An economic analysis of continuous positive airway pressure for the treatment of obstructive sleep apnea-hypopnea syndrome.
An important option for the medical treatment of obstructive sleep apnea-hypopnea syndrome (OSAHS) is continuous positive airway pressure (CPAP) during sleep. This study reports on the cost-effectiveness of CPAP compared with dental devices and lifestyle advice. The work was commissioned by the NHS HTA Programme to inform the National Institute of Health and Clinical Excellence's (NICE) appraisal of CPAP. A Markov model compared the interventions over the expected patient lifetime. The primary measure of cost-effectiveness was the incremental cost per quality-adjusted life-year (QALY) gained. The QALY incorporated the impact of treatments on daytime sleepiness, blood pressure and health-related quality of life (HRQoL). On average, CPAP was associated with higher costs and QALYs compared with dental devices or lifestyle advice. In the base-case analysis, the incremental cost-effectiveness ratio (ICER) for CPAP compared with dental devices was around 4,000 pounds per QALY (2005--06 prices). The probability that CPAP is more cost-effective than dental devices or lifestyle advice at a threshold value of 20,000 pounds per QALY was 0.78 for men and 0.80 for women. Several sensitivity analyses were undertaken and it was found that the ICER for CPAP consistently fell below 20,000 pounds per QALY gained, apart from in a subgroup with mild disease. The model suggests that CPAP is cost-effective compared with dental devices and lifestyle advice for adults with moderate or severe symptomatic OSAHS at the cost-effectiveness thresholds used by NICE. This finding is reflected in the NICE guidance.


The ERβ ligand 5α-androstane, 3β,17β-diol (3β-diol) regulates hypothalamic oxytocin (Oxt) gene expression.
The endocrine component of the stress response is regulated by glucocorticoids and sex steroids. Testosterone down-regulates hypothalamic-pituitary-adrenal (HPA) axis activity; however, the mechanisms by which it does so are poorly understood. A candidate testosterone target is the oxytocin gene (Oxt), given that it too inhibits HPA activity. Within the paraventricular nucleus of the hypothalamus, oxytocinergic neurons involved in regulating the stress response do not express androgen receptors but do express estrogen receptor-β (ERβ), which binds the dihydrotestosterone metabolite 3β,17β-diol (3β-diol). Testosterone regulation of the HPA axis thus appears to involve the conversion to the ERβ-selective ligand 5α-androstane, 3β-diol. To study mechanisms by which 3β-diol could regulate Oxt expression, we used a hypothalamic neuronal cell line derived from embryonic mice that expresses Oxt constitutively and compared 3β-diol with estradiol (E2) effects. E2 and 3β-diol elicited a phasic response in Oxt mRNA levels. In the presence of either ligand, Oxt mRNA levels were increased for at least 60 min and returned to baseline by 2 h. ERβ occupancy preceded an increase in Oxt mRNA levels in the presence of 3β-diol but not E2. In tandem with ERβ occupancy, 3β-diol increased occupancy of the Oxt promoter by cAMP response element-binding protein and steroid receptor coactivator-1 at 30 min. At the same time, 3β-diol led to the increased acetylation of histone H4 but not H3. Taken together, the data suggest that in the presence of 3β-diol, ERβ associates with cAMP response element-binding protein and steroid receptor coactivator-1 to form a functional complex that drives Oxt gene expression.


Green, orange, and red Pr(3+)∶YLiF(4) epitaxial waveguide lasers.
Efficient guided laser oscillation in the visible spectral region is demonstrated with praseodymium-doped YLiF(4) layers grown by liquid phase epitaxy. By exciting Pr(3+) ions at 479.2 nm with an optically pumped semiconductor laser, maximum slope efficiencies of 40% at 639 nm and 32% at 604 nm are obtained in a cw regime. Green laser oscillation at 522.5 nm, in a quasi-cw regime, with an average output power of 66 mW, is demonstrated for the first time, to our knowledge, in a crystalline fluoride epitaxial waveguide. Furthermore, a record efficiency of 60% at 639 nm in the quasi-cw regime is reported.


Radiation-induced lower cranial nerve palsy in patients with head and neck carcinoma.
Radiation-induced cranial nerve palsy (RICNP) is a severe long-term complication in patients with head and neck cancer following high-dose radiation therapy (RT). We present the case report of a patient with bilateral RICNP of the hypoglossal and vagus cranial nerves (XII/X) following postoperative RT in the era prior to the introduction of intensity-modulated RT (IMRT), and an analysis of our IMRT patient cohort at risk including the case of a XII RICNP. A total of 201 patients whose glosso-pharyngeal (IX), X and XII cranial nerves had been exposed to >65 Gy definitive IMRT in our institution between January, 2002 and December, 2012 with or without systemic therapy, were retrospectively identified. A total of 151 patients out of 201 fulfilling the following criteria were included in the analysis: Locoregionally controlled disease, with a follow-up (FU) of >24 months and >65 Gy exposure of the nerves of interest. So far, one of the assessed 151 IMRT patients at risk exhibited symptoms of RICNP after 6 years. The mean/median FU of the entire cohort was 71/68 months (range, 27-145). The results were compared with literature reports. In conclusion, RICNP appears to be a rare complication. However, a longer FU and a larger sample size are required to draw reliable conclusions on the incidence of RICNP in the era of IMRT.


Electrophysiological Characterization of Networks and Single Cells in the Hippocampal Region of a Transgenic Rat Model of Alzheimer's Disease.
The hippocampus and entorhinal cortex (EC) are areas affected early and severely in Alzheimer's disease (AD), and this is associated with deficits in episodic memory. Amyloid-β (Aβ), the main protein found in amyloid plaques, can affect neuronal physiology and excitability, and several AD mouse models with memory impairments display aberrant network activity, including hyperexcitability and seizures. In this study, we investigated single cell physiology in EC and network activity in EC and dentate gyrus (DG) in the McGill-R-Thy1-APP transgenic rat model, using whole-cell patch clamp recordings and voltage-sensitive dye imaging (VSDI) in acute slices. In slices from transgenic animals up to 4 months of age, the majority of the principal neurons in Layer II of EC, fan cells and stellate cells, expressed intracellular Aβ (iAβ). Whereas the electrophysiological properties of fan cells were unaltered, stellate cells were more excitable in transgenic than in control rats. Stimulation in the DG resulted in comparable patterns in both groups at three and nine months, but at 12 months, the elicited responses in the transgenic group showed a significant preference for the enclosed blade, without any change in overall excitability. Only transient changes in the local network activity were seen in the medial EC (MEC). Although the observed changes in the McGill rat model are subtle, they are specific, pointing to a differential and selective involvement of specific parts of the hippocampal circuitry in Aβ pathology.


Latrepirdine: molecular mechanisms underlying potential therapeutic roles in Alzheimer's and other neurodegenerative diseases.
Latrepirdine (Dimebon(TM)) was originally marketed as a non-selective antihistamine in Russia. It was repurposed as an effective treatment for patients suffering from Alzheimer's disease (AD) and Huntington's disease (HD) following preliminary reports showing its neuroprotective functions and ability to enhance cognition in AD and HD models. However, latrepirdine failed to show efficacy in phase III trials in AD and HD patients following encouraging phase II trials. The failure of latrepirdine in the clinical trials has highlighted the importance of understanding the precise mechanism underlying its cognitive benefits in neurodegenerative diseases before clinical evaluation. Latrepirdine has shown to affect a number of cellular functions including multireceptor activity, mitochondrial function, calcium influx and intracellular catabolic pathways; however, it is unclear how these properties contribute to its clinical benefits. Here, we review the studies investigating latrepirdine in cellular and animal models to provide a complete evaluation of its mechanisms of action in the central nervous system. In addition, we review recent studies that demonstrate neuroprotective functions for latrepirdine-related class of molecules including the β-carbolines and aminopropyl carbazoles in AD, Parkinson's disease and amyotrophic lateral sclerosis models. Assessment of their neuroprotective effects and underlying biological functions presents obvious value for developing structural analogues of latrepirdine for dementia treatment.


Paramagnetic Phospholipid-Based Micelles Targeting VCAM-1 Receptors for MRI Visualization of Inflammation.
Inflammation is signaled by the overexpression of epitopes on the vascular endothelium that primarily aim at recruiting immune cells into the inflamed area. The intravascular localization of these biomarkers makes them suitable targets for the MRI visualization of inflammation. Phospholipid-based nanosystems appear excellent candidates in virtue of their good biocompatibility, ability to deliver a high number of imaging units at the target site, and for the easy functionalization with targeting vectors. In this work, phospholipid-based micelles (hydrodynamic diameter of 20 nm) loaded with the amphiphilic Gd(III)-complex Gd-DOTAMA(C18)2 were vectorized with a small peptide able to specifically bind VCAM-1 receptors. The micelles displayed a high longitudinal relaxivity (36.4 s(-1)mmolGd(-1) at 25 °C and 0.7 T). A (1)H- and (17)O-water relaxometry study indicated that the paramagnetic complex embedded in the nanoparticles adopted two isomeric conformations, likely reflecting the well-known square antiprismatic (SAP) and twisted square antiprismatic (TSAP) configurations typically observed in DOTA-like lanthanide complexes. Interestingly, the TSAP structure, showing a much faster exchange rate for the water molecule coordinated to the metal ion, was the most abundant, thus explaining the high relaxivity of the micellar agent. The systemic administration of the micelles into a lipopolysaccharide-induced murine model of acute inflammation successfully demonstrated the ability of the targeting agents to detect the diseased area by T1 contrast enhanced MRI.


Towards minimal perturbations in transitional plane Couette flow.
For parallel shear flows, transition to turbulence occurs only for perturbations of sufficiently large amplitude. It is therefore relevant to study the shape, amplitude, and dynamics of the least energetic initial disturbances leading to transition. We suggest a numerical approach to find such minimal perturbations, applied here to the case of plane Couette flow. The optimization method seeks such perturbations at initial time as a linear combination of a finite number of linear optimal modes. The energy threshold of the minimal perturbation for a Reynolds number Re=400 is only 2% less than for a pair of symmetric oblique waves. The associated transition scenario shows a long transient approach to a steady state solution with special symmetries. Modal analysis shows how the oblique-wave mechanism can be optimized by the addition of other oblique modes breaking the flow symmetry and whose nonlinear interaction generates spectral components of the edge state. The Re dependence of energy thresholds is revisited, with evidence for a O(Re(-2)) -scaling for both oblique waves and streamwise vortices scenarios.


A survey of first-year biology student opinions regarding live lectures and recorded lectures as learning tools.
A cohort of first-year biology students was surveyed regarding their opinions and viewing habits for live and recorded lectures. Most respondents (87%) attended live lectures as a rule (attenders), with 66% attending more than two-thirds of the lectures. In contrast, only 52% accessed recordings and only 13% viewed more than two-thirds of the available recordings. Respondents regarded lectures as efficient for information delivery (75%), and 89% enjoyed live lectures because they were useful for learning (89%), understanding coursework (94%), and keeping up with the subject (93%). Lecture enjoyment was driven less by entertainment (34%) or interaction with the lecturers (47%), although most students preferred an entertaining lecturer to a factual expert (72%). Exam marks were positively correlated with the number of lectures attended (P < 0.001) and negatively correlated with the number of recordings viewed (P < 0.05), although marks were similar for lecture attenders and nonattenders (P > 0.05). Lecture attenders mostly missed lectures to complete assessments during the same week (68%), whereas nonattenders were more likely to miss lectures due to outside commitments or preference for study from books or recorded lectures (P < 0.001). Recordings were used to replace missed lectures (64%), rather than for revision, and were viewed mostly alone (96%) in one sitting (65%). Only 22% of respondents agreed that some lectures could be replaced by recordings, but 59% agreed with having some videoconference lectures from experts on another campus. Overall, this cohort showed a clear preference for live lectures over recordings, with limited support for synchronous videoconference lectures.


Short communication: HIV type 1 subtype C variants transmitted through the bottleneck of breastfeeding are sensitive to new generation broadly neutralizing antibodies directed against quaternary and CD4-binding site epitopes.
Mother-to-child transmission of HIV-1 subtype C can occur in utero, intrapartum, or via breast milk exposure. While not well understood, there are putative differences in the mechanisms involved with the distinct routes of vertical HIV transmission. Here, we address the question of whether specific viral characteristics are common to variants transmitted through breastfeeding that may facilitate evasion of innate or adaptive immune responses. We amplified the envelope gene (env) from the plasma of six infants during acute infection who were infected with HIV-1 subtype C through breastfeeding, and from three available matched maternal samples. We sequenced the full-length env genes in these subjects revealing heterogeneous viral populations in the mothers and homogeneous populations in the infants. In five infants, the viral population arose from a single variant, while two variants were detected in the remaining infant. Infant env sequences had fewer N-linked glycosylation sites and shorter sequences than those of the available matched maternal samples. Though the small size of the study precluded our ability to test statistical significance, these results are consistent with selection for virus with shorter variable loops and fewer glycosylation sites during transmission of HIV-1 subtype C in other settings. Transmitted envs were resistant to neutralization by antibodies 2G12 and 2F5, but were generally sensitive to the more broadly neutralizing PG9, PG16, and VRC01, indicating that this new generation of broadly neutralizing monoclonal antibodies could be efficacious in passive immunization strategies.


The Dynamics of Wealth Inequality and the Effect of Income Distribution.
The rapid increase of wealth inequality in the past few decades is one of the most disturbing social and economic issues of our time. Studying its origin and underlying mechanisms is essential for policy aiming to control and even reverse this trend. In that context, controlling the distribution of income, using income tax or other macroeconomic policy instruments, is generally perceived as effective for regulating the wealth distribution. We provide a theoretical tool, based on the realistic modeling of wealth inequality dynamics, to describe the effects of personal savings and income distribution on wealth inequality. Our theoretical approach incorporates coupled equations, solved using iterated maps to model the dynamics of wealth and income inequality. Notably, using the appropriate historical parameter values we were able to capture the historical dynamics of wealth inequality in the United States during the course of the 20th century. It is found that the effect of personal savings on wealth inequality is substantial, and its major decrease in the past 30 years can be associated with the current wealth inequality surge. In addition, the effect of increasing income tax, though naturally contributing to lowering income inequality, might contribute to a mild increase in wealth inequality and vice versa. Plausible changes in income tax are found to have an insignificant effect on wealth inequality, in practice. In addition, controlling the income inequality, by progressive taxation, for example, is found to have a very small effect on wealth inequality in the short run. The results imply, therefore, that controlling income inequality is an impractical tool for regulating wealth inequality.


Brokering orientations and social capital: Influencing others' relationships shapes status and trust.
Individuals often influence others' relationships, for better or worse. We conceptualize social influence processes that impact others' social networks as brokering, and advance a multifaceted model that explains how brokering behaviors can create, terminate, reinforce, and modify others' network ties. To empirically study brokering, we introduce and validate the Brokering Orientations Scale (BOS), a multidimensional measure that captures individuals' behavioral tendencies to act as intermediaries, conciliators, and dividers. Six studies (N = 1,723) explored the psychometric properties of the BOS (Studies 1a-c) and investigated the effects of distinct forms of brokering on brokers' social capital (Studies 2-4). The intermediary, conciliatory and divisive brokering orientations related differently to extraversion, agreeableness, perspective-taking, moral identity, and Machiavellianism, among other individual differences. The effects of brokering on social capital varied as a function of the brokering orientation and the aspect of social capital. Intermediary behavior garnered status; conciliatory behavior promoted trust and prestige; and divisive behavior fueled brokers' perceived dominance. Overall, the current article elucidates the concept of brokering orientations, introduces a novel measure of brokering orientations, and explains how brokering behavior shapes brokers' social capital. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Nutrition Information in Oncology - Extending the Electronic Patient-Record Data Set.
Electronic health records (EHRs) present extensive patient information and may be used as a tool to improve health care. However, the oncology context presents a complex content that increases the difficulties of EHR application. This study aimed at developing openEHR-archetypes representing clinical concepts in cancer nutrition-care, as well as to develop an openEHR-template including the aforementioned archetypes. The study involved the following stages: 1) a thorough literature review, followed by an expert's (nutrition guideline authors) survey, aiming to identify the main statements of published clinical guidelines on nutrition in cancer patients that were not included on the Clinical Knowledge Manager (CKM) repository; 2) modelling of the archetypes using the Ocean Archetype Software and submission to the CKM repository; 3) creating an example template with Template Designer; and 4) automatic conversion of the openEHR-template into a readily usable EHR using VCIntegrator. The clinical concepts (among 17 clinical concepts not yet available in the CKM repository) chosen for further development were: body composition, diet plan, dietary nutrients, dietary supplements, dietary intake assessment, and Malnutrition Screening Tool (MST). So far, four archetypes were accepted for review in the CKM repository and a template was created and converted into an EHR. This study designed new openEHR-archetypes for nutrition management in cancer patients. These archetypes can be included in EHR. Future studies are needed to assess their applicability in other areas and their practical impact on data quality, system interoperability and, ultimately, on clinical practice and research.


Radiological findings in an ancient Iranian salt mummy (Chehrābād ca. 410-350 BC).
To study pathologies, peri- and postmortal alterations as well as the general preservation state of an ancient Iranian salt mummy. Several mummified remains from two different time periods (1500-2500 BP) were found in the Chehrābād salt mine in Iran. Computed tomography was performed on Salt Man #4 (410-350 BC), the best preserved out of the six salt mummies (Siemens, Sensation 16; 512 × 512 matrix; 0.75-5 mm slice thickness, 240-mA tube current, 120-kV tube voltage, and 0.976-mm pixel size). Radiological analyses showed an excellent state of preservation of an adolescent body. Several normal variants such as aplasia of the frontal sinus as well as a rare congenital deformation of the 5th vertebral body (butterfly vertebra) have been observed. The individual shows multiple fractures, which is consistent with the theory that he died due to a collapse in the ancient salt mine. The salt preserved the soft tissue as well as parts of the inner organs remarkably well. However, further investigations including histology are needed to reveal additional details of the health status of this unique salt mummy.


Rapid cloud removal of dimethyl sulfide oxidation products limits SO2 and cloud condensation nuclei production in the marine atmosphere.
Oceans emit large quantities of dimethyl sulfide (DMS) to the marine atmosphere. The oxidation of DMS leads to the formation and growth of cloud condensation nuclei (CCN) with consequent effects on Earth's radiation balance and climate. The quantitative assessment of the impact of DMS emissions on CCN concentrations necessitates a detailed description of the oxidation of DMS in the presence of existing aerosol particles and clouds. In the unpolluted marine atmosphere, DMS is efficiently oxidized to hydroperoxymethyl thioformate (HPMTF), a stable intermediate in the chemical trajectory toward sulfur dioxide (SO2) and ultimately sulfate aerosol. Using direct airborne flux measurements, we demonstrate that the irreversible loss of HPMTF to clouds in the marine boundary layer determines the HPMTF lifetime (τHPMTF < 2 h) and terminates DMS oxidation to SO2 When accounting for HPMTF cloud loss in a global chemical transport model, we show that SO2 production from DMS is reduced by 35% globally and near-surface (0 to 3 km) SO2 concentrations over the ocean are lowered by 24%. This large, previously unconsidered loss process for volatile sulfur accelerates the timescale for the conversion of DMS to sulfate while limiting new particle formation in the marine atmosphere and changing the dynamics of aerosol growth. This loss process potentially reduces the spatial scale over which DMS emissions contribute to aerosol production and growth and weakens the link between DMS emission and marine CCN production with subsequent implications for cloud formation, radiative forcing, and climate.


A unified model of spatial and episodic memory.
Medial temporal lobe structures including the hippocampus are implicated by separate investigations in both episodic memory and spatial function. We show that a single recurrent attractor network can store both the discrete memories that characterize episodic memory and the continuous representations that characterize physical space. Combining both types of representation in a single network is actually necessary if objects and where they are located in space must be stored. We thus show that episodic memory and spatial theories of medial temporal lobe function can be combined in a unified model.


Total en bloc spondylectomy for spinal metastasis of differentiated thyroid cancers: a long-term follow-up.
A retrospective case series. To evaluate the long-term effectiveness and problems of total en bloc spondylectomy (TES) for treating metastatic thyroid cancer of the spine. Although TES is indicated for low-grade malignant spinal tumors, its efficacy in treating thyroid cancer metastases in the spine is uncertain. This study followed 8 patients who underwent TES for spinal metastasis of thyroid cancer (5 males, 3 females; mean age, 55.3 y; mean follow-up period, 6.4 y), 6 with follicular carcinomas and 2 with papillary carcinomas. In 6 patients without a marked paravertebral tumor extension, TES was performed using a posterior approach. Two patients had prominent anterior or anterolateral tumor extension into the thoracic and retroperitoneal cavities, and a combined anterior and posterior approach was used. We evaluated the patients' clinical symptoms, operative procedures, complications, and prognoses. Before surgery, the patients' neurological status was evaluated by the Frankel classification (grade C, 4 patients; grade D, 1 patient; grade E, 3 patients) and Tokuhashi scores (9, 1 patient; 11, 2 patients; 13 and 14, 1 patient each; 15, 3 patients). One year after surgery, all the patients had improved by at least a Frankel grade, and 4 patients classified as grade C before surgery had become ambulatory. At the final follow-up (average of 6.4 y), 5 patients had a grade E Frankel classification and 1 had grade D, but 2 patients had suffered neurological deterioration, because of tumor recurrence, at the same level as the TES in one patient and at an adjacent level in the other. At follow-up, all patients were alive; 5 showed no evidence of disease. Two patients experienced rod breakage, at 2.8 and at 3.3 years after TES, and 1 patient suffered an endplate fracture 6 months after TES; this patient developed a late infection, 7 years after TES. TES was effective in controlling spinal thyroid cancer metastasis locally and in preserving the ability to walk. However, instrumentation failure and other late complications arose during the patients' long survival times after TES.


Urinary incontinence and use of pads--clinical features and need for help in home care at 11 sites in Europe.
The aim of this study was to obtain evidenced-based knowledge about older persons in home care; we conducted a population-based study at 11 sites in Europe (2001/2002). This article focuses on urinary incontinence and need for help in home care. A sample of 4010 respondents 65 years or older were assessed by the Resident Assessment Instrument for Home Care. Urinary incontinence was defined as leakage once a week or more including use of catheters. A total of 1478 individuals had urinary incontinence, 45% men and 47% women. The use of pads ran from 29% to 52% between the sites. The associates of urinary incontinence were: moderate or severe cognitive impairment, dependency in toileting and other activities of daily living compared with less impaired; urinary infections, obesity and faecal incontinence. Caregivers to persons with urinary incontinence reported burden or stress more often then carers to nonurinary incontinence individuals (OR = 2.2, 95% CI 1.8-2.7). To enable older people with incontinence to stay at home with a better quality of life, they need caring assistance during toileting on a regular basis.


Dopamine Replacement Therapy, Learning and Reward Prediction in Parkinson's Disease: Implications for Rehabilitation.
The principal feature of Parkinson's disease (PD) is the impaired ability to acquire and express habitual-automatic actions due to the loss of dopamine in the dorsolateral striatum, the region of the basal ganglia associated with the control of habitual behavior. Dopamine replacement therapy (DRT) compensates for the lack of dopamine, representing the standard treatment for different motor symptoms of PD (such as rigidity, bradykinesia and resting tremor). On the other hand, rehabilitation treatments, exploiting the use of cognitive strategies, feedbacks and external cues, permit to "learn to bypass" the defective basal ganglia (using the dorsolateral area of the prefrontal cortex) allowing the patients to perform correct movements under executive-volitional control. Therefore, DRT and rehabilitation seem to be two complementary and synergistic approaches. Learning and reward are central in rehabilitation: both of these mechanisms are the basis for the success of any rehabilitative treatment. Anyway, it is known that "learning resources" and reward could be negatively influenced from dopaminergic drugs. Furthermore, DRT causes different well-known complications: among these, dyskinesias, motor fluctuations, and dopamine dysregulation syndrome (DDS) are intimately linked with the alteration in the learning and reward mechanisms and could impact seriously on the rehabilitative outcomes. These considerations highlight the need for careful titration of DRT to produce the desired improvement in motor symptoms while minimizing the associated detrimental effects. This is important in order to maximize the motor re-learning based on repetition, reward and practice during rehabilitation. In this scenario, we review the knowledge concerning the interactions between DRT, learning and reward, examine the most impactful DRT side effects and provide suggestions for optimizing rehabilitation in PD.


Volumetric quantification of lung nodules in CT with iterative reconstruction (ASiR and MBIR).
Volume quantifications of lung nodules with multidetector computed tomography (CT) images provide useful information for monitoring nodule developments. The accuracy and precision of the volume quantification, however, can be impacted by imaging and reconstruction parameters. This study aimed to investigate the impact of iterative reconstruction algorithms on the accuracy and precision of volume quantification with dose and slice thickness as additional variables. Repeated CT images were acquired from an anthropomorphic chest phantom with synthetic nodules (9.5 and 4.8 mm) at six dose levels, and reconstructed with three reconstruction algorithms [filtered backprojection (FBP), adaptive statistical iterative reconstruction (ASiR), and model based iterative reconstruction (MBIR)] into three slice thicknesses. The nodule volumes were measured with two clinical software (A: Lung VCAR, B: iNtuition), and analyzed for accuracy and precision. Precision was found to be generally comparable between FBP and iterative reconstruction with no statistically significant difference noted for different dose levels, slice thickness, and segmentation software. Accuracy was found to be more variable. For large nodules, the accuracy was significantly different between ASiR and FBP for all slice thicknesses with both software, and significantly different between MBIR and FBP for 0.625 mm slice thickness with Software A and for all slice thicknesses with Software B. For small nodules, the accuracy was more similar between FBP and iterative reconstruction, with the exception of ASIR vs FBP at 1.25 mm with Software A and MBIR vs FBP at 0.625 mm with Software A. The systematic difference between the accuracy of FBP and iterative reconstructions highlights the importance of extending current segmentation software to accommodate the image characteristics of iterative reconstructions. In addition, a calibration process may help reduce the dependency of accuracy on reconstruction algorithms, such that volumes quantified from scans of different reconstruction algorithms can be compared. The little difference found between the precision of FBP and iterative reconstructions could be a result of both iterative reconstruction's diminished noise reduction at the edge of the nodules as well as the loss of resolution at high noise levels with iterative reconstruction. The findings do not rule out potential advantage of IR that might be evident in a study that uses a larger number of nodules or repeated scans.


Anxiety selectively disrupts visuospatial working memory.
On the basis of a review of the extant literature describing emotion-cognition interactions, the authors propose 4 methodological desiderata for studying how task-irrelevant affect modulates cognition and present data from an experiment satisfying them. Consistent with accounts of the hemispheric asymmetries characterizing withdrawal-related negative affect and visuospatial working memory (WM) in prefrontal and parietal cortices, threat-induced anxiety selectively disrupted accuracy of spatial but not verbal WM performance. Furthermore, individual differences in physiological measures of anxiety statistically mediated the degree of disruption. A second experiment revealed that individuals characterized by high levels of behavioral inhibition exhibited more intense anxiety and relatively worse spatial WM performance in the absence of threat, solidifying the authors' inference that anxiety causally mediates disruption. These observations suggest a revision of extant models of how anxiety sculpts cognition and underscore the utility of the desiderata.


A planktonic diatom displays genetic structure over small spatial scales.
Marine planktonic microalgae have potentially global dispersal, yet reduced gene flow has been confirmed repeatedly for several species. Over larger distances (>200 km) geographic isolation and restricted oceanographic connectivity have been recognized as instrumental in driving population divergence. Here we investigated whether similar patterns, that is, structured populations governed by geographic isolation and/or oceanographic connectivity, can be observed at smaller (6-152 km) geographic scales. To test this we established 425 clonal cultures of the planktonic diatom Skeletonema marinoi collected from 11 locations in the Archipelago Sea (northern Baltic Sea). The region is characterized by a complex topography, entailing several mixing regions of which four were included in the sampling area. Using eight microsatellite markers and conventional F-statistics, significant genetic differentiation was observed between several sites. Moreover, Bayesian cluster analysis revealed the co-occurrence of two genetic groups spread throughout the area. However, geographic isolation and oceanographic connectivity could not explain the genetic patterns observed. Our data reveal hierarchical genetic structuring whereby despite high dispersal potential, significantly diverged populations have developed over small spatial scales. Our results suggest that biological characteristics and historical events may be more important in generating barriers to gene flow than physical barriers at small spatial scales.


Accounting for Taste: A Multi-Attribute Neurocomputational Model Explains the Neural Dynamics of Choices for Self and Others.
How do we make choices for others with different preferences from our own? Although neuroimaging studies implicate similar circuits in representing preferences for oneself and others, some models propose that additional corrective mechanisms come online when choices for others diverge from one's own preferences. Here we used event-related potentials (ERPs) in humans, in combination with computational modeling, to examine how social information is integrated in the time leading up to choices for oneself and others. Hungry male and female participants with unrestricted diets selected foods for themselves, a similar unrestricted eater, and a dissimilar, self-identified healthy eater. Across choices for both oneself and others, ERP value signals emerged within the same time window but differentially reflected taste and health attributes based on the recipient's preferences. Choices for the dissimilar recipient were associated with earlier activity localized to brain regions implicated in social cognition, including temporoparietal junction. Finally, response-locked analysis revealed a late ERP component specific to choices for the similar recipient, localized to the parietal lobe, that appeared to reflect differences in the response threshold based on uncertainty. A multi-attribute computational model supported the link between specific ERP components and distinct model parameters, and was not significantly improved by adding time-dependent dual processes. Model simulations suggested that longer response times previously associated with effortful correction may alternatively arise from higher choice uncertainty. Together, these results provide a parsimonious neurocomputational mechanism for social decision-making, additionally explaining divergent patterns of choice and response time data in decisions for oneself and others.SIGNIFICANCE STATEMENT How do we choose for others, particularly when they have different preferences? Whereas some studies suggest that similar neural circuits underlie decision-making for oneself and others, others argue for additional, slower perspective-taking mechanisms. Combining event-related potentials with computational modeling, we found that integration of others' preferences occurs over the same timescale as for oneself while differentially tracking recipient-relevant attributes. Although choosing for others took longer and produced differences in late-emerging neural responses, computational modeling attributed these patterns to greater response caution rather than egocentric bias correction. Computational simulations also correctly predicted when and why choosing differently for others takes longer, suggesting that a model incorporating value integration and evidence accumulation can parsimoniously account for complex patterns in social decision-making.


Is Mycobacterium bovis in the environment important for the persistence of bovine tuberculosis?
Mycobacterium bovis is the causative agent of bovine tuberculosis (bTB) in cattle and wildlife. Direct aerosol contact is thought to be the primary route of infection between conspecifics, whereas indirect transmission via an environmental reservoir of M. bovis is generally perceived not to be a significant source for infection. Here, we report on the application of molecular technology (PCR) to quantify the prevalence of M. bovis in the environment and to explore its epidemiological significance. We show that the detectability of viable M. bovis at badger setts and latrines is strongly linked to the frequency of M. bovis excretion by infected badgers, and that putative M. bovis in the environment is prevalent on a large proportion of endemic cattle farms in Britain. These results raise important questions about the role of an environmental reservoir in bTB persistence.


A SNAP-tag fluorogenic probe mimicking the chromophore of the red fluorescent protein Kaede.
Self-labelling protein tags with fluorogenic probes serve as great fluorescence imaging tools to understand key questions of protein dynamics and functions in living cells. In the present study, we report a SNAP-tag fluorogenic probe 4c mimicking the chromophore of the red fluorescent protein Kaede. The molecular rotor properties of 4c were utilized as a fluorogenic probe for SNAP-tag, such that conjugation with SNAPf protein leads to inhibition of twisted intramolecular charge transfer, triggering fluorogenecity. Upon conjugation with SNAPf, 4c exhibited approximately a 90-fold enhancement in fluorescence intensity with fast labelling kinetics (k2 = 15 000 M-1 s-1). Biochemical and spectroscopic studies confirmed that fluorescence requires formation of folded SNAPf·4c covalent conjugate between Cys 145 and 4c. Confocal microscopy and flow cytometry showed that 4c is capable of detecting SNAPf proteins or SNAPf fused with a protein of interest in living cells. This work provides a framework to develop the large family of FP chromophores into fluorogenic probes for self-labelling protein tags.


Effects of global financial crisis on funding for health development in nineteen countries of the WHO African Region.
There is ample evidence in Asia and Latin America showing that past economic crises resulted in cuts in expenditures on health, lower utilization of health services, and deterioration of child and maternal nutrition and health outcomes. Evidence on the impact of past economic crises on health sector in Africa is lacking. The objectives of this article are to present the findings of a quick survey conducted among countries of the WHO African Region to monitor the effects of global financial crisis on funding for health development; and to discuss the way forward. This is a descriptive study. A questionnaire was prepared and sent by email to all the 46 Member States in the WHO African Region through the WHO Country Office for facilitation and follow up. The questionnaires were completed by directors of policy and planning in ministries of health. The data were entered and analyzed in Excel spreadsheet. The main limitations of this study were that authors did not ask whether other relevant sectors were consulted in the process of completing the survey questionnaire; and that the overall response rate was low. The main findings were as follows: the response rate was 41.3% (19/46 countries); 36.8% (7/19) indicated they had been notified by the Ministry of Finance that the budget for health would be cut; 15.8% (3/19) had been notified by partners of their intention to cut health funding; 61.1% (11/18) indicated that the prices of medicines had increased recently; 83.3% (15/18) indicated that the prices of basic food stuffs had increased recently; 38.8% (7/18) indicated that their local currency had been devalued against the US dollar; 47.1% (8/17) affirmed that the levels of unemployment had increased since the onset of global financial crisis; and 64.7% (11/17) indicated that the ministry of health had taken some measures already, either in reaction to the global financing crisis, or in anticipation. A rapid assessment, like the one reported in this article, of the effects of the global financial crisis on a few variables, is important to alert the Ministry of Health on the looming danger of cuts in health funding from domestic and external sources. However, it is even more important for national governments to monitor the effects of the economic crisis and the policy responses on the social determinants of health, health inputs, health system outputs and health system outcomes, e.g. health.


Balloon test occlusion with hypotensive challenge for main trunk occlusion of internal carotid artery aneurysms and pseudoaneurysms.
Balloon test occlusion of carotid artery is a useful procedure in managing patients with internal carotid aneurysms and psuedoaneurysms. Previous studies using intravenous sodium nitroprusside for hypotensive challenge yielded false-negative results for haemodynamic ischaemia, highlighting the difference between pharmacological and compensatory vasodilatory responses. We reviewed our management result of a combined approach of clinical assessment and angiographic assessment of venous drainage using intravenous labetalol for hypotensive challenge. A retrospective review of all balloon test occlusions carried in a single neurosurgical institute between August 1996 and August 2009 was carried out. Patients with internal carotid artery aneurysms and pseudoaneurysms were reviewed accordingly. The diagnosis at the time of treatment included radiotherapy-induced internal carotid artery pseudoaneurysms in nasopharyngeal carcinoma patients (11/23, 48%), cavernous internal carotid artery giant aneurysm (6/23, 26%) and ophthalmic segment internal carotid artery giant aneurysm (4/23, 17%). Nineteen (79%) patients passed the balloon test occlusion. In the cohort of patients that passed balloon test occlusion and underwent main trunk occlusion, there were no (0/20, 0%) permanent and no (0, 0%) transient neurological complications related to a subsequent parent artery occlusion. A combined approach of clinical assessment and angiographic assessment of venous drainage, using intravenous labetalol for hypotensive challenge, is effective in screening out patients who were at a risk for ischaemia after internal carotid artery occlusion and can serve as a guideline for the selection of patients requiring extracranial-intracranial bypass.


Burden of disease and lifestyle habits in adolescents and young adults prone to frequent episodic migraine: A secondary comparative analysis.
The objective of this study was to assess the burden of disease and prevalence of lifestyle factors for adolescents and young adults with frequent episodic migraine. We conducted a secondary comparative analysis of data collected during two previous studies. Inclusion criteria for this analysis were age 15-35 years, 15 to 44 migraine episodes within 12 weeks, and completeness of Migraine Disability Assessment and lifestyle questionnaire data. Datasets of 37 adults (median age [interquartile range]: 25 [6]) and 27 adolescents (median age [interquartile range]: 15 [1]) were analyzed. 81% (n = 30) of adults reported severe disability (16% [n = 3] of adolescents; p < 0.001). Headache frequency (24 vs. 17 days; p = 0.005) and prevalence of regular analgesic use (60% [n = 22] vs. 18% [n = 5]; p = 0.002) were significantly higher in adults. In adults, sleep duration on weekdays was significantly lower (8.5 vs. 10 h; p < 0.001). Any consumption of caffeine tended to be higher in adolescents and alcohol consumption tended to be higher in adults (p > 0.05). This study underlines the importance of educating adolescents and young adults with migraine about lifestyle habits that are likely to interfere with the condition.


The genetic interactome of prohibitins: coordinated control of cardiolipin and phosphatidylethanolamine by conserved regulators in mitochondria.
Prohibitin ring complexes in the mitochondrial inner membrane regulate cell proliferation as well as the dynamics and function of mitochondria. Although prohibitins are essential in higher eukaryotes, prohibitin-deficient yeast cells are viable and exhibit a reduced replicative life span. Here, we define the genetic interactome of prohibitins in yeast using synthetic genetic arrays, and identify 35 genetic interactors of prohibitins (GEP genes) required for cell survival in the absence of prohibitins. Proteins encoded by these genes include members of a conserved protein family, Ups1 and Gep1, which affect the processing of the dynamin-like GTPase Mgm1 and thereby modulate cristae morphogenesis. We show that Ups1 and Gep1 regulate the levels of cardiolipin and phosphatidylethanolamine in mitochondria in a lipid-specific but coordinated manner. Lipid profiling by mass spectrometry of GEP-deficient mitochondria reveals a critical role of cardiolipin and phosphatidylethanolamine for survival of prohibitin-deficient cells. We propose that prohibitins control inner membrane organization and integrity by acting as protein and lipid scaffolds.


Genome sequence of the lager brewing yeast, an interspecies hybrid.
This work presents the genome sequencing of the lager brewing yeast (Saccharomyces pastorianus) Weihenstephan 34/70, a strain widely used in lager beer brewing. The 25 Mb genome comprises two nuclear sub-genomes originating from Saccharomyces cerevisiae and Saccharomyces bayanus and one circular mitochondrial genome originating from S. bayanus. Thirty-six different types of chromosomes were found including eight chromosomes with translocations between the two sub-genomes, whose breakpoints are within the orthologous open reading frames. Several gene loci responsible for typical lager brewing yeast characteristics such as maltotriose uptake and sulfite production have been increased in number by chromosomal rearrangements. Despite an overall high degree of conservation of the synteny with S. cerevisiae and S. bayanus, the syntenies were not well conserved in the sub-telomeric regions that contain lager brewing yeast characteristic and specific genes. Deletion of larger chromosomal regions, a massive unilateral decrease of the ribosomal DNA cluster and bilateral truncations of over 60 genes reflect a post-hybridization evolution process. Truncations and deletions of less efficient maltose and maltotriose uptake genes may indicate the result of adaptation to brewing. The genome sequence of this interspecies hybrid yeast provides a new tool for better understanding of lager brewing yeast behavior in industrial beer production.


Design and Modelling of a Continuum Robot for Distal Lung Sampling in Mechanically Ventilated Patients in Critical Care.
In this paper, we design and develop a novel robotic bronchoscope for sampling of the distal lung in mechanically-ventilated (MV) patients in critical care units. Despite the high cost and attributable morbidity and mortality of MV patients with pneumonia which approaches 40%, sampling of the distal lung in MV patients suffering from range of lung diseases such as Covid-19 is not standardised, lacks reproducibility and requires expert operators. We propose a robotic bronchoscope that enables repeatable sampling and guidance to distal lung pathologies by overcoming significant challenges that are encountered whilst performing bronchoscopy in MV patients, namely, limited dexterity, large size of the bronchoscope obstructing ventilation, and poor anatomical registration. We have developed a robotic bronchoscope with 7 Degrees of Freedom (DoFs), an outer diameter of 4.5 mm and inner working channel of 2 mm. The prototype is a push/pull actuated continuum robot capable of dexterous manipulation inside the lung and visualisation/sampling of the distal airways. A prototype of the robot is engineered and a mechanics-based model of the robotic bronchoscope is developed. Furthermore, we develop a novel numerical solver that improves the computational efficiency of the model and facilitates the deployment of the robot. Experiments are performed to verify the design and evaluate accuracy and computational cost of the model. Results demonstrate that the model can predict the shape of the robot in <0.011s with a mean error of 1.76 cm, enabling the future deployment of a robotic bronchoscope in MV patients.


Maternal side-effects after multiple courses of antenatal corticosteroids (MACS): the three-month follow-up of women in the randomized controlled trial of MACS for preterm birth study.
A single course of antenatal corticosteroids (ACS) is associated with a reduction in respiratory distress syndrome and neonatal death. Multiple Courses of Antenatal Corticosteroids Study (MACS), a study involving 1858 women, was a multicentre randomized placebo-controlled trial of multiple courses of ACS, given every 14 days until 33+6 weeks or birth, whichever came first. The primary outcome of the study, a composite of neonatal mortality and morbidity, was similar for the multiple ACS and placebo groups (12.9% vs. 12.5%), but infants exposed to multiple courses of ACS weighed less, were shorter, and had smaller head circumferences. Thus for women who remain at increased risk of preterm birth, multiple courses of ACS (every 14 days) are not recommended. Chronic use of corticosteroids is associated with numerous side effects including weight gain and depression. The aim of this postpartum assessment was to ascertain if multiple courses of ACS were associated with maternal side effects. Three months postpartum, women who participated in MACS were asked to complete a structured questionnaire that asked about maternal side effects of corticosteroid use during MACS and included the Edinburgh Postnatal Depression Scale. Women were also asked to evaluate their study participation. Of the 1858 women randomized, 1712 (92.1%) completed the postpartum questionnaire. There were no significant differences in the risk of maternal side effects between the two groups. Large numbers of women met the criteria for postpartum depression (14.1% in the ACS vs. 16.0% in the placebo group). Most women (94.1%) responded that they would participate in the trial again. In pregnancy, corticosteroids are given to women for fetal lung maturation and for the treatment of various maternal diseases. In this international multicentre randomized controlled trial, multiple courses of ACS (every 14 days) were not associated with maternal side effects, and the majority of women responded that they would participate in such a study again.


Peripherally InSerted CEntral catheter dressing and securement in patients with cancer: the PISCES trial. Protocol for a 2x2 factorial, superiority randomised controlled trial.
Around 30% of peripherally inserted central catheters (PICCs) fail from vascular, infectious or mechanical complications. Patients with cancer are at highest risk, and this increases morbidity, mortality and costs. Effective PICC dressing and securement may prevent PICC failure; however, no large randomised controlled trial (RCT) has compared alternative approaches. We designed this RCT to assess the clinical and cost-effectiveness of dressing and securements to prevent PICC failure. Pragmatic, multicentre, 2×2 factorial, superiority RCT of (1) dressings (chlorhexidine gluconate disc (CHG) vs no disc) and (2) securements (integrated securement dressing (ISD) vs securement device (SED)). A qualitative evaluation using a knowledge translation framework is included. Recruitment of 1240 patients will occur over 3 years with allocation concealment until randomisation by a centralised service. For the dressing hypothesis, we hypothesise CHG discs will reduce catheter-associated bloodstream infection (CABSI) compared with no CHG disc. For the securement hypothesis, we hypothesise that ISD will reduce composite PICC failure (infection (CABSI/local infection), occlusion, dislodgement or thrombosis), compared with SED. types of PICC failure; safety; costs; dressing/securement failure; dwell time; microbial colonisation; reversible PICC complications and consumer acceptability. Relative incidence rates of CABSI and PICC failure/100 devices and/1000 PICC days (with 95% CIs) will summarise treatment impact. Kaplan-Meier survival curves (and log rank Mantel-Haenszel test) will compare outcomes over time. Secondary end points will be compared between groups using parametric/non-parametric techniques; p values <0.05 will be considered to be statistically significant. Ethical approval from Queensland Health (HREC/15/QRCH/241) and Griffith University (Ref. No. 2016/063). Results will be published. Trial registration number is: ACTRN12616000315415.


Dominant inhibitory Ras delays Sindbis virus-induced apoptosis in neuronal cells.
Mature neurons are more resistant than dividing cells or differentiating neurons to Sindbis virus-induced apoptotic death. Therefore, we hypothesized that mitogenic signal transduction pathways may influence susceptibility to Sindbis virus-induced apoptosis. Since Ras, a 21-kDa GTP-binding protein, plays an important role in cellular proliferation and neuronal differentiation, we investigated the effect of an inducible dominant inhibitory Ras on Sindbis virus-induced death of a rat pheochromocytoma cell line, PC12 cells. Dexamethasone induction of dominant inhibitory Ras (Ha Ras(Asn17)) expression in transfected PC12 cell lines (MMTV-M17-21 and GSrasDN6 cells) resulted in a marked delay in Sindbis virus-induced apoptosis, compared with infected, uninduced cells. The delay in death after Sindbis virus infection in induced versus uninduced PC12 cells was not associated with differences in viral titers or viral infectivity. No delay in Sindbis virus-induced apoptosis was observed in Ha Ras(Asn17)-transfected PC12 cells if dexamethasone induction was initiated less than 12 h before Sindbis virus infection or in wild-type PC12 cells infected with a chimeric Sindbis virus construct that expresses Ha Ras(Asn17). The delay in Sindbis virus-induced apoptosis in induced Ha Ras(Asn17)-transfected PC12 cells was associated with a decrease in cellular DNA synthesis as measured by 5'-bromo-2'-deoxyuridine incorporation. Thus, in PC12 cells, inducible dominant inhibitory Ras inhibits cellular proliferation and delays Sindbis virus-induced apoptosis. These findings suggest that a Ras-dependent signaling pathway is a determinant of neuronal susceptibility to Sindbis virus-induced apoptosis.


Effect of yoga on mental health: Comparative study between young and senior subjects in Japan.
Japan has a large number of senior citizens. Yoga can be wisely applied in old age care. There is no any age restriction to practice yoga. The effect may differ by age. There is a need to study the mechanism of action of yoga with respect to age. This study was conducted in Japan to find the effect of yoga on mental health between young and senior people. Twenty-five normal healthy volunteers of both sexes were divided into two groups according to age. Fifteen participants of the age group between 65 to 75 years and 10 participants of the age group between 20 to 30 years were selected. This study was approved by the ethical committee of Kawasaki University of Medical Welfare. Selected individuals were subjected to 90 min of yoga classes once or twice a week for a month. Salivary amylase activity was assessed before and after yoga practice. State Trait Anxiety Inventory (STAI) was given before yoga on the first day and after one month of practice to assess the change in State anxiety and Trait anxiety. Senior group - Salivary amylase activity decreased from 111.2±42.7 to 83.48±39.5 kU/L [average±standard deviation]. Younger group - Salivary amylase activity reduced from 60.74±31.8 to 42.39±24 kU/L. Senior group - State anxiety score decreased from 41.13 ±8.43 to 30.8±6.49, Trait anxiety score reduced from 45.66±7.5 to 40.73±8.3. Younger group - State anxiety score reduced from 38.7±4.8 to 30.8±4.1,Trait anxiety score reduced from 46.2±7.9 to 42.9±9.1. Changes were statistically significant with P<0.05. Decrease in Salivary amylase activity may be due to reduction in sympathetic response. Reduction in State and Trait anxiety score signifies that yoga has both immediate as well as long-term effect on anxiety reduction. Thus yoga helps to improve the mental health in both the groups.


Commercializing genetically modified crops under EU regulations: objectives and barriers.
Agriculture faces serious problems in feeding 9 billion people by 2050: production must be increased and ecosystem services maintained under conditions for growing crops that are predicted to worsen in many parts of the world. A proposed solution is sustainable intensification of agriculture, whereby yields are increased on land that is currently cultivated, so sparing land to deliver other ecosystem services. Genetically modified (GM) crops are already contributing to sustainable intensification through higher yields and lower environmental impacts, and have potential to deliver further significant improvements. Despite their widespread successful use elsewhere, the European Union (EU) has been slow to introduce GM crops: decisions on applications to import GM commodities are lengthy, and decision-making on applications to cultivate GM crops has virtually ceased. Delayed import approvals result in economic losses, particularly in the EU itself as a result of higher commodity prices. Failure to grant cultivation approvals costs EU farmers opportunities to reduce inputs, and results in loss of agricultural research and development from the EU to countries such as the United States and China. Delayed decision-making in the EU ostensibly results from scientific uncertainty about the effects of using GM crops; however, scientific uncertainty may be a means to justify a political decision to restrict cultivation of GM crops in the EU. The problems associated with delayed decision-making will not improve until there is clarity about the EU's agricultural policy objectives, and whether the use of GM crops will be permitted to contribute to achieving those objectives.


Optimising strategies to address mental ill-health in doctors and medical students: 'Care Under Pressure' realist review and implementation guidance.
Mental ill-health in health professionals, including doctors, is a global and growing concern. The existing literature on interventions that offer support, advice and/or treatment to sick doctors has not yet been synthesised in a way that considers the complexity and heterogeneity of the interventions, and the many dimensions of the problem. We (1) reviewed interventions to tackle doctors' and medical students' mental ill-health and its impacts on the clinical workforce and patient care-drawing on diverse literature sources and engaging iteratively with diverse stakeholder perspectives-and (2) produced recommendations that support the tailoring, implementation, monitoring and evaluation of contextually sensitive strategies to tackle mental ill-health and its impacts. Realist literature review consistent with the RAMESES quality and reporting standards. Sources for inclusion were identified through bibliographic database searches supplemented by purposive searches-resulting also from engagement with stakeholders. Data were extracted from included articles and subjected to realist analysis to identify (i) mechanisms causing mental ill-health in doctors and medical students and relevant contexts or circumstances when these mechanisms were likely to be 'triggered' and (ii) 'guiding principles' and features underpinning the interventions and recommendations discussed mostly in policy document, reviews and commentaries. One hundred seventy-nine records were included. Most were from the USA (45%) and were published since 2009 (74%). The analysis showed that doctors were more likely to experience mental ill-health when they felt isolated or unable to do their job and when they feared repercussions of help-seeking. Healthy staff were necessary for excellent patient care. Interventions emphasising relationships and belonging were more likely to promote wellbeing. Interventions creating a people-focussed working culture, balancing positive/negative performance and acknowledging positive/negative aspects of a medical career helped doctors to thrive. The way that interventions were implemented seemed critically important. Doctors and medical students needed to have confidence in an intervention for the intervention to be effective. Successful interventions to tackle doctors' and students' mental ill-health are likely to be multidimensional and multilevel and involve multiple stakeholders. Evaluating and improving existing interventions is likely to be more effective than developing new ones. Our evidence synthesis provides a basis on which to do this. PROSPERO CRD42017069870. Research project webpage http://sites.exeter.ac.uk/cup/.


Typing of methicillin-resistant Staphylococcus aureus isolates from Düsseldorf by six genotypic methods.
Nosocomial infections caused by methicillin-resistant Staphylococcus aureus (MRSA) represent an increasing problem in hospitals. Quick and reliable typing methods are required to obtain information about the relatedness of MRSA isolates and to allow faster implementation of appropriate infection control measures. This investigation describes the distribution of MRSA isolates from 11 hospitals in the Düsseldorf region of Germany, and the ability of six different genotypic typing techniques -- pulsed-field gel electrophoresis (PFGE), random amplification of polymorphic DNA (RAPD), 16S-23S rDNA spacer amplification, protein A-gene PCR, PCR characterisation of the hypervariable region (HVR) adjacent to mecA, and coagulase gene-PCR -- to detect different unrelated types. Of 7814 S. aureus isolates tested, 489 (6.3%) were MRSA, of which 183 were selected for subsequent molecular analyses on the basis of being the first MRSA isolated from colonised or infected patients. Larger hospitals had a higher incidence of MRSA and a greater variability in genotypes than smaller hospitals. All methods confirmed the presence of two main clonal types. The ability of techniques to detect different unrelated types was found to be as follows: PFGE, 28 types; 16S-23S rDNA spacer-amplification, 10 types; RAPD, nine types; protein A-gene PCR, five types; HVR-PCR, five types; and coa gene-PCR, two types. Combination of PFGE and one other PCR-based method (spacer-amplification, RAPD or protein-A gene PCR) provided the best resolution of types and allowed the identification of subtypes. Similar molecular types were identified with international MRSA isolates. Although PCR-based techniques have the advantage of rapid performance and easy handling, their discriminatory capacity is inferior compared to the more labour intensive PFGE.


Migration and first-year maternal mortality among HIV-positive postpartum women: A population-based longitudinal study in rural South Africa.
In South Africa, within-country migration is common. Mobility affects many of the factors in the pathway for entry to or retention in care among people living with HIV. We characterized the patterns of migration (i.e., change in residency) among peripartum women from rural South Africa and their association with first-year postpartum mortality. All pregnant women aged ≥15 years were followed-up during pregnancy and the first year postpartum in a population-based longitudinal demographic and HIV surveillance program in KwaZulu-Natal, South Africa, from 2000 to 2016. During the household surveys (every 4-6 months), each household head was interviewed to record demographic components of the household, including composition, migration, and mortality. External migration was defined as moving (i.e., change in residency) into or out of the study area. For women of reproductive age, detailed information on new pregnancy and birth was recorded. Maternal death was ascertained via verbal autopsy and HIV status at delivery via annual HIV surveys. We fitted mixed-effects Cox regression models adjusting for multiple pregnancies per individual. Overall, 19,334 women had 30,291 pregnancies: 3,339 were HIV-positive, 10,958 were HIV-negative, and 15,994 had unknown HIV status at delivery. The median age was 24 (interquartile range: 20-30) years. During pregnancy and the first year postpartum, 64% (n = 19,344) and 13% (n = 3,994) did not migrate and resided within and outside the surveillance area, respectively. Of the 23% who had externally migrated at least once, 39% delivered outside the surveillance area. Overall, the mortality rate was 5.8 per 1,000 person-years (or 831 deaths per 100,000 live births) in the first year postpartum. The major causes of deaths were AIDS- or tuberculosis-related conditions both within 42 days of delivery (53%) and during the first year postpartum (62%). In this study, we observed that HIV-positive peripartum women who externally migrated and delivered outside the surveillance area had a hazard of mortality more than two times greater (hazard ratio = 2.74; 95% confidence interval 1.01-7.40, p-value = 0.047)-after adjusting for age, time period (before or after 2010), and sociodemographic status-compared to that of HIV-positive women who continuously resided within the surveillance area. Study limitations include lack of data on access to antiretroviral therapy (ART) care and social or clinical context at the destinations among mobile participants, which could lead to unmeasured confounding. Further information on how mobile postpartum women access and remain in care would be instructive. In this study, we found that a substantial portion of peripartum women moved within the country around the time of delivery and experienced a significantly higher risk of mortality. Despite the scale-up of universal ART and declining trends in maternal mortality, there is an urgent need to derive a greater understanding of the mechanisms underlying this finding and to develop targeted interventions for mobile HIV-positive peripartum women.


Metabolic control of methylation and acetylation.
Methylation and acetylation of DNA and histone proteins are the chemical basis for epigenetics. From bacteria to humans, methylation and acetylation are sensitive to cellular metabolic status. Modification rates depend on the availability of one-carbon and two-carbon substrates (S-adenosylmethionine, acetyl-CoA, and in bacteria also acetyl-phosphate). In addition, they are sensitive to demodification enzyme cofactors (α-ketoglutarate, NAD(+)) and structural analog metabolites that function as epigenetic enzyme inhibitors (e.g., S-adenosylhomocysteine, 2-hydroxyglutarate). Methylation and acetylation likely initially evolved to tailor protein activities in microbes to their metabolic milieu. While the extracellular environment of mammals is more tightly controlled, the combined impact of nutrient abundance and metabolic enzyme expression impacts epigenetics in mammals sufficiently to drive important biological outcomes such as stem cell fate and cancer.


Validation of the MEDFICTS dietary questionnaire: a clinical tool to assess adherence to American Heart Association dietary fat intake guidelines.
Dietary assessment tools are often too long, difficult to quantify, expensive to process, and largely used for research purposes. A rapid and accurate assessment of dietary fat intake is critically important in clinical decision-making regarding dietary advice for coronary risk reduction. We assessed the validity of the MEDFICTS (MF) questionnaire, a brief instrument developed to assess fat intake according to the American Heart Association (AHA) dietary "steps". We surveyed 164 active-duty US Army personnel without known coronary artery disease at their intake interview for a primary prevention cardiac intervention trial using the Block food frequency (FFQ) and MF questionnaires. Both surveys were completed on the same intake visit and independently scored. Correlations between each tools' assessment of fat intake, the agreement in AHA step categorization of dietary quality with each tool, and the test characteristics of the MF using the FFQ as the gold standard were assessed. Subjects consumed a mean of 36.0 +/- 13.0% of their total calories as fat, which included saturated fat consumption of 13.0 +/- 0.4%. The majority of subjects (125/164; 76.2%) had a high fat (worse than AHA Step 1) diet. There were significant correlations between the MF and the FFQ for the intake of total fat (r = 0.52, P < 0.0001) and saturated fat (r = 0.52, P < 0.0001). Despite these modest correlations, the currently recommended MF cutpoints correctly identified only 29 of 125 (23.3%) high fat (worse than AHA Step 1) diets. Overall agreement for the AHA diet step between the FFQ and MF (using the previously proposed MF score cutoffs of 0-39 [AHA Step 2], 40-70 [Step 1], and > 70 [high fat diet]) was negligible (kappa statistic = 0.036). The MF was accurate at the extremes of fat intake, but could not reliably identify the 3 AHA dietary classifications. Alternative MF cutpoints of < 30 (Step 2), 30-50 (Step 1), and > 50 (high fat diet) were highly sensitive (96%), but had low specificity (46%) for a high fat diet. ROC curve analysis identified that a MF score cutoff of 38 provided optimal sensitivity 75% and specificity 72%, and had modest agreement (kappa = 0.39, P < 0.001) with the FFQ for the identification of subjects with a high fat diet. The MEDFICTS questionnaire is most suitable as a tool to identify high fat diets, rather than discriminate AHA Step 1 and Step 2 diets. Currently recommended MEDFICTS cutpoints are too high, leading to overestimation of dietary quality. A cutpoint of 38 appears to be providing optimal identification of patients who do not meet AHA dietary guidelines for fat intake.


Application of batch tests to assess antibiotic loads in anaerobic processes.
The presence of antibiotics in drinking water and wastewater has not been widely studied because the sanitary engineering sector mainly focuses on the removal of organic matter and nutrients. There is a lack of environmental regulations for pollutants like antibiotics. Batch tests analyse biodegradability to measure the anaerobic degradation potential of the substrate, or they can be used as toxicity tests. Oxytetracycline, florfenicol (FLO), ceftiofur (CEF) and penicillin G (PEN), commonly used in Colombia for the treatment of livestock diseases, were added in different concentrations to anaerobic sludge contained in serological glass bottles. The production of methane stored in the empty spaces of the bottles was monitored in order to determine the effect of the aforementioned antibiotics on the anaerobic process. It was found that CEF did not have any inhibitory effect on methanogenic activity, while PEN showed inhibition at all concentrations evaluated.


Renal atrophy and arterial stenosis. A prospective study with duplex ultrasound.
Renal artery disease is an important cause of both renal failure and hypertension. Duplex ultrasound is a reliable noninvasive method for classifying the severity of renal artery lesions and can be repeated to follow the course of the disease over time. The purpose of this study was to determine the changes in kidney size associated with various degrees of renal artery disease. Serial kidney lengths were measured as part of a prospective duplex ultrasound study of patients with renal artery narrowing. Fifty-four patients (22 men, 32 women; mean age, 65.8 years) with 101 renal artery and kidney sides eligible for follow-up were evaluated at 6-month intervals for an average of 14.4 months (range, 4 to 24 months). No kidneys with renal arteries classified as normal or less than 60% diameter stenosis by duplex criteria were found to have a decrease in length of greater than 1 cm during follow-up. In kidneys with a high-grade renal artery stenosis (> or = 60% diameter reduction), 26% (13 of 49 sides) were found to have a decrease in length of greater than 1 cm. The average decrease in length was 1.9 cm (range, 1.2 to 3.4 cm). By life table analysis, the estimated risk of a decrease in length of greater than 1 cm for kidneys with 60% stenosis or greater was 19% at 1 year. Loss of renal mass, as documented by ultrasound measurement of kidney length, is an important consequence of high-grade renal artery stenosis.


Determining carpal collapse. An improved method.
The carpal height index (carpal height ratio of the diseased wrist divided by that of the normal wrist, as described by Kato et al.) was calculated in forty normal subjects, ten patients who had Stage-III lunatomalacia, and eight patients who had non-union of a fracture of the scaphoid. The method of Youm et al. for determining the carpal height index was altered to include the use of defined points of reference and a standardized radiographic technique. Two tests of reproducibility demonstrated the reliability of the method. The carpal height index was found to be superior to the carpal height ratio for the evaluation of unilateral disease. The mean carpal height index of diseased wrists differed significantly from that of normal wrists. The carpal height index (for unilateral disease) or the carpal height ratio (for bilateral disease) can be used to describe the progression of collapse of the wrist quantitatively and to evaluate and compare various forms of treatment.


'Do it for the kids': barriers and facilitators to smoke-free homes and vehicles.
Despite abundant evidence about the adverse effects of secondhand smoke exposure on children's health, few reports describe barriers and facilitators encountered by parents in making their homes and vehicles smoke-free. This article describes perceptions of barriers and facilitators to making homes and vehicles smoke-free among 36 parents with a child five years of age or younger. Qualitative data were collected in interviews with parents in the context of a randomized controlled trial that tested an intervention to empower parents to make their homes and vehicles smoke-free. Themes that emerged in the analysis were congruent with an ecological conceptualization of health. The greatest barriers were intrapersonal factors, and nicotine addiction was the intrapersonal barrier identified most frequently. The most frequently reported facilitators were intrapersonal factors, such as quitting smoking. Parents reported not seeking advice from health care providers. The transition process to make homes and vehicles smoke-free is complex and individualistic; nurses may need to tailor strategies to take the specific contexts of each individual into account.


Development of bacterial biofilms on artificial corals in comparison to surface-associated microbes of hard corals.
Numerous studies have demonstrated the differences in bacterial communities associated with corals versus those in their surrounding environment. However, these environmental samples often represent vastly different microbial micro-environments with few studies having looked at the settlement and growth of bacteria on surfaces similar to corals. As a result, it is difficult to determine which bacteria are associated specifically with coral tissue surfaces. In this study, early stages of passive settlement from the water column to artificial coral surfaces (formation of a biofilm) were assessed. Changes in bacterial diversity (16S rRNA gene), were studied on artificially created resin nubbins that were modelled from the skeleton of the reef building coral Acropora muricata. These models were dip-coated in sterile agar, mounted in situ on the reef and followed over time to monitor bacterial community succession. The bacterial community forming the biofilms remained significantly different (R = 0.864 p<0.05) from that of the water column and from the surface mucus layer (SML) of the coral at all times from 30 min to 96 h. The water column was dominated by members of the α-proteobacteria, the developed community on the biofilms dominated by γ-proteobacteria, whereas that within the SML was composed of a more diverse array of groups. Bacterial communities present within the SML do not appear to arise from passive settlement from the water column, but instead appear to have become established through a selection process. This selection process was shown to be dependent on some aspects of the physico-chemical structure of the settlement surface, since agar-coated slides showed distinct communities to coral-shaped surfaces. However, no significant differences were found between different surface coatings, including plain agar and agar enhanced with coral mucus exudates. Therefore future work should consider physico-chemical surface properties as factors governing change in microbial diversity.


In-situ one-step hydrothermal synthesis of a lead germanate-graphene composite as a novel anode material for lithium-ion batteries.
Lead germanate-graphene nanosheets (PbGeO3-GNS) composites have been prepared by an efficient one-step, in-situ hydrothermal method and were used as anode materials for Li-ion batteries (LIBs). The PbGeO3 nanowires, around 100-200 nm in diameter, are highly encapsulated in a graphene matrix. The lithiation and de-lithiation reaction mechanisms of the PbGeO3 anode during the charge-discharge processes have been investigated by X-ray diffraction and electrochemical characterization. Compared with pure PbGeO3 anode, dramatic improvements in the electrochemical performance of the composite anodes have been obtained. In the voltage window of 0.01-1.50 V, the composite anode with 20 wt.% GNS delivers a discharge capacity of 607 mAh g(-1) at 100 mA g(-1) after 50 cycles. Even at a high current density of 1600 mA g(-1), a capacity of 406 mAh g(-1) can be achieved. Therefore, the PbGeO3-GNS composite can be considered as a potential anode material for lithium ion batteries.


Alpha4 is a ubiquitin-binding protein that regulates protein serine/threonine phosphatase 2A ubiquitination.
Multiple regulatory mechanisms control the activity of the protein serine/threonine phosphatase 2A catalytic subunit (PP2Ac), including post-translational modifications and its association with regulatory subunits and interacting proteins. Alpha4 is a PP2Ac-interacting protein that is hypothesized to play a role in PP2Ac ubiquitination via its interaction with the E3 ubiquitin ligase Mid1. In this report, we show that alpha4 serves as a necessary adaptor protein that provides a binding platform for both PP2Ac and Mid1. We also identify a novel ubiquitin-interacting motif (UIM) within alpha4 (amino acid residues 46-60) and analyze the interaction between alpha4 and ubiquitin using NMR. Consistent with other UIM-containing proteins, alpha4 is monoubiquitinated. Interestingly, deletion of the UIM within alpha4 enhances its association with polyubiquitinated proteins. Lastly, we demonstrate that addition of wild-type alpha4 but not an alpha4 UIM deletion mutant suppresses PP2Ac polyubiquitination. Thus, the polyubiquitination of PP2Ac is inhibited by the UIM within alpha4. These findings reveal direct regulation of PP2Ac polyubiquitination by a novel UIM within the adaptor protein alpha4.


Serum bicarbonate, anion gap and insulin resistance in the National Health and Nutrition Examination Survey.
Metabolic acidosis may contribute to the development of insulin resistance. To date, there have been no population-based studies of acid-base status and insulin resistance. We examined the cross-sectional relations between serum bicarbonate, anion gap, and insulin resistance in a subset of healthy participants in the 1999-2000 and 2001-2002 National Health and Nutrition Examination Surveys. We included 1496 adults without diabetes or other chronic diseases. Insulin sensitivity was estimated by an index based on fasting insulin and triglyceride levels (MFFM). Linear regression was used to adjust for age, race, body mass index, albumin and other factors. Sample weights were used to produce weighted regression parameters. Median values of bicarbonate, anion gap and fasting levels of insulin, triglycerides and glucose were 23 mmol/l, 12.5 mmol/l, 48 pmol/l, 1.08 mmol/l and 5.0 mmol/l, respectively. After multivariable adjustment, bicarbonate was positively associated and anion gap was inversely associated with MFFM (P < 0.01). Participants in the highest quartile of bicarbonate had fasting insulin 12.76 pmol/l lower [95% confidence interval (CI) 5.96, 19.55; P for trend < 0.01] than those in the lowest quartile. Participants in the highest quartile of anion gap had fasting insulin 4.39 pmol/l higher (95% CI 0.47, 8.31; P for trend < 0.01) than those in the lowest quartile. Lower bicarbonate and higher anion gap are independently associated with insulin resistance. Further research is needed to elucidate the relations between organic acid production, insulin resistance, and the pathogenesis of Type 2 diabetes.


Young adult mental health and functional outcomes among individuals with remitted, persistent and late-onset ADHD.
Attention-deficit hyperactivity disorder (ADHD) is associated with mental health problems and functional impairment across many domains. However, how the longitudinal course of ADHD affects later functioning remains unclear.AimsWe aimed to disentangle how ADHD developmental patterns are associated with young adult functioning. The Environmental Risk (E-Risk) Longitudinal Twin Study is a population-based cohort of 2232 twins born in England and Wales in 1994-1995. We assessed ADHD in childhood at ages 5, 7, 10 and 12 years and in young adulthood at age 18 years. We examined three developmental patterns of ADHD from childhood to young adulthood - remitted, persistent and late-onset ADHD - and compared these groups with one another and with non-ADHD controls on functioning at age 18 years. We additionally tested whether group differences were attributable to childhood IQ, childhood conduct disorder or familial factors shared between twins. Compared with individuals without ADHD, those with remitted ADHD showed poorer physical health and socioeconomic outcomes in young adulthood. Individuals with persistent or late-onset ADHD showed poorer functioning across all domains, including mental health, substance misuse, psychosocial, physical health and socioeconomic outcomes. Overall, these associations were not explained by childhood IQ, childhood conduct disorder or shared familial factors. Long-term associations of childhood ADHD with adverse physical health and socioeconomic outcomes underscore the need for early intervention. Young adult ADHD showed stronger associations with poorer mental health, substance misuse and psychosocial outcomes, emphasising the importance of identifying and treating adults with ADHD.Declaration of interestNone.


Practice Bulletin No. 168: Cervical Cancer Screening and Prevention.
The incidence of cervical cancer in the United States has decreased more than 50% in the past 30 years because of widespread screening. In 1975, the rate was 14.8 per 100,000 women. By 2011, it decreased to 6.7 per 100,000 women. Mortality from the disease has undergone a similar decrease from 5.55 per 100,000 women in 1975 to 2.3 per 100,000 women in 2011 (1). The American Cancer Society (ACS) estimated that there would be 12,900 new cases of cervical cancer in the United States in 2015, with 4,100 deaths from the disease (2). Cervical cancer is much more common worldwide, particularly in countries without screening programs, with an estimated 527,624 new cases of the disease and 265,672 resultant deaths each year (3). When cervical cancer screening programs have been introduced into communities, marked reductions in cervical cancer incidence have followed (4, 5).New technologies for cervical cancer screening continue to evolve, as do recommendations for managing the results. In addition, there are different risk-benefit considerations for women at different ages, as reflected in age-specific screening recommendations. In 2011, the ACS, the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP) updated their joint guidelines for cervical cancer screening (6), as did the U.S. Preventive Services Task Force (USPSTF) (7). Subsequently, in 2015, ASCCP and the Society of Gynecologic Oncology (SGO) issued interim guidance for the use of a human papillomavirus (HPV) test for primary screening for cervical cancer that was approved in 2014 by the U.S. Food and Drug Administration (FDA) (8). The purpose of this document is to provide a review of the best available evidence regarding the prevention and early detection of cervical cancer.


Lichen-like association of Chlamydomonas reinhardtii and Aspergillus nidulans protects algal cells from bacteria.
Organismal interactions within microbial consortia and their responses to harmful intruders remain largely understudied. An important step toward the goal of understanding functional ecological interactions and their evolutionary selection is the study of increasingly complex microbial interaction systems. Here, we discovered a tripartite biosystem consisting of the fungus Aspergillus nidulans, the unicellular green alga Chlamydomonas reinhardtii, and the algicidal bacterium Streptomyces iranensis. Genetic analyses and MALDI-IMS demonstrate that the bacterium secretes the algicidal compound azalomycin F upon contact with C. reinhardtii. In co-culture, A. nidulans attracts the motile alga C. reinhardtii, which becomes embedded and surrounded by fungal mycelium and is shielded from the algicide. The filamentous fungus Sordaria macrospora was susceptible to azalomycin F and failed to protect C. reinhardtii despite chemotactically attracting the alga. Because S. macrospora was susceptible to azalomycin F, this data imply that for protection the fungus needs to be resistant. Formation of the lichen-like association between C. reinhardtii and A. nidulans increased algal growth. The protection depends on the increased amounts of membrane lipids provided by resistant fungi, thereby generating a protective shelter against the bacterial toxin. Our findings reveal a strategy whereby algae survive lethal environmental algicides through cooperation with fungi.


The Role of Impulsivity Dimensions in the Relation Between Probable Posttraumatic Stress Disorder and Aggressive Behavior Among Substance Users.
Individuals with co-occurring posttraumatic stress disorder (PTSD) and substance use disorder report heightened levels of numerous risky and health-compromising behaviors, including aggressive behaviors. Given evidence that aggressive behavior is associated with negative substance use disorder treatment outcomes, research is needed to identify the factors that may account for the association between PTSD and aggressive behavior among patients with substance use disorder. Thus, the goal of this study was to examine the role of impulsivity dimensions (i.e., negative urgency, lack of premeditation, lack of perseverance, and sensation seeking) in the relations between probable PTSD status and both verbal and physical aggression. Participants were 92 patients in residential substance use disorder treatment (75% male; 59% African American; M age = 40.25) who completed self-report questionnaires. Patients with co-occurring PTSD-substance use disorder (vs. substance use disorder alone) reported significantly greater verbal and physical aggression as well as higher levels of negative urgency and lack of premeditation. Lack of premeditation and lack of perseverance were significantly positively associated with verbal aggression, whereas negative urgency, lack of premeditation, and lack of perseverance were significantly positively associated with physical aggression. The indirect relation of probable PTSD status to physical aggression through negative urgency was significant. Results highlight the potential utility of incorporating skills focused on controlling impulsive behaviors in the context of negative emotional arousal in interventions for physical aggression among patients with co-occurring PTSD-substance use disorder.


Effect and clinical prediction of worsening renal function in acute decompensated heart failure.
We aimed to establish the prevalence and effect of worsening renal function (WRF) on survival among patients with acute decompensated heart failure. Furthermore, we sought to establish a risk score for the prediction of WRF and externally validate the previously established Forman risk score. A total of 657 consecutive patients with acute decompensated heart failure presenting to the emergency department and undergoing serial creatinine measurements were enrolled. The potential of the clinical parameters at admission to predict WRF was assessed as the primary end point. The secondary end point was all-cause mortality at 360 days. Of the 657 patients, 136 (21%) developed WRF, and 220 patients had died during the first year. WRF was more common in the nonsurvivors (30% vs 41%, p = 0.03). Multivariate regression analysis found WRF to independently predict mortality (hazard ratio 1.92, p <0.01). In a single parameter model, previously diagnosed chronic kidney disease was the only independent predictor of WRF and achieved an area under the receiver operating characteristic curve of 0.60. After the inclusion of the blood gas analysis parameters into the model history of chronic kidney disease (hazard ratio 2.13, p = 0.03), outpatient diuretics (hazard ratio 5.75, p <0.01), and bicarbonate (hazard ratio 0.91, p <0.01) were all predictive of WRF. A risk score was developed using these predictors. On receiver operating characteristic curve analysis, the Forman and Basel prediction rules achieved an area under the curve of 0.65 and 0.71, respectively. In conclusion, WRF was common in patients with acute decompensated heart failure and was linked to significantly worse outcomes. However, the clinical parameters failed to adequately predict its occurrence, making a tailored therapy approach impossible.


Sneaker "jack" males outcompete dominant "hooknose" males under sperm competition in Chinook salmon (Oncorhynchus tshawytscha).
In a variety of taxa, males deploy alternative reproductive tactics to secure fertilizations. In many species, small "sneaker" males attempt to steal fertilizations while avoiding encounters with larger, more aggressive, dominant males. Sneaker males usually face a number of disadvantages, including reduced access to females and the higher likelihood that upon ejaculation, their sperm face competition from other males. Nevertheless, sneaker males represent an evolutionarily stable strategy under a wide range of conditions. Game theory suggests that sneaker males compensate for these disadvantages by investing disproportionately in spermatogenesis, by producing more sperm per unit body mass (the "fair raffle") and/or by producing higher quality sperm (the "loaded raffle"). Here, we test these models by competing sperm from sneaker "jack" males against sperm from dominant "hooknose" males in Chinook salmon. Using two complementary approaches, we reject the fair raffle in favor of the loaded raffle and estimate that jack males were ∼1.35 times as likely as hooknose males to fertilize eggs under controlled competitive conditions. Interestingly, the direction and magnitude of this skew in paternity shifted according to individual female egg donors, suggesting cryptic female choice could moderate the outcomes of sperm competition in this externally fertilizing species.


Induced pluripotent stem-cell-derived cardiomyocytes: cardiac applications, opportunities, and challenges.
Chronic diseases are the primary cause of mortality worldwide, accounting for 67% of deaths. One of the major challenges in developing new treatments is the lack of understanding of the exact underlying biological and molecular mechanisms. Chronic cardiovascular diseases are the single most common cause of death worldwide, and sudden deaths due to cardiac arrhythmias account for approximately 50% of all such cases. Traditional genetic screening for genes involved in cardiac disorders is labourious and frequently fails to detect the mutation that explains or causes the disorder. However, when mutations are identified, human induced pluripotent stem cells (hiPSCs) derived from affected patients make it possible to address fundamental research questions directly relevant to human health. As such, hiPSC technology has recently been used to model human diseases and patient-specific hiPSC-derived cardiomyocytes (hiPSC-CMs) thus offer a unique opportunity to investigate potential disease-causing genetic variants in their natural environment. The purpose of this review is to present the current state of knowledge regarding hiPSC-CMs, including their potential, limitations, and challenges and to discuss future prospects.


Benefits and risks of long-term amiodarone therapy for persistent atrial fibrillation: a meta-analysis.
To assess whether amiodarone, as part of a strategy to achieve sinus rhythm, is safe and effective compared with a placebo or rate control drug in patients with persistent atrial fibrillation (AF) of more than 30 days' duration. Randomized controlled trials comparing amiodarone with a placebo or rate control drug were identified through the EMBASE (January 1, 1988, to October 18, 2008), MEDLINE (January 1, 1966, to October 18, 2008), and Cochrane Controlled Trials Register (second issue 2008) databases with no language restrictions. Twelve randomized controlled trials that involved a total of 5060 patients with persistent AF were considered. Amiodarone was more effective than a placebo or rate control drug in achieving sinus rhythm (21.3 vs 9.2 per 100 patient-years in sinus rhythm; relative risk [RR], 3.2; 95% confidence interval [CI], 1.9-5.5), and its use was not associated with an increased risk of long-term mortality (4.7 vs 3.9 per 100 patient-years; RR, 0.95; 95% CI, 0.8-1.1; P=.51; I2=0%). Cessation of amiodarone therapy because of intolerable adverse effects was more common compared with a placebo or rate control drug (10.7 vs 1.9 per 100 patient-years; RR, 3.0; 95% CI, 1.4-6.2; P<.001; I2=70%), but amiodarone was not associated with an increased incidence of hospitalizations (RR, 1.1; 95% CI, 0.6-2.1; P=.77; I2=90%). Amiodarone, as part of a strategy to achieve and maintain sinus rhythm, appears to be safe and effective in patients with persistent AF. However, some patients may not tolerate the adverse effects of this agent.


Preserved sensory-motor function despite large-scale morphological alterations in a series of patients with holocord syringomyelia.
Although the central nervous system has a limited capacity for regeneration after acute brain and spinal cord injuries, it can reveal extensive morphological changes. Occasionally, the formation of an extensive syrinx in the spinal cord can be observed that causes no or only limited signs of functional impairment. This condition creates a unique opportunity to evaluate the mismatch between substantial morphological changes and functional outcomes. We identified seven patients with holocord syringomyelia affecting the cervical cord following chronic traumatic thoracic/lumbar spinal cord injury (19-34 years after injury) or holocord syringomyelia of non-traumatic origin, and anatomical syrinx dimensions (length, cross-sectional area) were determined using sagittal and axial magnetic resonance imaging scans. Motor- and sensory-pathway integrity were evaluated using electrophysiological assessments (i.e., motor, dermatomal sensory, and dermatomal contact-heat [dCHEP] evoked potentials, as well as nerve conduction studies). These were specifically compared to clinical measures of upper-limb strength and grasping performance, including three-dimensional motion analysis. Despite extensive anatomical changes of the cervical cord (on average 26% reduction of residual spinal cord area and intrusion of almost the entire cervical spinal cord), a clinically relevant impairment of upper-limb motor function was absent while only subtle sensory deficits could be detected. dCHEPs revealed the highest sensitivity by disclosing impairments of spinothalamic pathways. Comparable to that of the brain, extensive anatomical changes of the spinal cord can occur with only subtle functional impairment. The time scale of slowly-emerging morphological alterations is essential to permit an enormous capacity for plasticity of the spinal cord.