectious, neurodegenerative, autoimmune and cancer due to its low toxicity in comparison with other type I interferon´s. The objective of our study was established the effect of the bovine IFN-τ on human (SiHa) and murine (BMK-16/myc) cells transformed with HPV 16 and evaluates the antitumor effect in a murine tumor model HPV 16 positive. We determine that bovine IFN-τ has antiproliferative effects, pro-apoptotic activity and induces repression of viral E6 and E7 oncogenes (time- and dose-dependent) on human and murine cells transformed with HPV 16 similar to the effects of IFN-β. However, IFN-τ induces greater antiproliferative effect, apoptosis and repression of both oncogenes in BMK-16/myc cells compared to SiHa cells. The differences were explained by the presence and abundance of the type I interferon receptor (IFNAR) in each cell line. On the other hand, we treated groups of tumor-bearing mice (HPV16 positive) with IFN-τ and showed the inhibition tumor growth effect in vivo. Our finding indicates that bovine IFN-τ may be a good candidate for immunotherapy against cervical cancer.


Association between renal replacement therapy in critically ill patients with severe acute kidney injury and mortality.
To evaluate the characteristics and outcomes of critically ill patients with severe acute kidney injury (AKI) treated and not treated with renal replacement therapy (RRT). Secondary analysis of a multi-centre cohort study. Primary exposure was RRT. Primary outcome was propensity and multi-variable adjusted-hospital mortality. We studied 1250 patients (71.3%) who received and 502 (28.7%) who did not receive RRT. Reasons for not starting RRT (not mutually exclusive) were limitations of support (33.6%, n = 169), adequate urine output (46.2%; n = 232), plan to observe (56.4%; n = 283), and advanced age (12.6%; n = 63). Mortality was higher in those not receiving RRT due to limitations and advanced age but lower for adequate urine output and plan to observe. Propensity and multi-variable adjusted analysis showed no statistical difference in hospital mortality (adj-OR 1.47; 95% CI, 0.93-2.24) in patients receiving RRT. Results were similar in a sensitivity analysis restricted to patients fulfilling risk, injury, failure, loss, end-stage kidney disease-FAILURE criteria (37.0%; n = 446) (adj-OR 1.36; 95% CI, 0.70-2.66). In this cohort, reasons for not starting RRT included limitations of support and perception of impending renal recovery. Despite similar risk of mortality after adjusting for selection bias and confounders, RRT-treated patients were fundamentally different from non-treated patients across a spectrum of variables that precludes valid comparison in observational data.


Production and characterization of mammary-derived growth factor 1 in mammary epithelial cell lines.
A mammary-derived growth factor, MDGF1, which stimulates collagen synthesis and proliferation in mammary epithelial cells was previously detected and purified from human milk and primary human breast tumors. MDGF1 binds to putative cell-surface receptors of 120-140 kDa and stimulates proliferation of normal and malignant human mammary epithelial cells. Partial protein sequence (N-terminal 18 amino acid sequence) shows that MDGF1 has no homology to any other known growth-promoting peptides. Polyclonal antiserum raised against this synthetic peptide recognizes native milk-derived MDGF1. We hypothesize that MDGF1 might be an autocrine or paracrine factor produced by and acting on normal and malignant human breast epithelial cells possessing MDGF1 receptors. As a first step in testing this possibility, we examined whether human breast epithelial cells in culture produce the growth factor. A protein with the size of MDGF1 was immunologically detected in the concentrated conditioned medium prepared from human breast cancer cell line MDA-MB 231, the mammary-derived but nontumorigenic HBL-100 line, and the normal reduction mammoplasty-derived, nonimmortalized 184 cell strain. A competitive radioreceptor assay (RRA) was used to estimate the level of MDGF1 in the conditioned medium. MDGF1 was present in the nanogram range per 1 million cells. A 62-kDa protein was detected in the above cell lysates by Western immunoblotting or by immunoprecipitation of metabolically labeled cell-conditioned media. The polyclonal antisera directed against the 18 amino acid peptide sequence from milk-derived MDGF1 could adsorb MDGF1 biological activity from conditioned medium. In vitro translation of cell mRNA yielded a protein of 55 kDa which was immunoprecipitated by anti-MDGF1 antibody.(ABSTRACT TRUNCATED AT 250 WORDS)


Clinical development of gene therapy for colorectal cancer.
Colorectal cancer (CRC) is the second most common type of malignancy in Western nations. Improvements in surgical and radiotherapeutic techniques and the increased availability of new cytotoxic drugs have improved outcome, but 50% of patients still die from recurrent or metastatic disease. Several features of its natural history render CRC a good candidate for gene therapy. Techniques include gene replacement, virus-directed enzyme-prodrug therapy, immune manipulation and virotherapy, all of which have entered clinical trials.


Primary care physicians' perspectives on the prescription opioid epidemic.
Prescription opioid use disorder and overdose have risen substantially in the U.S. Primary care physicians are critical to many ongoing and proposed efforts to address the prescription opioid epidemic. Yet, little is known about their attitudes and beliefs surrounding this issue. This study aimed to determine primary care physicians' perceptions of the seriousness of the problem, its causes, groups responsible for addressing it, attitudes toward individuals with prescription opioid use disorder, beliefs about the effectiveness of addiction treatments, and support for various policies. We conducted a national web-based survey in 2014 among 1010 primary care physicians. We gauged responses to attitude and belief items on 7-point Likert scales. We examined the proportion agreeing with each statement, and whether responses differed among physicians prescribing higher and lower volumes of opioids. Respondents largely attributed the causes of prescription opioid use disorder to individual-oriented factors and certain physician-oriented factors, and believed that individuals with prescription opioid use disorder and physicians were primarily responsible for addressing the problem. Negative attitudes toward people with prescription opioid use disorder were prevalent, but a majority believed that treatment could be effective. There was majority support for all measured policies, with the highest levels of support for policies to monitor prescribing among patients potentially at risk for an opioid use disorder and to improve physician education and training. Given strong endorsement of recommended policies, physician support could be leveraged to advance efforts to curb prescription opioid use disorder and overdose.


Genetic Variation of the Mu Opioid Receptor (OPRM1) and Dopamine D2 Receptor (DRD2) is Related to Smoking Differences in Patients with Schizophrenia but not Bipolar Disorder.
It is not known why mentally ill persons smoke excessively. Inasmuch as endogenous opioid and dopaminergic systems are involved in smoking reinforcement, it is important to study mu opioid receptor (OPRM1) A118G (rs1799971), dopamine D2 receptor (DRD2) Taq1A (rs1800497) genotypes, and sex differences among patients with schizophrenia or bipolar disorder. Smokers and nonsmokers with schizophrenia (n=177) and bipolar disorder (n=113) were recruited and genotyped. They were classified into three groups: current smoker, former smoker, and never smoker by tobacco smoking status self-report. The number of cigarettes smoked per day was used as the major tobacco smoking parameter. In patients with schizophrenia, tobacco smoking prevalence was greater in males than in females as expected, but women had greater daily cigarette consumption (p<0.01). Subjects with schizophrenia who had the OPRM1 *G genotype smoked more cigarettes per day than the AA allele carriers with schizophrenia (p<0.05). DRD2 Taq1A genotype differences had no effect on the number of cigarettes smoked per day. However, female smokers with schizophrenia who were GG homozygous of the DRD2 receptor smoked more than the *A male smokers with schizophrenia (p<0.05). In bipolar patients, there were no OPRM1 and DRD2 Taq1A genotype differences in smoking status. There also were no sex differences for smoking behavior among the bipolar patients. The results of this study indicate that single nucleotide polymorphism (SNP) of the less functional mu opioid receptor increases tobacco smoking in patients with schizophrenia. Alteration of DRD2 receptor function also increased smoking behavior in females with schizophrenia.


Chromosomal abnormalities identify high-risk and low-risk patients with acute lymphoblastic leukemia.
The importance of banded chromosome analyses in predicting long-term outcome in acute lymphoblastic leukemia (ALL) was evaluated in this follow-up study of 329 patients from the Third International Workshop on Chromosomes in Leukemia. Patients were divided into ten groups according to pretreatment karyotype: no abnormalities, one of the following structural abnormalities [the Philadelphia chromosome, translocations involving 8q24,t(4;11), 14q+, 6q-] or, in the remaining cases, modal number [less than 46, 46, 47 to 50, greater than 50]. Achievement and duration of complete remission (CR) and survival differed among chromosome groups (P less than .0001). Karyotype was an independent prognostic factor for duration of first CR and survival, even when age, initial leukocyte count (WBC), French-American-British (FAB) type, and immunologic phenotype were considered. Among adults, prolonged remission and survival were uncommon in all chromosome groups. Only in the normal karyotype group was median survival even two years. Among children, striking differences in long-term remission and survival were seen depending upon karyotype. Children in the greater than 50 group did best, with 70% remaining in first CR for a median duration in excess of five years. Children in the 47-50, 6q-, and normal karyotype groups also had prolonged survivals. In contrast, certain translocations [t(9;22)(q34;q11), t(4;11)(q21;q14-23), t(8;14)(q24;q32)] identified children who had short survivals, even in the presence of favorable prognostic factors including a low WBC, L1 morphology, and non-T, non-B immunologic phenotype. We conclude that chromosome analysis is required at diagnosis in patients with ALL, and that children with these specific translocations should be managed as having high-risk ALL.


Sparse matrix approximation method for an active optical control system.
We develop a sparse matrix approximation method to decompose a wave front into a basis set of actuator influence functions for an active optical system consisting of a deformable mirror and a segmented primary mirror. The wave front used is constructed by Zernike polynomials to simulate the output of a phase-retrieval algorithm. Results of a Monte Carlo simulation of the optical control loop are compared with the standard, nonsparse approach in terms of accuracy and precision, as well as computational speed and memory. The sparse matrix approximation method can yield more than a 50-fold increase in the speed and a 20-fold reduction in matrix size and a commensurate decrease in required memory, with less than 10% degradation in solution accuracy. Our method is also shown to be better than when elements are selected for the sparse matrix on a magnitude basis alone. We show that the method developed is a viable alternative to use of the full control matrix in a phase-retrieval-based active optical control system.


Asthma--quality of life for Swedish children.
The purpose of this study was to describe how Swedish children with asthma experience their QoL and to search for possible associations between their experience of QoL and some determinants. Asthma is a chronic disorder that can restrict a child's life, physically, emotionally, socially and spiritually, and this has an impact on a child's quality of life (QoL). Two hundred and twenty-six children with asthma (37% girls and 63% boys) and 371 parents of these children participated in the study. The Paediatric Asthma Quality Of Life Questionnaire (PAQLQ) was used to measure the children's QoL. This questionnaire reveals how the children's asthma interferes with their normal activities, their symptoms and how this interference has made them feel. The findings show that most children with asthma estimated their QoL towards the positive end of the scale. The children reported more impairment in the domain of activities than in emotions and symptoms. The most commonly restricted activity was the children's ability to run. Significant associations were found between a higher QoL outcome and being a boy, as well as living in the south of Sweden. A higher QoL was also found in children with mothers older than 40 years of age and in children with cohabiting parents. It was also associated with their fathers' QoL in a positive direction. It is important that children with asthma will maintain a high QoL. In this study the children were being treated with asthma medication when they evaluated their QoL. Perhaps this fact might have influenced the results in a positive direction. The findings of our study underline the importance of accurate nursing assessment including background variables of the children. Nurses also have to be aware that some of the children in the study have a low QoL and these children must not be forgotten. In addition, as caring tends to focus on the patients' limitations, another important issue for nurses is to try to discover those aspects in a child's daily life that contribute to a high QoL in order to improve and maintain the child's wellbeing.


Faecal contamination of drinking water during collection and household storage: the need to extend protection to the point of use.
Paired water samples were collected and analysed for thermotolerant coliforms (TTC) from 20 sources (17 developed or rehabilitated by Oxfam and 3 others) and from the stored household water supplies of 100 households (5 from each source) in 13 towns and villages in the Kailahun District of Sierra Leone. In addition, the female head of the 85 households drawing water from Oxfam improved sources was interviewed and information recorded on demographics, hygiene instruction and practices, sanitation facilities and water collection and storage practices. At the non-improved sources, the arithmetic mean TTC load was 407/100 ml at the point of distribution, rising to a mean count of 882/100 ml at the household level. Water from the improved sources met WHO guidelines, with no faecal contamination. At the household level, however, even this safe water was subject to frequent and extensive faecal contamination; 92.9% of stored household samples contained some level of TTC, 76.5% contained more than the 10 TTC per 100 ml threshold set by the Sphere Project for emergency conditions. The arithmetic mean TTC count for all samples from the sampled households was 244 TTC per 100 ml (geometric mean was 77). These results are consistent with other studies that demonstrate substantial levels of faecal contamination of even safe water during collection, storage and access in the home. They point to the need to extend drinking water quality beyond the point of distribution to the point of consumption. The options for such extended protection, including improved collection and storage methods and household-based water treatment, are discussed.


Phase-dependent respiratory-motor interactions in reaction time tasks during rhythmic voluntary breathing.
The study investigated squeezing reaction time (RT) in response to a visual cue during rhythmic voluntary breathing at 0.6 Hz paced by a metronome, breath holding, or at rest in 13 healthy subjects. Rhythmic voluntary breathing slowed down RT, only in the expiratory phase with accompanied changes in the length of respiratory phases, while breath-holding reduced RT. The prolonged RT during voluntary expiratory phases and the absence of changes in RT during voluntary inspiratory phases are most likely related to disproportionally increased cognitive demands during the expiratory phase of voluntary breathing. The absence of changes in RT during voluntary inspiration is likely to be compensated by respiratory-motor facilitation mechanisms in this phase. Shortened RT during breath holding is possibly associated with increased attention.


Discovering biological networks from diverse functional genomic data.
Recent advances in biotechnology have produced a wealth of genomic data, which capture a variety of complementary cellular features. While these data promise to yield key insights into molecular biology, much of the available information remains underutilized because of the lack of scalable approaches for integrating signals across large, diverse data sets. A proper framework for capturing these numerous snapshots of complementary phenomena under a variety of conditions can provide the holistic view necessary for developing precise systems-level hypotheses. Here we describe bioPIXIE, a system for combining information from diverse genomic data sets to predict biological networks. bioPIXIE utilizes a Bayesian framework for probabilistic integration of several high-throughput genomic data types including gene expression, protein-protein interactions, genetic interactions, protein localization, and sequence data to predict biological networks. The main purpose of the system is to support user-driven exploration through the inferred functional network, which is enabled by a public, web-based interface. We describe the features and supporting methods of this integration and discovery framework and present case examples where bioPIXIE has been used to generate specific, testable hypotheses for Saccharomyces cerevisiae, many of which have been confirmed experimentally.


The association of clinical frailty with outcomes of patients reviewed by rapid response teams: an international prospective observational cohort study.
Frailty is a state of vulnerability to poor resolution of homeostasis after a stressor event and is strongly associated with adverse outcomes. Therefore, the assessment of frailty may be an essential part of evaluation in any healthcare encounter that might result in an escalation of care. The purpose of the study was to assess the frequency and association of frailty with clinical outcomes in patients subject to rapid response team (RRT) review. In this multi-national prospective observational cohort study, centres with existing RRTs collected data over a 7-day period, with follow up of all patients at 24 h following their RRT call and at hospital discharge or 30 days following the event trigger (whichever came sooner). Investigators also collected data on the triggers and interventions provided and a bedside assessment on the level of patients' frailty using a clinical frailty scale. Amongst 1133 patients, 40% were screened as frail, which was associated with older age (p < 0.001), admission under a medical speciality (p < 0.001), increased severity of illness at the time of the RRT review (p = 0.0047), and substantially higher frequency of limitations of care (p < 0.001). Importantly, 72% of patients screened as frail were either dead or dependent on hospital care by 30 days (p < 0.001). In the multivariable analysis, the significant risk factors for the composite endpoint "poor recovery" (died or were hospital-dependent by 30 days) were age (odds ratio (OR), 1.04; 95% confidence interval (CI), 1.03-1.05; p < 0.001), frailty level (p < 0.001), existing limitation of care (OR, 2.0; 95% CI, 1.3-3.0; p < 0.001), and the quick sequential organ failure assessment (qSOFA) score (p < 0.001). Higher frailty scores were associated with increased mortality and dependence on health care at 30 days. Our results indicate that frailty has an influence on the clinical trajectory of deteriorating patients and that such assessment should be included in discussion of goals and expectations of care. Netherlands Trial Registry, NTR5535 . Registered on 23 December 2015.


Altered kynurenine pathway metabolites in serum of chronic migraine patients.
Activation of glutamate (Glu) receptors plays a key role in the pathophysiology of migraine. Both NMDA and metabotropic Glu receptors are activated or inhibited by metabolites of the kynurenine pathway, such as kynureninic acid (KYNA), quinolinic acid (QUINA), and xanthurenic acid (XA). In spite of the extensive research carried out on KYNA and other kynurenine metabolites in experimental models of migraine, no studies have ever been carried out in humans. Here, we measured all metabolites of the kynurenine pathway in the serum of patients affected by chronic migraine (CM) and age- and gender-matched healthy controls. We assessed serum levels of tryptophan (Trp), L-kynurenine (KYN), KYNA, anthranilic acid (ANA), 3-hydroxyanthranilic acid (3-HANA), 3-hydroxykynirenine (3-HK), XA, QUINA, and 5-hydroxyindolacetic acid (5-HIAA) in 119 patients affected by CM (ICHD-3beta criteria) and 84 age-matched healthy subjects. Patients with psychiatric co-morbidities, systemic inflammatory, endocrine or neurological disorders, and mental retardation were excluded. Serum levels of all metabolites were assayed using liquid chromatography/tandem mass spectrometry (LC-MS/MS). LC-MS/MS analysis of kynurenine metabolites showed significant reductions in the levels of KYN (-32 %), KYNA (-25 %), 3-HK (-49 %), 3-HANA (-63 %), 5-HIAA (-36 %) and QUINA (-80 %) in the serum of the CM patients, as compared to healthy controls. Conversely, levels of Trp, ANA and XA were significantly increased in CM patients (+5 %, +339 % and +28 %, respectively). These findings suggest that in migraine KYN is unidirectionally metabolized into ANA at expenses of KYNA and 3-HK. The reduction in the levels of KYNA, which behaves as a competitive antagonist of the glycine site of NMDA receptors, is consistent with the hypothesis that NMDA receptors are overactive in migraine. The increase in XA, a putative activator of Glu2 receptors, may represent a compensatory event aimed at reinforcing endogenous analgesic mechanisms. The large increase in the levels of ANA encourages research aimed at establishing whether ANA has any role in the regulation of nociceptive transmission.


Insertion and assembly of human tom7 into the preprotein translocase complex of the outer mitochondrial membrane.
Tom7 is a component of the translocase of the outer mitochondrial membrane (TOM) and assembles into a general import pore complex that translocates preproteins into mitochondria. We have identified the human Tom7 homolog and characterized its import and assembly into the mammalian TOM complex. Tom7 is imported into mitochondria in a nucleotide-independent manner and is anchored to the outer membrane with its C terminus facing the intermembrane space. Unlike studies in fungi, we found that human Tom7 assembles into an approximately 120-kDa import intermediate in HeLa cell mitochondria. To detect subunits within this complex, we employed a novel supershift analysis whereby mitochondria containing newly imported Tom7 were incubated with antibodies specific for individual TOM components prior to separation by blue native electrophoresis. We found that the 120-kDa complex contains Tom40 and lacks receptor components. This intermediate can be chased to the stable approximately 380-kDa mammalian TOM complex that additionally contains Tom22. Overexpression of Tom22 in HeLa cells results in the rapid assembly of Tom7 into the 380-kDa complex indicating that Tom22 is rate-limiting for TOM complex formation. These results indicate that the levels of Tom22 within mitochondria dictate the assembly of TOM complexes and hence may regulate its biogenesis.


Biosorption of heavy metal ions from aqueous solution by red macroalgae.
Biosorption is an effective process for the removal and recovery of heavy metal ions from aqueous solutions. The biomass of marine algae has been reported to have high biosorption capacities for a number of heavy metal ions. In this study, four species of red seaweeds Corallina mediterranea, Galaxaura oblongata, Jania rubens and Pterocladia capillacea were examined to remove Co(II), Cd(II), Cr(III) and Pb(II) ions from aqueous solution. The experimental parameters that affect the biosorption process such as pH, contact time and biomass dosage were studied. The maximum biosorption capacity of metal ions was 105.2mg/g at biomass dosage 10 g/L, pH 5 and contact time 60 min. The biosorption efficiency of algal biomass for the removal of heavy metal ions from industrial wastewater was evaluated for two successive cycles. Galaxaura oblongata biomass was relatively more efficient to remove metal ions with mean biosorption efficiency of 84%. This study demonstrated that these seaweeds constitute a promising, efficient, cheap and biodegradable sorbent biomaterial for lowering the heavy metal pollution in the environment.


Decision trees in epidemiological research.
In many studies, it is of interest to identify population subgroups that are relatively homogeneous with respect to an outcome. The nature of these subgroups can provide insight into effect mechanisms and suggest targets for tailored interventions. However, identifying relevant subgroups can be challenging with standard statistical methods. We review the literature on decision trees, a family of techniques for partitioning the population, on the basis of covariates, into distinct subgroups who share similar values of an outcome variable. We compare two decision tree methods, the popular Classification and Regression tree (CART) technique and the newer Conditional Inference tree (CTree) technique, assessing their performance in a simulation study and using data from the Box Lunch Study, a randomized controlled trial of a portion size intervention. Both CART and CTree identify homogeneous population subgroups and offer improved prediction accuracy relative to regression-based approaches when subgroups are truly present in the data. An important distinction between CART and CTree is that the latter uses a formal statistical hypothesis testing framework in building decision trees, which simplifies the process of identifying and interpreting the final tree model. We also introduce a novel way to visualize the subgroups defined by decision trees. Our novel graphical visualization provides a more scientifically meaningful characterization of the subgroups identified by decision trees. Decision trees are a useful tool for identifying homogeneous subgroups defined by combinations of individual characteristics. While all decision tree techniques generate subgroups, we advocate the use of the newer CTree technique due to its simplicity and ease of interpretation.