Genomewide association analysis in diverse inbred mice: power and population structure.
The discovery of quantitative trait loci (QTL) in model organisms has relied heavily on the ability to perform controlled breeding to generate genotypic and phenotypic diversity. Recently, we and others have demonstrated the use of an existing set of diverse inbred mice (referred to here as the mouse diversity panel, MDP) as a QTL mapping population. The use of the MDP population has many advantages relative to traditional F(2) mapping populations, including increased phenotypic diversity, a higher recombination frequency, and the ability to collect genotype and phenotype data in community databases. However, these methods are complicated by population structure inherent in the MDP and the lack of an analytical framework to assess statistical power. To address these issues, we measured gene expression levels in hypothalamus across the MDP. We then mapped these phenotypes as quantitative traits with our association algorithm, resulting in a large set of expression QTL (eQTL). We utilized these eQTL, and specifically cis-eQTL, to develop a novel nonparametric method for association analysis in structured populations like the MDP. These eQTL data confirmed that the MDP is a suitable mapping population for QTL discovery and that eQTL results can serve as a gold standard for relative measures of statistical power.


High-Resolution Three-Dimensional Structural Data Quantify the Impact of Photoinhibition on Long-Term Carbon Gain in Wheat Canopies in the Field.
Photoinhibition reduces photosynthetic productivity; however, it is difficult to quantify accurately in complex canopies partly because of a lack of high-resolution structural data on plant canopy architecture, which determines complex fluctuations of light in space and time. Here, we evaluate the effects of photoinhibition on long-term carbon gain (over 1 d) in three different wheat (Triticum aestivum) lines, which are architecturally diverse. We use a unique method for accurate digital three-dimensional reconstruction of canopies growing in the field. The reconstruction method captures unique architectural differences between lines, such as leaf angle, curvature, and leaf density, thus providing a sensitive method of evaluating the productivity of actual canopy structures that previously were difficult or impossible to obtain. We show that complex data on light distribution can be automatically obtained without conventional manual measurements. We use a mathematical model of photosynthesis parameterized by field data consisting of chlorophyll fluorescence, light response curves of carbon dioxide assimilation, and manual confirmation of canopy architecture and light attenuation. Model simulations show that photoinhibition alone can result in substantial reduction in carbon gain, but this is highly dependent on exact canopy architecture and the diurnal dynamics of photoinhibition. The use of such highly realistic canopy reconstructions also allows us to conclude that even a moderate change in leaf angle in upper layers of the wheat canopy led to a large increase in the number of leaves in a severely light-limited state.


A neural region of abstract working memory.
Over 350 years ago, Descartes proposed that the neural basis of consciousness must be a brain region in which sensory inputs are combined. Using fMRI, we identified at least one such area for working memory, the limited information held in mind, described by William James as the trailing edge of consciousness. Specifically, a region in the left intraparietal sulcus was found to demonstrate load-dependent activity for either visual stimuli (colored squares) or a combination of visual and auditory stimuli (spoken letters). This result was replicated across two experiments with different participants and methods. The results suggest that this brain region, previously well known for working memory of visually presented materials, actually holds or refers to information from more than one modality.


Web-based simulation: a tool for teaching critical care nursing.
The objectives of this study were to develop, to implement and to evaluate a web-based simulation for critical care nursing, as a tool for teaching nursing students at the undergraduate level. An adapted methodology was used to develop teaching material in a web-based learning environment, consisting of three evaluation phases (ergonomic, pedagogical and usability), carried out by web-designers/programmers, nursing teachers/nurses, and undergraduate nursing students. The research tools used were three different evaluation forms, based on a five-point Likert scale, which were applied after using the simulation. The results garnered from the forms show positive analyses in every evaluation, with special emphasis on the encouragement of learning in the pedagogical evaluation period. In the usability evaluation, the highlight was on the students' satisfaction in using the environment and how easy it was to navigate. This shows the feasibility of using this simulation to improve the learning process.


Prion pathogenesis is faithfully reproduced in cerebellar organotypic slice cultures.
Prions cause neurodegeneration in vivo, yet prion-infected cultured cells do not show cytotoxicity. This has hampered mechanistic studies of prion-induced neurodegeneration. Here we report that prion-infected cultured organotypic cerebellar slices (COCS) experienced progressive spongiform neurodegeneration closely reproducing prion disease, with three different prion strains giving rise to three distinct patterns of prion protein deposition. Neurodegeneration did not occur when PrP was genetically removed from neurons, and a comprehensive pharmacological screen indicated that neurodegeneration was abrogated by compounds known to antagonize prion replication. Prion infection of COCS and mice led to enhanced fodrin cleavage, suggesting the involvement of calpains or caspases in pathogenesis. Accordingly, neurotoxicity and fodrin cleavage were prevented by calpain inhibitors but not by caspase inhibitors, whereas prion replication proceeded unimpeded. Hence calpain inhibition can uncouple prion replication from its neurotoxic sequelae. These data validate COCS as a powerful model system that faithfully reproduces most morphological hallmarks of prion infections. The exquisite accessibility of COCS to pharmacological manipulations was instrumental in recognizing the role of calpains in neurotoxicity, and significantly extends the collection of tools necessary for rigorously dissecting prion pathogenesis.


Environmental and Occupational Risk Factors of Amyotrophic Lateral Sclerosis: A Population-Based Case-Control Study.
Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with still unknown etiology. We aimed at investigating the association between environmental and occupational factors with ALS risk. Methods: We performed a population-based case-control study in four Italian provinces (Catania, Modena, Novara, and Reggio Emilia) by administration of tailored questionnaires to ALS cases (n = 95) and randomly selected population referents (n = 135). We estimated ALS risk by calculating the odds ratio (OR) with its 95% confidence interval (CI) using an unconditional logistic regression model. Results: We found a positive association with disease risk for history of occupation in the agricultural sector (OR = 2.09, 95% CI 0.79-7.54), especially for longer than 10 years (OR = 2.72, 95% 1.02-7.20). Overall occupational exposure to solvents also suggested a positive association, especially for thinners (OR = 2.27, 95% CI 1.14-4.54) and paint removers (OR = 2.01, 95% CI 0.90-4.48). Both occupational and environmental exposure to electromagnetic fields show a slightly increased risk with OR = 1.69 (95% CI 0.70-4.09) and 2.41 (95% CI 1.13-5.12), respectively. Occupational but not environmental exposure to pesticides (OR = 1.22, 95% CI 0.63-2.37), particularly fungicides, and exposure to metals (OR = 4.20, 95% CI 1.88-9.38), particularly lead, mercury, and selenium, showed an imprecise but positive association. Finally, there was an indication of increased risk for living in proximity to water bodies. Conclusions: Despite the caution that needs to be used due to some study limitations, such as the low number of exposed subjects and the possibility of recall bias, these results suggest the potential role of some environmental and occupational factors in ALS etiology.


Urine and serum concentrations of inhaled and oral terbutaline.
We examined urine and serum concentrations after therapeutic use of single and repetitive doses of inhaled and supratherapeutic oral use of terbutaline. We compared the concentrations in 10 asthmatics and 10 healthy subjects in an open-label, cross-over study with 2 mg inhaled and 10 mg oral terbutaline on 2 study days. Further, 10 healthy subjects were administrated 1 mg inhaled terbutaline in 4 repetive doses with total 4 mg. Blood samples were collected at baseline and during 6 h after the first inhalations. Urine samples were collected at baseline and during 12 h after the first inhalations. Median (IQR) urine concentrations peaked in the period 0-4 h after inhalation with Cmax 472 (324) ng/mL in asthmatics and 661 (517) ng/mL in healthy subjects, and 4-8 h after oral use with Cmax 666 (877) ng/mL in asthmatic and 402 (663) ng/mL in healthy subjects. In conclusion we found no significant differences in urine and serum concentrations between asthmatic and healthy subjects. We compared urine and serum concentrations after therapeutic inhaled doses and supratherapeutic oral doses and observed significant statistical differences in both groups but found it impossible to distinguish between therapeutic and prohibited use based on doping tests with urine and blood samples.


Image-Guided High-Dose Rate Brachytherapy in Cervix Carcinoma Using Balloon Catheter and Belt Immobilization System.
The efficacy of image-guided high-dose rate brachytherapy for cervical cancer is limited by the ineffective rectal sparing devices available commercially and the potential applicator movement. We developed a novel device using a balloon catheter and a belt immobilization system, serving for rectal dose reduction and applicator immobilization purposes, respectively. The balloon catheter is constructed by gluing a short inflatable tube to a long regular open-end catheter. Contrast agent (10) cm3 is injected into the inflatable end, which is affixed to the tandem and ring applicator, to displace the posterior vaginal wall. The belt immobilization system consists of a specially designed bracket that can hold and fix itself to the applicator, a diaper-like Velcro fastener package used for connecting the patient's pelvis to the bracket, and a buckle that holds the fasteners to stabilize the whole system. The treatment data for 21 patients with cervical cancer using both balloon catheter and belt immobilization system were retrospectively analyzed. Computed tomography and magnetic resonance images, acquired about 30 minutes apart, were registered to evaluate the effectiveness of the immobilization system. In comparison with a virtual rectal blade, the balloon decreased the rectal point dose by 34% ± 4.2% (from 276 ± 57 to 182 ± 38 cGy), corresponding to an extra sparing distance of 7.9 ± 1.1 mm. The maximum sparing distance variation per patient is 1.4 ± 0.6 mm, indicating the high interfractional reproducibility for rectum sparing. With the immobilization system, the mean translational and rotational displacements of the applicator set are <3 mm and <1.5°, respectively, in all directions. The rectal balloon provides significant dose reduction to the rectum and it may potentially minimize patient discomfort. The immobilization system permits almost no movement of the applicator during treatment. This work has the potential to be promoted as a standardized solution for high-dose rate treatment of cervical cancer.


Refractive index sensing of green fluorescent proteins in living cells using fluorescence lifetime imaging microscopy.
We show that fluorescence lifetime imaging microscopy (FLIM) of green fluorescent protein (GFP) molecules in cells can be used to report on the local refractive index of intracellular GFP. We expressed GFP fusion constructs of Rac2 and gp91(phox), which are both subunits of the phagocyte NADPH oxidase enzyme, in human myeloid PLB-985 cells and showed by high-resolution confocal fluorescence microscopy that GFP-Rac2 and GFP-gp91(phox) are targeted to the cytosol and to membranes, respectively. Frequency-domain FLIM experiments on these PLB-985 cells resulted in average fluorescence lifetimes of 2.70 ns for cytosolic GFP-Rac2 and 2.31 ns for membrane-bound GFP-gp91(phox). By comparing these lifetimes with a calibration curve obtained by measuring GFP lifetimes in PBS/glycerol mixtures of known refractive index, we found that the local refractive indices of cytosolic GFP-Rac2 and membrane-targeted GFP-gp91(phox) are approximately 1.38 and approximately 1.46, respectively, which is in good correspondence with reported values for the cytosol and plasma membrane measured by other techniques. The ability to measure the local refractive index of proteins in living cells by FLIM may be important in revealing intracellular spatial heterogeneities within organelles such as the plasma and phagosomal membrane.


Point prevalence surveys of antimicrobial use among eight neonatal intensive care units in India: 2016.
Information about antimicrobial use is scarce and poorly understood among neonatal intensive care units (NICUs) in India. In this study, we describe antimicrobial use in eight NICUs using four point prevalence surveys (PPSs). As part of the Global Antimicrobial Resistance, Prescribing, and Efficacy in Neonates and Children (GARPEC) study, one-day, cross-sectional, hospital-based PPSs were conducted four times between 1 February 2016 and 28 February 2017 in eight NICUs. Using a standardized web-based electronic data entry form, detailed data were collected for babies on antimicrobials. A total of 403 babies were admitted to NICUs across all survey days, and 208 (51.6%) were prescribed one or more antimicrobials. Among 208 babies, 155 (74.5%) were prescribed antimicrobials for treatment of an active infection. Among 155 babies with an active infection, treatment was empiric in 109 (70.3%). Sepsis (108, 49.1%) was the most common reason for prescribing antimicrobials. Amikacin (17%) followed by meropenem (12%) were the two most commonly prescribed antimicrobials. For community-acquired sepsis, piperacillin-tazobactam (17.5%) was the most commonly prescribed drug. A combination of ampicillin and gentamicin was prescribed in only two babies (5%). The recommended first-line antimicrobial agents, ampicillin and gentamicin, were rarely prescribed in Indian NICUs for community acquired neonatal sepsis.


The flavanol (-)-epicatechin prevents stroke damage through the Nrf2/HO1 pathway.
Epidemiologic studies have shown that foods rich in polyphenols, such as flavanols, can lower the risk of ischemic heart disease; however, the mechanism of protection has not been clearly established. In this study, we investigated whether epicatechin (EC), a flavanol in cocoa and tea, is protective against brain ischemic damage in mice. Wild-type mice pretreated orally with 5, 15, or 30 mg/kg EC before middle cerebral artery occlusion (MCAO) had significantly smaller brain infarcts and decreased neurologic deficit scores (NDS) than did the vehicle-treated group. Mice that were posttreated with 30 mg/kg of EC at 3.5 hours after MCAO also had significantly smaller brain infarcts and decreased NDS. Similarly, WT mice pretreated with 30 mg/kg of EC and subjected to N-methyl-D-aspartate (NMDA)-induced excitotoxicity had significantly smaller lesion volumes. Cell viability assays with neuronal cultures further confirmed that EC could protect neurons against oxidative insults. Interestingly, the EC-associated neuroprotection was mostly abolished in mice lacking the enzyme heme oxygenase 1 (HO1) or the transcriptional factor Nrf2, and in neurons derived from these knockout mice. These results suggest that EC exerts part of its beneficial effect through activation of Nrf2 and an increase in the neuroprotective HO1 enzyme.


FastEpistasis: a high performance computing solution for quantitative trait epistasis.
Genome-wide association studies have become widely used tools to study effects of genetic variants on complex diseases. While it is of great interest to extend existing analysis methods by considering interaction effects between pairs of loci, the large number of possible tests presents a significant computational challenge. The number of computations is further multiplied in the study of gene expression quantitative trait mapping, in which tests are performed for thousands of gene phenotypes simultaneously. We present FastEpistasis, an efficient parallel solution extending the PLINK epistasis module, designed to test for epistasis effects when analyzing continuous phenotypes. Our results show that the algorithm scales with the number of processors and offers a reduction in computation time when several phenotypes are analyzed simultaneously. FastEpistasis is capable of testing the association of a continuous trait with all single nucleotide polymorphism (SNP) pairs from 500 000 SNPs, totaling 125 billion tests, in a population of 5000 individuals in 29, 4 or 0.5 days using 8, 64 or 512 processors. FastEpistasis is open source and available free of charge only for non-commercial users from http://www.vital-it.ch/software/FastEpistasis.


Quantum-electrodynamical photon splitting in magnetized nonlinear pair plasmas.
We present for the first time the nonlinear dynamics of quantum electrodynamic (QED) photon splitting in a strongly magnetized electron-positron (pair) plasma. By using a QED corrected Maxwell equation, we derive a set of equations that exhibit nonlinear couplings between electromagnetic (EM) waves due to nonlinear plasma currents and QED polarization and magnetization effects. Numerical analyses of our coupled nonlinear EM wave equations reveal the possibility of a more efficient decay channel, as well as new features of energy exchange among the three EM modes that are nonlinearly interacting in magnetized pair plasmas. Possible applications of our investigation to astrophysical settings, such as magnetars, are pointed out.


Structural insights into the recognition of peroxisomal targeting signal 1 by Trypanosoma brucei peroxin 5.
Glycosomes are peroxisome-like organelles essential for trypanosomatid parasites. Glycosome biogenesis is mediated by proteins called "peroxins," which are considered to be promising drug targets in pathogenic Trypanosomatidae. The first step during protein translocation across the glycosomal membrane of peroxisomal targeting signal 1 (PTS1)-harboring proteins is signal recognition by the cytosolic receptor peroxin 5 (PEX5). The C-terminal PTS1 motifs interact with the PTS1 binding domain (P1BD) of PEX5, which is made up of seven tetratricopeptide repeats. Obtaining diffraction-quality crystals of the P1BD of Trypanosoma brucei PEX5 (TbPEX5) required surface entropy reduction mutagenesis. Each of the seven tetratricopeptide repeats appears to have a residue in the alpha(L) conformation in the loop connecting helices A and B. Five crystal structures of the P1BD of TbPEX5 were determined, each in complex with a hepta- or decapeptide corresponding to a natural or nonnatural PTS1 sequence. The PTS1 peptides are bound between the two subdomains of the P1BD. These structures indicate precise recognition of the C-terminal Leu of the PTS1 motif and important interactions between the PTS1 peptide main chain and up to five invariant Asn side chains of PEX5. The TbPEX5 structures reported here reveal a unique hydrophobic pocket in the subdomain interface that might be explored to obtain compounds that prevent relative motions of the subdomains and interfere selectively with PTS1 motif binding or release in trypanosomatids, and would therefore disrupt glycosome biogenesis and prevent parasite growth.


Prehospital Cricothyrotomy Kits Used in Combat.
Surgical cricothyrotomy remains the only definitive airway management modality for the tactical setting recommended by Tactical Combat Casualty Care guidelines. Some units have fielded commercial cricothyrotomy kits to assist Combat Medics with surgical cricothyrotomy. To our knowledge, no previous publications report data on the use of these kits in combat settings. This series reports the the use of two kits in four patients in the prehospital combat setting. Using the Department of Defense Trauma Registry and the Prehospital Trauma Registry, we identified four cases of patients who underwent prehospital cricothyrotomy with the use of commercial kits. In the first two cases, a Medic successfully used a North American Rescue CricKit (NARCK) to obtain a surgical airway in a Servicemember with multiple amputations from an improvised explosive device explosion. In case 3, the Medic unsuccessfully used an H&H Medical kit to attempt placement of a surgical airway in a Servicemember shot in the head by small arms fire. A second attempt to place a surgical airway using a NARCK was successful. In case 4, a Soldier sustained a gunshot wound to the chest. A Medic described fluid in the airway precluding bag-valve-mask ventilation; the Medic attempted to place a surgical airway with the H&H kit without success. Four cases of prehospital surgical airway cannulation on the battlefield demonstrated three successful uses of prehospital cricothyrotomy kits. Further research should focus on determining which kits may be most useful in the combat setting.


Experts practice what they preach: A descriptive study of best and normative practices in end-of-life discussions.
Advance directives (ADs) are widely regarded as the best available mechanism to ensure that patients' wishes about medical treatment at the end of life are respected. However, observational studies suggest that these discussions often fail to meet their stated goals. To explore best practices by describing what physicians who are considered expert in the area of end of-life bioethics or medical communication do when discussing ADs with their patients and to explore the ways in which best practices of the expert group might differ in content or style from normative practice derived from primary care physicians' discussions of ADs with their patients collected as part of an earlier study. Nonexperimental, descriptive study of audiotaped discussions. Outpatient primary care practices in the United States. Eighteen internists who have published articles in the areas of bioethics or communication and 48 of their patients. Fifty-six academic internists and 56 of their established patients in 5 practice sites in 2 locations-Durham, NC, and Pittsburgh, Pa. Eligible patients were at least 65 years old or suffered from serious medical illness and had not previously discussed ADs with their physician. Expert clinicians had discretion regarding patient selection, while the internists chose patients according to a predetermined protocol. Coders applied the Roter Interaction Analysis System (RIAS) to audiotapes of the medical visits to describe communication dynamics. In addition, the audiotapes were scored on 21 items reflecting physician performance in specific skills related to AD discussions. Experts spent close to twice as much time (14.7 vs 8.1 minutes, P<.001) and were less verbally dominant (P<.05) than other physicians during AD discussions. When length of visit was controlled statistically, the expert physicians gave less information about treatment procedures and biomedical issues (P<.05) and asked fewer related questions (P<. 05) but tended toward more psychosocial and lifestyle discussion and questions. Experts engaged in more partnership building (P<.05) with their patients. Patients of the expert physicians engaged in more psychosocial and lifestyle discussion (P<.001), and more positive talk (P<.05) than patients of community physicians. Expert physicians scored higher on the 21 items reflecting AD-specific skills (P<.001). Best practices as reflected in the performance of expert physicians reflect differences in measures of communication style and in specific AD-related proficiencies. Physician training in ADs must be broad enough to include both of these domains. Arch Intern Med. 2000;160:3477-3485.


Evidence Base on Outpatient Behavioral Treatments for Adolescent Substance Use, 2014-2017: Outcomes, Treatment Delivery, and Promising Horizons.
This article updates the evidence base on outpatient behavioral treatments for adolescent substance use (ASU) since publication of the previous review completed for this journal by Hogue, Henderson, Ozechowski, and Robbins (2014). It first summarizes the Hogue et al. findings along with those from recent literature reviews and meta-analytic studies of ASU treatments. It then presents study design and methods criteria used to select 11 comparative studies subjected to Journal of Clinical Child and Adolescent Psychology level of support evaluation. These 11 studies are detailed in terms of their sample characteristics, methodological quality, and substance use outcomes. Cumulative level of support designations are then made for each identified treatment approach. These cumulative designations are virtually identical to those of the previous review: ecological family-based treatment, individual cognitive-behavioral therapy, and group cognitive-behavioral therapy remain well-established; behavioral family-based treatment and motivational interviewing remain probably efficacious; drug counseling remains possibly efficacious; and an updated total of 5 multicomponent treatments combining more than 1 approach (3 of which include contingency management) are deemed well-established or probably efficacious. Treatment delivery issues associated with evidence-based approaches are then reviewed, focusing on client engagement, fidelity and mediator, and predictor and moderator effects. Finally, to help accelerate innovation in ASU treatment science and practice, the article outlines promising horizons in improving youth identification and access, specifying and implementing pragmatic treatment in community settings, and leveraging emerging lessons from implementation science.


Radiation therapy in small cell lung cancer: a national Italian survey.
Radiation therapy plays an important role in the management of SCLC both in curative and palliative setting, however, conflicting data from clinical trials incite debate over the appropriate use of radiation therapy regarding prophylactic cranial irradiation (PCI) and/or thoracic consolidative in extensive-stage SCLC (ES-SCLC). This survey is conducted to evaluate the current pattern of care among Italian radiation oncologists. In June 2016, all Italian radiation oncologists were invited to a web-based survey. The survey contained 34 questions regarding the role of RT in SCLC. Questions pertaining the role of RT in the clinical management of both limited-stage (LS) and ES-SCLC were included. We received 48 responses from Italian radiation oncologists. More than half of respondents had been practicing for more than 10 years after completing residency training and 55% are subspecialists in lung cancer. Preferred management of LS-SCLC favored primary concurrent chemoradiotherapy (89%), even if the 36.9% usually delivered RT during or after the cycle 3 of chemotherapy, due to organizational issues. The most common dose and fractionation schedule in this setting was 60 Gy in 30 once-daily fractions. Furthermore, almost all respondents recommended PCI in patients with LS-SCLC. For ES-SCLC scenario, chemotherapy was defined the standard treatment by all respondents. PCI was recommended in ES-SCLC patients with thoracic complete remission (63% of respondents), with thoracic partial response (45%) and with thoracic stable disease (17%) after first-line chemotherapy. Lastly, the thoracic consolidative RT was recommended by 51% of respondents in patients with ES-SCLC in good response after first-line chemotherapy and a great variability was shown in clinical target volume definition, doses and fractionation schedules. Our analysis showed a high adherence to current guidelines among the respondents in regard to chemoradiation approach in LS-SCLC patients and to PCI indications and doses. The great variability in radiation therapy doses and volumes in the thoracic consolidative radiotherapy in ES-SCLC is concerning. Future clinical trials are needed to standardize these treatment approaches to improve treatment outcomes among patients with ES-SCLC.


The impact of tobacco prices on smoking onset: a methodological review.
The benefits of preventing smoking onset are well known. Existing reviews clearly demonstrate that increasing the prices of tobacco products reduces smoking prevalence and cigarette consumption. However, only a small number of studies included in existing reviews have examined smoking onset (the transition between never smoking and smoking). Moreover, existing reviews provide limited quality assessment of the data and methods utilised. This paper systematically searches for and critically reviews studies that examine the impact of tobacco prices or taxes on smoking onset. Most studies reviewed have important methodological limitations, including recall bias; a general failure to apply diagnostic tests, to discuss the choice of estimators and distributional assumptions and to conduct sensitivity analysis; and a reliance on empirical approaches that are methodologically weak. On the whole, existing studies do not provide strong evidence that tobacco prices or taxes affect smoking onset.


Synthesis and characterization of a family of thioether-dithiolate-bridged heteronuclear iron complexes.
The thioether-dithiolate-bridged heterotrinuclear complexes [Cp*Fe(μ-1k3SSS':2k2SS-tpdt)M(μ-2k2SS:3k3SSS'-tpdt)FeCp*][PF6]2 (Cp* = η5-C5Me5; tpdt = S(CH2CH2S)2; 2, M = Co; 3, M = Ni; 4, M = Pd) have been prepared by a reaction of [Cp*Fe(η3-tpdt)] (1) with complexes CoCl2, NiCl2(PPh3)2, and PdCl2(PPh3)2, respectively. Similarly, treatment of complex 1 with CuCl(PPh3) or AgPF6 afforded two heterotrinuclear complexes, [Cp*Fe(μ-1k3SSS':2k2SS-tpdt)M(μ-2k2SS:3k3SSS'-tpdt)FeCp*][PF6] (5, M = Cu; 6, M = Ag), while reaction of 1 with the complex AuCl(PPh3) gave a heterobinuclear complex, [Cp*Fe(μ-1k3SSS':2k1S-tpdt)Au(PPh3)][PF6] (7). These complexes have been spectroscopically and crystallographically characterized. An X-ray diffraction analysis showed that complexes 2, 3, 5, and 6 feature a heterometal center binding four sulfur atoms of two tpdt ligands with a cis orientation. However, in the Pd-containing complex 4, two tpdt ligands are arranged in a trans configuration. The μeff data and EPR results indicate that complexes 2, 4, 5, 6, and 7 are paramagnetic and only complex 3 is diamagnetic. Electrochemical experiments on these heteronuclear clusters were performed at room temperature. Discrepancy of the redox couples in the CV plots of these complexes indicates different one-electron transfer processes.


Two weeks of watermelon juice supplementation improves nitric oxide bioavailability but not endurance exercise performance in humans.
This study tested the hypothesis that watermelon juice supplementation would improve nitric oxide bioavailability and exercise performance. Eight healthy recreationally-active adult males reported to the laboratory on two occasions for initial testing without dietary supplementation (control condition). Thereafter, participants were randomly assigned, in a cross-over experimental design, to receive 16 days of supplementation with 300 mL·day(-1) of a watermelon juice concentrate, which provided ∼3.4 g l-citrulline·day(-1) and an apple juice concentrate as a placebo. Participants reported to the laboratory on days 14 and 16 of supplementation to assess the effects of the interventions on blood pressure, plasma [l-citrulline], plasma [l-arginine], plasma [nitrite], muscle oxygenation and time-to-exhaustion during severe-intensity exercise. Compared to control and placebo, plasma [l-citrulline] (29 ± 4, 22 ± 6 and 101 ± 23 μM), [l-arginine] (74 ± 9, 67 ± 13 and 116 ± 9 μM) and [nitrite] (102 ± 29, 106 ± 21 and 201 ± 106 nM) were higher after watermelon juice supplementation (P < 0.01). However, systolic blood pressure was higher in the watermelon juice (130 ± 11) and placebo (131 ± 9) conditions compared to the control condition (124 ± 8 mmHg; P < 0.05). The skeletal muscle oxygenation index during moderate-intensity exercise was greater in the watermelon juice condition than the placebo and control conditions (P < 0.05), but time-to-exhaustion during the severe-intensity exercise test (control: 478 ± 80, placebo: 539 ± 108, watermelon juice: 550 ± 143 s) was not significantly different between conditions (P < 0.05). In conclusion, while watermelon juice supplementation increased baseline plasma [nitrite] and improved muscle oxygenation during moderate-intensity exercise, it increased resting blood pressure and did not improve time-to-exhaustion during severe-intensity exercise. These findings do not support the use of watermelon juice supplementation as a nutritional intervention to lower blood pressure or improve endurance exercise performance in healthy adults.


Hallucinogen persisting perception disorder: what do we know after 50 years?
'Flashbacks' following use of hallucinogenic drugs have been reported for decades; they are recognized in DSM-IV as 'Hallucinogen Persisting Perception Disorder (Flashbacks)', or HPPD. We located and analyzed 20 quantitative studies between 1955 and 2001 examining this phenomenon. However, many of these studies were performed before operational criteria for HPPD were published in DSM-III-R, so they are difficult to interpret in the light of current diagnostic criteria. Overall, current knowledge of HPPD remains very limited. In particular (1) the term 'flashbacks' is defined in so many ways that it is essentially valueless; (2) most studies provide too little information to judge how many cases could meet DSM-IV criteria for HPPD; and consequently (3) information about risk factors for HPPD, possible etiologic mechanisms, and potential treatment modalities must be interpreted with great caution. At present, HPPD appears to be a genuine but uncommon disorder, sometimes persisting for months or years after hallucinogen use and causing substantial morbidity. It is reported most commonly after illicit LSD use, but less commonly with LSD administered in research or treatment settings, or with use of other types of hallucinogens. There are case reports, but no randomized controlled trials, of successful treatment with neuroleptics, anticonvulsants, benzodiazepines, and clonidine. Although it may be difficult to collect large samples of HPPD cases, further studies are critically needed to augment the meager data presently available regarding the prevalence, etiology, and treatment of HPPD.


Ethnicity and breast cancer in the UK: Where are we now?
Outcomes from breast cancer for women in the UK have improved significantly over recent decades. These gains are largely attributable to a combination of earlier diagnosis and access to treatments delivered to patients by the National Health Service irrespective of cost. Ethnic minority groups make up almost fifteen percent of the UK population and there is concern however that these groups may have poorer outcomes from the disease. In this short report we seek to summarise what the current evidence tells us about the patterns of breast cancer incidence and outcomes in ethnic minority women in the UK in order to raise awareness about this topic and provide consideration for what future research is needed to address the gaps that may exist.


Construction and characterization of normalized cDNA libraries by 454 pyrosequencing and estimation of DNA methylation levels in three distantly related termite species.
In termites, division of labor among castes, categories of individuals that perform specialized tasks, increases colony-level productivity and is the key to their ecological success. Although molecular studies on caste polymorphism have been performed in termites, we are far from a comprehensive understanding of the molecular basis of this phenomenon. To facilitate future molecular studies, we aimed to construct expressed sequence tag (EST) libraries covering wide ranges of gene repertoires in three representative termite species, Hodotermopsis sjostedti, Reticulitermes speratus and Nasutitermes takasagoensis. We generated normalized cDNA libraries from whole bodies, except for guts containing microbes, of almost all castes, sexes and developmental stages and sequenced them with the 454 GS FLX titanium system. We obtained >1.2 million quality-filtered reads yielding >400 million bases for each of the three species. Isotigs, which are analogous to individual transcripts, and singletons were produced by assembling the reads and annotated using public databases. Genes related to juvenile hormone, which plays crucial roles in caste differentiation of termites, were identified from the EST libraries by BLAST search. To explore the potential for DNA methylation, which plays an important role in caste differentiation of honeybees, tBLASTn searches for DNA methyltransferases (dnmt1, dnmt2 and dnmt3) and methyl-CpG binding domain (mbd) were performed against the EST libraries. All four of these genes were found in the H. sjostedti library, while all except dnmt3 were found in R. speratus and N. takasagoensis. The ratio of the observed to the expected CpG content (CpG O/E), which is a proxy for DNA methylation level, was calculated for the coding sequences predicted from the isotigs and singletons. In all of the three species, the majority of coding sequences showed depletion of CpG O/E (less than 1), and the distributions of CpG O/E were bimodal, suggesting the presence of DNA methylation.


Novel approaches to preventing chemotherapy-induced cognitive dysfunction in breast cancer: the art of the possible.
Chemotherapy-induced cognitive dysfunction in women with breast cancer has become an increasingly important clinical issue. To date, little is known about its incidence, exact characteristics, and exact pathophysiology. Likewise, no treatments have been shown to prevent or decrease cognitive changes thought to result from chemotherapy. However, ongoing scientific research might help us understand the mechanisms that will help patients maintain maximal cognitive function. Changes in cognition due to chemotherapy might result from indirect chemical toxicity and oxidative damage, direct injury to neurons, inflammation, or a type of autoimmune response. Based on these potential causes, and based on interventions that have been tested in dementia and Alzheimer's disease, there are a number of potential, novel interventions that could be tested in clinical trials as treatments for chemotherapy-induced cognitive dysfunction. Possible anecdotal strategies to consider include hormonal interventions, antioxidants, monoamine oxidase inhibitors, growth factors, dopamine agonists, cholinesterase inhibitors, antiinflammatory agents, and behavioral interventions


Acute intracranial hemorrhage in CT: benefits of sinogram-affirmed iterative reconstruction techniques.
Acute intracranial hemorrhage represents a severe and time critical pathology that requires precise and quick diagnosis, mainly by performing a CT scan. The purpose of this study was to compare image quality and intracranial hemorrhage conspicuity in brain CT with sinogram-affirmed iterative reconstruction and filtered back-projection reconstruction techniques at standard (340 mAs) and low-dose tube current levels (260 mAs). A total of 94 consecutive patients with intracranial hemorrhage received CT scans either with standard or low-dose protocol by random assignment. Group 1 (n=54; mean age, 64 ± 20 years) received CT at 340 mAs, and group 2 (n=40; mean age, 57 ± 23 years) received CT at 260 mAs. Images of both groups were reconstructed with filtered back-projection reconstruction and 5 iterative strengths (S1-S5) and ranked blind by 2 radiologists for image quality and intracranial hemorrhage on a 5-point scale. Image noise, SNR, dose-length product (mGycm), and mean effective dose (mSv) were calculated. In both groups, image quality and intracranial hemorrhage conspicuity were rated subjectively with an excellent/good image quality. A higher strength of sinogram-affirmed iterative reconstruction showed an increase in image quality with a difference to filtered back-projection reconstruction (P < .05). Subjective rating showed the best score of image quality and intracranial hemorrhage conspicuity achieved through S3/S4-5. Objective analysis of image quality showed in an increase of SNR with a higher strength of sinogram-affirmed iterative reconstruction. Patients in group 2 (mean: 744 mGycm/1.71 mSv) were exposed to a significantly lower dose than those in group 1 (mean: 1045 mGycm/2.40 mSv, P < .01). S3 provides better image quality and visualization of intracranial hemorrhage in brain CT at 260 mAs. Dose reduction by almost one-third is possible without significant loss in diagnostic quality.


Gene expression profile analysis of mouse colon embryonic development.
During late embryogenesis, the mouse colon develops from a pseudostratified, undifferentiated endoderm to a single-layered columnar epithelium with accompanying mesenchymal maturation. To identify regulatory genetic programs underlying these morphological changes, we profiled gene expression of the developing mouse colon by microarray from embryonic day (E)13.5 to E18.5. Unbiased cluster analysis of 13,484 cDNA elements revealed two distinct groups of genes whose expression changes reflect the dynamic morphological events of the epithelium and mesenchyme during this period. Additional analyses revealed two subsets of genes whose expression is either upregulated or downregulated over the same developmental period. Of those genes whose expression increases from E13.5 to E18.5 (n = 158), known functions include acquisition and/or maintenance of colonic differentiation. Genes whose transcription is downregulated over this period (n = 49) have demonstrated roles in nuclear organization, transcriptional regulation, and cell proliferation. These results provide the basis for a molecular portrait of colonic development during late embryogenesis and should be a valuable resource for investigators interested in colonic development and neoplasia, as well as comparative organogenesis.


Self-assembly and modified luminescence properties of NaY(MoO₄)₂:Tb³⁺, Eu³⁺ inverse opals.
Three-dimensional (3D) inverse opal photonic crystals can not only modulate the emissions of the inserted emitters, they also have the advantage of a large surface to volume ratio, which permits their use in noninvasive fluorescence detection. In this work, novel NaY(MoO4)2:Eu(3+) and NaY(MoO4)2:Tb(3+), Eu(3+) inverse opals were synthesized using a polymethylmethacrylate (PMMA) template by the sol-gel method. It was observed that the photoluminescence (PL) intensity and spontaneous decay rates (SDRs) of the inverse opals were suppressed, in contrast to the corresponding ground reference (REF) samples, due to the modulation of the effective refractive index (n(eff)). The concentration quenching of Eu(3+) and energy transfer from Tb(3+) to Eu(3+) were suppressed, due to the periodic empty cavity structure of the inverse opals.


Meta-analysis of Genome-Wide Association Studies for Extraversion: Findings from the Genetics of Personality Consortium.
Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with an architecture possibly different from other complex human traits, including other personality traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion.


Cost-effectiveness of 13-valent pneumococcal conjugate vaccination in Mongolia.
The Ministry of Health (MOH), Mongolia, is considering introducing 13-valent pneumococcal conjugate vaccine (PCV13) in its national immunization programme to prevent the burden of disease caused by Streptococcus pneumoniae. This study evaluates the cost-effectiveness and budget impact of introducing PCV13 compared to no PCV vaccination in Mongolia. The incremental cost-effectiveness ratio (ICER) of introducing PCV13 compared to no PCV vaccination was assessed using an age-stratified static multiple cohort model. The risk of various clinical presentations of pneumococcal disease (meningitis, pneumonia, non-meningitis non-pneumonia invasive pneumococcal disease and acute otitis media) at all ages for thirty birth cohorts was assessed. The analysis considered both health system and societal perspectives. A 3+0 vaccine schedule and price of US$3.30 per dose was assumed for the baseline scenario based on Gavi, the Vaccine Alliance's advance market commitment tail price. The ICER of PCV13 introduction is estimated at US$52 per disability-adjusted life year (DALY) averted (health system perspective), and cost-saving (societal perspective). Although indirect effects of PCV have been well-documented, a conservative scenario that does not consider indirect effects estimated PCV13 introduction to cost US$79 per DALY averted (health system perspective), and US$19 per DALY averted (societal perspective). Vaccination with PCV13 is expected to cost around US$920,000 in 2016, and thereafter US$820,000 every year. The programme is likely to reduce direct disease-related costs to MOH by US$440,000 in the first year, increasing to US$510,000 by 2025. Introducing PCV13 as part of Mongolia's national programme appears to be highly cost-effective when compared to no vaccination and cost-saving from a societal perspective at vaccine purchase prices offered through Gavi. Notwithstanding uncertainties around some parameters, cost-effectiveness of PCV introduction for Mongolia remains robust over a range of conservative scenarios. Availability of high-quality national data would improve future economic analyses for vaccine introduction.


Food sharing and perceptions of the status of a relationship.
This study examined how individuals may form an impression of the closeness of the relationship between two individuals based on an observation of them sharing food. An opportunity sample of 72 participants watched a video clip of young adults in same-sex or mixed-sex dyads eating a meal together. In the experimental conditions, each member of the dyad also offered or fed a morsel of food to the other person. Analysis showed that food sharing was seen as indicative of familiarity between the members of a dyad. Actually feeding the other person a morsel of food was seen as an indicator of intimacy in male dyads but not in mixed-sex or female dyads. Results are discussed in terms of expectations of intimacy in male and female relationships.


Antihyperlipidemic and antiatherogenic activities of Terminalia pallida Linn. fruits in high fat diet-induced hyperlipidemic rats.
Hyperlipidemia contributes significantly in the manifestation and development of atherosclerosis and coronary heart disease (CHD). Although synthetic lipid-lowering drugs are useful in treating hyperlipidemia, there are number of adverse effects. So the current interest has stimulated the search for new lipid-lowering agents with minimal side effects from natural sources. The present study was designed to investigate the antihyperlipidemic and antiatherogenic potentiality of ethanolic extract of Terminalia pallida fruits in high fat diet-induced hyperlipidemic rats. T. pallida fruits ethanolic extract (TPEt) was prepared using Soxhlet apparatus. Sprague-Dawley male rats were made hyperlipidemic by giving high fat diet, supplied by NIN (National Institute of Nutrition), Hyderabad, India. TPEt was administered in a dose of 100 mg/kg.b.w./day for 30 days in high fat diet-induced hyperlipidemic rats. The body weights, plasma lipid, and lipoprotein levels were measured before and after the treatment. TPEt showed significant antihyperlipidemic and antiatherogenic activities as evidenced by significant decrease in plasma total cholesterol, triglycerides, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol levels coupled together with elevation of high-density lipoprotein cholesterol levels and diminution of atherogenic index in high fat diet-induced hyperlipidemic rats. There was a significantly reduced body weight gain in TPEt-treated hyperlipidemic rats than in the control group. The present study demonstrates that TPEt possesses significant antihyperlipidemic and antiatherogenic properties, thus suggesting its beneficial effect in the treatment of cardiovascular diseases.


Comfort and patient-centred care without excessive sedation: the eCASH concept.
We propose an integrated and adaptable approach to improve patient care and clinical outcomes through analgesia and light sedation, initiated early during an episode of critical illness and as a priority of care. This strategy, which may be regarded as an evolution of the Pain, Agitation and Delirium guidelines, is conveyed in the mnemonic eCASH-early Comfort using Analgesia, minimal Sedatives and maximal Humane care. eCASH aims to establish optimal patient comfort with minimal sedation as the default presumption for intensive care unit (ICU) patients in the absence of recognised medical requirements for deeper sedation. Effective pain relief is the first priority for implementation of eCASH: we advocate flexible multimodal analgesia designed to minimise use of opioids. Sedation is secondary to pain relief and where possible should be based on agents that can be titrated to a prespecified target level that is subject to regular review and adjustment; routine use of benzodiazepines should be minimised. From the outset, the objective of sedation strategy is to eliminate the use of sedatives at the earliest medically justifiable opportunity. Effective analgesia and minimal sedation contribute to the larger aims of eCASH by facilitating promotion of sleep, early mobilization strategies and improved communication of patients with staff and relatives, all of which may be expected to assist rehabilitation and avoid isolation, confusion and possible long-term psychological complications of an ICU stay. eCASH represents a new paradigm for patient-centred care in the ICU. Some organizational challenges to the implementation of eCASH are identified.


Prototype Development, Usability, and Preference of a Culturally-relevant Pictorial Aid to Facilitate Comprehension of Likert-type Levels of Agreement in Caregivers of Children Living With HIV in Ghana.
Pictorial illustrations of Likert-type scales are culturally useful and may reduce error associated with usage of Westernized self-report measures in low- and middle-income countries. Pictorial illustrations can be encounter-specific decision aids in populations with low literacy or English proficiency. In an unanticipated finding from the SANKOFA study, caregivers of children living with human immunodeficiency virus experienced challenges comprehending Likert-type scales. A cross-sectional, qualitative study was conducted with a SANKOFA participant subset (n = 30) in Ghana. Using an informatics-based formative design approach, we developed a culturally-relevant pictorial aid to assess usability and preference when compared to a Likert-type self-report measure. Ninety percent (n = 27) of substudy participants preferred the pictorial of a traditional Bolga basket over a shallow basket. Forty-three percent (n = 13) preferred the pictorial aid over the Likert-type measure. Fifty percent reported the pictorial aid was easy to use. Fifty-seven percent preferred the Likert-type measure, potentially because English proficiency is regarded in Ghana as a means of upward social and financial mobility. Such cultural norms may have contributed to the lack of consensus and must be considered for pictorial aids to be meaningful. Pictorial aids have been designed for use in clinical and research settings. They reduce barriers associated with lower textual literacy while facilitating comprehension and decision-making.


One-dimensional mathematical model of the atrioventricular node including atrio-nodal, nodal, and nodal-his cells.
Mathematical models are a repository of knowledge as well as research and teaching tools. Although action potential models have been developed for most regions of the heart, there is no model for the atrioventricular node (AVN). We have developed action potential models for single atrio-nodal, nodal, and nodal-His cells. The models have the same action potential shapes and refractoriness as observed in experiments. Using these models, together with models for the sinoatrial node (SAN) and atrial muscle, we have developed a one-dimensional (1D) multicellular model including the SAN and AVN. The multicellular model has slow and fast pathways into the AVN and using it we have analyzed the rich behavior of the AVN. Under normal conditions, action potentials were initiated in the SAN center and then propagated through the atrium and AVN. The relationship between the AVN conduction time and the timing of a premature stimulus (conduction curve) is consistent with experimental data. After premature stimulation, atrioventricular nodal reentry could occur. After slow pathway ablation or block of the L-type Ca(2+) current, atrioventricular nodal reentry was abolished. During atrial fibrillation, the AVN limited the number of action potentials transmitted to the ventricle. In the absence of SAN pacemaking, the inferior nodal extension acted as the pacemaker. In conclusion, we have developed what we believe is the first detailed mathematical model of the AVN and it shows the typical physiological and pathophysiological characteristics of the tissue. The model can be used as a tool to analyze the complex structure and behavior of the AVN.


Genome-wide modeling of transcription kinetics reveals patterns of RNA production delays.
Genes with similar transcriptional activation kinetics can display very different temporal mRNA profiles because of differences in transcription time, degradation rate, and RNA-processing kinetics. Recent studies have shown that a splicing-associated RNA production delay can be significant. To investigate this issue more generally, it is useful to develop methods applicable to genome-wide datasets. We introduce a joint model of transcriptional activation and mRNA accumulation that can be used for inference of transcription rate, RNA production delay, and degradation rate given data from high-throughput sequencing time course experiments. We combine a mechanistic differential equation model with a nonparametric statistical modeling approach allowing us to capture a broad range of activation kinetics, and we use Bayesian parameter estimation to quantify the uncertainty in estimates of the kinetic parameters. We apply the model to data from estrogen receptor α activation in the MCF-7 breast cancer cell line. We use RNA polymerase II ChIP-Seq time course data to characterize transcriptional activation and mRNA-Seq time course data to quantify mature transcripts. We find that 11% of genes with a good signal in the data display a delay of more than 20 min between completing transcription and mature mRNA production. The genes displaying these long delays are significantly more likely to be short. We also find a statistical association between high delay and late intron retention in pre-mRNA data, indicating significant splicing-associated production delays in many genes.


The psychometric properties of the Kessler Psychological Distress Scale (K6) in a general population sample of adolescents.
The 6-item Kessler Psychological Distress Scale (K6; Kessler et al., 2002) is a screener for psychological distress that has robust psychometric properties among adults. Given that a significant proportion of adolescents experience mental illness, there is a need for measures that accurately and reliably screen for mental disorders in this age group. This study examined the psychometric properties of the K6 in a large general population sample of adolescents (N = 4,434; mean age = 13.5 years; 44.6% male). Factor analyses were conducted to examine the dimensionality of the K6 in adolescents and to investigate sex-based measurement invariance. This study also evaluated the K6 as a predictor of scores on the Strengths and Difficulties Questionnaire (SDQ; Goodman, 1997). The K6 demonstrated high levels of internal consistency, with the 6 items loading primarily on 1 factor. Consistent with previous research, females reported higher mean levels of psychological distress when compared with males. The identification of sex-based measurement noninvariance in the item thresholds indicated that these mean differences most likely represented reporting bias in the K6 items rather than true differences in the underlying psychological distress construct. The K6 was a fair to good predictor of abnormal scores on the SDQ, but predictive utility was relatively low among males. Future research needs to focus on refining and augmenting the K6 scale to maximize its utility in adolescents. (PsycINFO Database Record


Evaluating policy responses to noncommunicable diseases in seven Caribbean countries: challenges to addressing unhealthy diets and physical inactivity.
To identify, assess, and compare existing policies on noncommunicable diseases (NCDs) in the Caribbean, gaps in policy responses, and the factors influencing successful policy development and implementation following the Port of Spain Declaration of 2007. Specifically, to examine policies that target the upstream determinants of two NCD risk factors-unhealthy diets and physical inactivity. A total of 76 semi-structured interviews with 80 relevant stakeholders in government, the private sector, and civil society were complemented by policy document analysis. Interviews were analyzed pragmatically, framed by the CARICOM government commitments, the WHO NCD Action Plan, a Multiple Streams framework approach, and realist evaluation ideas. The most widely-reported policy successes involved health promotion activities (e.g., school meal programs) that leveraged multisectoral collaboration among government ministries, such as Health, Education, and Agriculture. Large policy gaps still exist around creating legislative, physical, and social environments to support healthy eating and physical activity at the population level. Multisectoral NCD commissions successfully reached across sectors, but had limited influence on policy development. Different policy levels emerged with national-level policies considered a lengthy process, while "On-the-ground" programming was considered faster to implement than national policies. External barriers included a reliance on food imports enabled by international trade agreements limited availability, quality, and affordability of healthy foods. International pushback limited legislation to reduce food imports and the absence of an international/regional framework, similar to the Framework Convention on Tobacco Control, further impedes efforts. Regional collaboration and political support across sectors are essential to accelerating the pace of action to support healthy eating and active living environments. Policy "blueprints" could accelerate the process of development. Regional "NCD champions" could spearhead such responses and approaches.


Dual effects of cortical polarization on peripheral motor activity in the rabbit.
Anodal direct currents at intensities ranging from 0.3 to 30.0 microA were unilaterally applied for 30 min once a day to the premotor area of the rabbit cerebral cortex. The anodal polarization was repeated 10 times at intervals of 2-3 days, and the effect on the motor activity of the forelimbs during and after each polarization trial was compared with that before polarization. Peripheral motor activity was classified as either gentle flexion of forelimbs or struggle with violent movement of forelimbs. A current of 0.3 microA caused no change in motor behavior. Flexion of the forelimb contralateral to the polarized cortex was clearly increased when a polarizing current of 1.0 or 3.0 microA was applied, and peak flexion was observed between the third and seventh polarization trials. A current of 10 or 30 microA had no effect on forelimb flexion. Conversely, forelimb struggle on both sides was decreased when 10.0 or 30.0 microA, but not 1.0 or 3.0 microA, was applied. These results show that anodal polarization of the cerebral cortex exerts dual effects on peripheral motor activity, probably through changes in cortical excitability associated with the current intensity.


A new species of Saccharosydne Kirkaldy from Argentina (Hemiptera: Delphacidae).
Saccharosydne is the most diverse genus of the tribe Saccharosydnini. Male, female and nymphal Saccharosydne have been captured in recent collections from garlic (Allium sativum), rye (Secale cereale) and pampas grass (Cortaderia spp.) in Argentina. In this contribution, we describe and illustrate a new species S. subandina sp. nov., adding information on the geographical distribution and host plants. Saccharosydne subandina can be distinguished from its congeners by the following combination of features: uniformly light green-yellowish color with a distinctive rounded black macula on both genae; vertex 1.5x longer than wide, and projecting beyond eyes almost one half of its length; parameres divergent with internal and external angles acute; and dorsolateral angles of pygofer produced caudad. A key for species identification based on male genitalia and external morphology, is provided.


Airway hyperresponsiveness in the elderly: prevalence and clinical implications.
Airway hyperresponsiveness is associated with an increased risk of developing respiratory symptoms. The assessment of airway hyperresponsiveness can provide valuable information regarding the natural course of respiratory diseases. However, little information is available for populations of more advanced age, and data are conflicting. It was assessed whether age influences the occurrence of airway hyperresponsiveness by reviewing those studies that specifically addressed this issue, and attempting to identify the factors responsible for discrepancies between studies. Eighteen studies, published between 1983 and 2002, are included in this review. Overall, the results of the analysis are in favour of a positive association between age and airway hyperresponsiveness, the prevalence of which appears to increase in the elderly. The most important determinants were reduced lung function, probably due to geometric factors, and a history of smoking, primarily because of the length of exposure, although acute effects were also demonstrated. Atopy should also be considered as an independent determinant of airway hyperresponsiveness in the elderly population. In addition, inflammatory and neuronal mechanisms could be involved. Finally, the role of sex requires further investigation. Assessing the impact of age on the occurrence of airway hyperresponsiveness has important implications: the age-associated alterations to the lung provide a model for evaluating the contribution of structural changes to the pathogenesis of airway hyperresponsiveness. From a clinical standpoint, evaluation of the magnitude of airway hyperresponsiveness could permit the early identification of individuals who are at risk, even at more advanced age. Assessment of airway hyperresponsiveness in the aged should be considered as an additional tool in the diagnostic work-up in the subset of elderly subjects with long-term smoking exposure and/or documented atopy.


Violence in the United States: Status, Challenges, and Opportunities.
Interpersonal violence, which includes child abuse and neglect, youth violence, intimate partner violence, sexual violence, and elder abuse, affects millions of US residents each year. However, surveillance systems, programs, and policies to address violence often lack broad, cross-sector collaboration, and there is limited awareness of effective strategies to prevent violence. To describe the burden of interpersonal violence in the United States, explore challenges to violence prevention efforts and to identify prevention opportunities. We reviewed data from health and law enforcement surveillance systems including the National Vital Statistics System, the Federal Bureau of Investigation's Uniform Crime Reports, the US Justice Department's National Crime Victimization Survey, the National Survey of Children's Exposure to Violence, the National Child Abuse and Neglect Data System, the National Intimate Partner and Sexual Violence Survey, the Youth Risk Behavior Surveillance System, and the National Electronic Injury Surveillance System-All Injury Program. Homicide rates have decreased from a peak of 10.7 per 100,000 persons in 1980 to 5.1 per 100,000 in 2013. Aggravated assault rates have decreased from a peak of 442 per 100,000 in 1992 to 242 per 100,000 in 2012. Nevertheless, annually, there are more than 16,000 homicides and 1.6 million nonfatal assault injuries requiring treatment in emergency departments. More than 12 million adults experience intimate partner violence annually and more than 10 million children younger than 18 years experience some form of maltreatment from a caregiver, ranging from neglect to sexual abuse, but only a small percentage of these violent incidents are reported to law enforcement, health care clinicians, or child protective agencies. Moreover, exposure to violence increases vulnerability to a broad range of mental and physical health problems over the life course; for example, meta-analyses indicate that exposure to physical abuse in childhood is associated with a 54% increased odds of depressive disorder, a 78% increased odds of sexually transmitted illness or risky sexual behavior, and a 32% increased odds of obesity. Rates of violence vary by age, geographic location, sex, and race/ethnicity, and significant disparities exist. Homicide is the leading cause of death for non-Hispanic blacks from age 1 through 44 years, whereas it is the fifth most common cause of death among non-Hispanic whites in this age range. Additionally, efforts to understand, prevent, and respond to interpersonal violence have often neglected the degree to which many forms of violence are interconnected at the individual level, across relationships and communities, and even intergenerationally. The most effective violence prevention strategies include parent and family-focused programs, early childhood education, school-based programs, therapeutic or counseling interventions, and public policy. For example, a systematic review of early childhood home visitation programs found a 38.9% reduction in episodes of child maltreatment in intervention participants compared with control participants. Progress has been made in reducing US rates of interpersonal violence even though a significant burden remains. Multiple strategies exist to improve violence prevention efforts, and health care providers are an important part of this solution.


Heme Induces Endoplasmic Reticulum Stress (HIER Stress) in Human Aortic Smooth Muscle Cells.
Accumulation of damaged or misfolded proteins resulted from oxidative protein modification induces endoplasmic reticulum (ER) stress by activating the pathways of unfolded protein response. In pathologic hemolytic conditions, extracellular free hemoglobin is submitted to rapid oxidation causing heme release. Resident cells of atherosclerotic lesions, after intraplaque hemorrhage, are exposed to heme leading to oxidative injury. Therefore, we raised the question whether heme can also provoke ER stress. Smooth muscle cells are one of the key players of atherogenesis; thus, human aortic smooth muscle cells (HAoSMCs) were selected as a model cell to reveal the possible link between heme and ER stress. Using immunoblotting, quantitative polymerase chain reaction and immunocytochemistry, we quantitated the markers of ER stress. These were: phosphorylated eIF2α, Activating transcription factor-4 (ATF4), DNA-damage-inducible transcript 3 (also known as C/EBP homology protein, termed CHOP), X-box binding protein-1 (XBP1), Activating transcription factor-6 (ATF6), GRP78 (glucose-regulated protein, 78kDa) and heme responsive genes heme oxygenase-1 and ferritin. In addition, immunohistochemistry was performed on human carotid artery specimens from patients who had undergone carotid endarterectomy. We demonstrate that heme increases the phosphorylation of eiF2α in HAoSMCs and the expression of ATF4. Heme also enhances the splicing of XBP1 and the proteolytic cleavage of ATF6. Consequently, there is up-regulation of target genes increasing both mRNA and protein levels of CHOP and GRP78. However, TGFβ and collagen type I decreased. When the heme binding proteins, alpha-1-microglobulin (A1M) and hemopexin (Hpx) are present in cell media, the ER stress provoked by heme is inhibited. ER stress pathways are also retarded by the antioxidant N-acetyl cysteine (NAC) indicating that reactive oxygen species are involved in heme-induced ER stress. Consistent with these findings, elevated expression of the ER stress marker GRP78 and CHOP were observed in smooth muscle cells of complicated lesions with hemorrhage compared to either atheromas or healthy arteries. In conclusion, heme triggers ER stress in a time- and dose-dependent manner in HAoSMCs. A1M and Hpx as well as NAC effectively hamper heme-induced ER stress, supporting their use as a potential therapeutic approach to reverse such a deleterious effects of heme toxicity.


Perceptions of equipoise are crucial to trial participation: a qualitative study of men in the ProtecT study.
Recruitment to trials is known to be difficult. Previous research suggests that a crucial factor may be participants' difficulty with the concept of randomization. This study explored patients' perceptions of randomization and reasons for consent or refusal to participate in the ProtecT study (a randomized trial of surgery, radiotherapy, and monitoring for localized prostate cancer). In-depth interviews were conducted with 21 men diagnosed with localized prostate cancer who were invited to participate in the ProtecT treatment trial. Interviewees were selected purposefully from three U.K. clinical centers to ensure the inclusion of similar proportions of those agreeing or refusing random treatment allocation in each of the treatment groups. Interviews explored men's recall and understanding of chance, comparison, and equipoise, and reasons for consent/refusal of randomization and acceptance/rejection of treatment allocation. Data were analyzed methodically using the techniques of constant comparison. Checking of coding and interpretation was assured by four experienced qualitative researchers. Recall and understanding of the major principles of the randomized design were good and were similar for "chance" and "comparison" between those who consented to and refused randomization. Clinical equipoise, however, caused difficulty. Almost all recalled and understood it, but those who found it acceptable tended to consent to randomization and those who could not accept it tended to refuse to participate. Belief in clinical equipoise was key to participants' consent to randomization. Ensuring patients understand and accept equipoise may thus increase their readiness to consent to participate in trials. A priority for future research is to focus on the provision and presentation of suitable and effective trial information, concentrating in particular on the neglected concept of clinical equipoise.


Embracing the comparative approach: how robust phylogenies and broader developmental sampling impacts the understanding of nervous system evolution.
Molecular biology has provided a rich dataset to develop hypotheses of nervous system evolution. The startling patterning similarities between distantly related animals during the development of their central nervous system (CNS) have resulted in the hypothesis that a CNS with a single centralized medullary cord and a partitioned brain is homologous across bilaterians. However, the ability to precisely reconstruct ancestral neural architectures from molecular genetic information requires that these gene networks specifically map with particular neural anatomies. A growing body of literature representing the development of a wider range of metazoan neural architectures demonstrates that patterning gene network complexity is maintained in animals with more modest levels of neural complexity. Furthermore, a robust phylogenetic framework that provides the basis for testing the congruence of these homology hypotheses has been lacking since the advent of the field of 'evo-devo'. Recent progress in molecular phylogenetics is refining the necessary framework to test previous homology statements that span large evolutionary distances. In this review, we describe recent advances in animal phylogeny and exemplify for two neural characters-the partitioned brain of arthropods and the ventral centralized nerve cords of annelids-a test for congruence using this framework. The sequential sister taxa at the base of Ecdysozoa and Spiralia comprise small, interstitial groups. This topology is not consistent with the hypothesis of homology of tripartitioned brain of arthropods and vertebrates as well as the ventral arthropod and rope-like ladder nervous system of annelids. There can be exquisite conservation of gene regulatory networks between distantly related groups with contrasting levels of nervous system centralization and complexity. Consequently, the utility of molecular characters to reconstruct ancestral neural organization in deep time is limited.


Cell plasticity in lung injury and repair: report from an NHLBI workshop, April 19-20, 2010.
In April 2010, a NIH workshop was convened to discuss the current state of understanding of lung cell plasticity, including the responses of epithelial cells to injury, with the objectives of summarizing what is known, what the field needs to know, and how to get there. The proximal stimulus for this workshop is the body of recent evidence suggesting that plasticity is a prominent but incompletely characterized property of lung epithelial cells, and that a focus on understanding this aspect of epithelial cell biology in particular, may be an important window into disease pathobiology and pathogenesis. In addition to their many vital functions in maintaining tissue homeostasis, epithelial cells have emerged as both a central target of disease initiation and an active contributor to disease progression, making a workshop to investigate the role of cell plasticity in lung injury and repair timely. The workshop was organized around four major themes: lung epithelial cell plasticity, signaling control of plasticity, fibroblast plasticity and crosstalk, and translation to human disease. Although this breakdown was recognized to be somewhat artificial, it was felt that this approach would promote cross-fertilization among groups that ordinarily do not communicate and lend itself to the generation of new approaches. The summary reports of individual group discussions below are followed by consensus priorities and recommendations of the workshop participants.


Policy responses to viral hepatitis B and C among people who inject drugs in Member States of the WHO European region: a sub-analysis of the WHO 2013 global hepatitis policy survey.
Unsafe injections, through infectious bodily fluids, are a major route of transmission for hepatitis B and C. Viral hepatitis burden among people who inject drugs is particularly high in many Member States of central and Eastern Europe while national capacity and willingness to address it varies greatly. The initial survey included 43 questions covering awareness, data, prevention, and screening and treatment. It was sent in five languages to identified national focal points. This sub-analysis included 11 questions and 53 Member States in the WHO European Region. Descriptive analyses of national activities are presented. As a secondary outcome bivariate analyses of differences between Member States of the European Union (EU) and European Free Trade Association (EFTA) compared to those not in said grouping are presented. Forty-four of the 53 Member States responded to the survey (response rate of 83%). More than three-quarters reported offering publicly-funded treatment for HBV or HCV (82% and 80%, respectively), with a significantly higher proportion of EU/EFTA Member States (P=0.004 and P=0.010, respectively). Half of Member States (53%) reported the existence of a national policy for hepatitis prevention and control; however less than one-third (27%) reported having written national strategies. Under half of the responding Member States reported holding events for World Hepatitis Day 2012. One-fifth reported offering hepatitis B and C testing free of charge, with less than one-third reportedly conducting regular serosurveys among people who inject drugs. Findings highlight key gaps requiring attention in order to improve national policies and programmes in the region and ensure an adequate response to injection drug use-associated viral hepatitis. Further studies are required to assess quality and impact of national policies and services.


Nasopharyngeal isolates and their clinical impact on young children with asthma: a pilot study.
Respiratory infections have significant effects on childhood asthma. Viral respiratory infections, such as rhinovirus and respiratory syncytial virus are likely to be important in the development and exacerbation of asthma. In this study, we investigated the nasopharyngeal colonization in children with asthma to determine the prevalence of pathogens and their contribution to respiratory symptoms and airway resistance during winter. From December 2016 to March 2017, 50 nasopharyngeal specimens were collected from 18 patients (age, 5.0±1.1 years) with asthma and 9 specimens from 9 control children (age, 4.9±1.0 years). Samples were tested for 19 viruses and 7 bacteria, using multiplex real-time PCR. Respiratory disease markers included the Global Asthma Network Questionnaire, the Common-Cold Questionnaire, the Global Initiative for Asthma assessment of asthma control, and the airway resistance at 5 Hz by forced-oscillation technique. The most commonly isolated organisms in both groups (patients and controls) were Streptococcus pneumoniae, Haemophilus influenzae, and rhinovirus. Most patients had multiple isolates (median, 3.5; range, 1-5), which changed during the study period. Types of isolates were 4 bacteria (S. pneumoniae, H. influenzae, Bordetella pertussis, and Bordetella parapertussis) and 6 viruses (rhinovirus, enterovirus, metapneumovirus, adenovirus, coronaviruses, and parainfluenza viruses). Similar isolates, including influenza A-H3 virus and bocavirus, were detected in the controls. Of the 9 patients with "wheezing disturbing sleep ≥1 per week", 6 had rhinovirus, 2 coronaviruses, and 1 no detectable viruses. Patients with mild common cold symptoms had significantly higher airway resistance at 5 Hz z-score (P=0.025). Multiple respiratory pathogens were isolated from many patients with asthma, which appeared to contribute to disease symptoms and airway resistance. Minimizing children's exposure to respiratory pathogens might be beneficial, especially during winter.


Porous metal acetabular components have a low rate of mechanical failure in THA after operatively treated acetabular fracture.
Total hip arthroplasty (THA) for the treatment of posttraumatic osteoarthritis (OA) after acetabular fracture has been associated with a high likelihood of aseptic loosening, instability, and infection. Porous metal components may help to address the issue of loosening, but there are few data on the use of porous metal acetabular components for posttraumatic OA after acetabular fracture. Using an institutional registry, we aimed to report (1) radiographic evidence of fixation; (2) survivorship free from revision; (3) Harris hip scores; and (4) complications and reoperations after THA with a porous metal acetabular component for posttraumatic OA in patients previously treated with open reduction and internal fixation (ORIF) of a displaced acetabular fracture. Thirty primary THAs were performed with a porous metal acetabular component for the treatment of posttraumatic OA after ORIF of an acetabular fracture from 1999 through 2010; of these, 28 (93%) were available for followup at a minimum of 2 years. During that same time, 51 primary THAs were performed using other acetabular designs in patients who had previously undergone ORIF of the acetabulum. During the period in question, the general indications for use of porous metal in this setting included compromised acetabular bone stock or quality to the extent that the treating surgeon believed primary fixation with a titanium shell and screws may have been difficult to achieve. Mean age at the time of arthroplasty was 45 years (range, 23-75 years). Median time from ORIF to THA and from THA to last followup was 107 months (range, 4 months to 42 years) and 60 months (range, 25 months to 10 years), respectively. Radiographs were reviewed for this specific study to evaluate the components for evidence of osteointegration. Survivorship free from revision, hip scores, and complications were extracted from our institutional database and electronic medical record. No acetabular or femoral components were revised for aseptic loosening. Five-year survival with revision for any reason as the endpoint was 88% (95% confidence interval, 0.70-0.96). Harris hip scores improved from a median of 39 preoperatively (range, 3-87) to 82 at last followup (range, 21-100; p<0.01). Three hips (11%) underwent resection for infection and all three had been treated with staged arthroplasty for concern of infection. Two patients (7%) experienced at least one dislocation postoperatively. The short-term results of the use of porous metal acetabular components in THA for treatment of posttraumatic OA after acetabular fracture demonstrate low rates of mechanical failure. Although infection and instability remain major concerns in patients with this diagnosis seemingly regardless of the implant design used, porous metal components appear to offer a high likelihood of osseointegration in this clinical setting. Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.


Cytometric sorting based on the fluorescence lifetime of spectrally overlapping signals.
Flow cytometry is a well-established and powerful high- throughput fluorescence measurement tool that also allows for the sorting and enrichment of subpopulations of cells expressing unique fluorescence signatures. Owing to the reliance on intensity-only signals, flow cytometry sorters cannot easily discriminate between fluorophores that spectrally overlap. In this paper we demonstrate a new method of cell sorting using a fluorescence lifetime-dependent methodology. This approach, referred to herein as phase-filtered cell sorting (PFCS), permits sorting based on the average fluorescence lifetime of a fluorophore by separating fluorescence signals from species that emit differing average fluorescence lifetimes. Using lifetime-dependent hardware, cells and microspheres labeled with fluorophores were sorted with purities up to 90%. PFCS is a practical approach for separating populations of cells that are stained with spectrally overlapping fluorophores or that have interfering autofluorescence signals.


Bone marrow transplantation improves proximal tubule dysfunction in a mouse model of Dent disease.
Dent disease is a rare X-linked tubulopathy caused by mutations in the endosomal chloride-proton exchanger (ClC-5) resulting in defective receptor-mediated endocytosis and severe proximal tubule dysfunction. Bone marrow transplantation has recently been shown to preserve kidney function in cystinosis, a lysosomal storage disease causing proximal tubule dysfunction. Here we test the effects of bone marrow transplantation in Clcn5Y/- mice, a faithful model for Dent disease. Transplantation of wild-type bone marrow in Clcn5Y/- mice significantly improved proximal tubule dysfunction, with decreased low-molecular-weight proteinuria, glycosuria, calciuria, and polyuria four months after transplantation, compared to Clcn5Y/- mice transplanted with ClC-5 knockout bone marrow. Bone marrow-derived cells engrafted in the interstitium, surrounding proximal tubule cells, which showed a rescue of the apical expression of ClC-5 and megalin receptors. The improvement of proximal tubule dysfunction correlated with Clcn5 gene expression in kidneys of mice transplanted with wild-type bone marrow cells. Coculture of Clcn5Y/- proximal tubule cells with bone marrow-derived cells confirmed rescue of ClC-5 and megalin, resulting in improved endocytosis. Nanotubular extensions between the engrafted bone marrow-derived cells and proximal tubule cells were observed in vivo and in vitro. No rescue was found when the formation of the tunneling nanotubes was prevented by actin depolymerization or when cells were physically separated by transwell inserts. Thus, bone marrow transplantation may rescue the epithelial phenotype due to an inherited endosomal defect. Direct contacts between bone marrow-derived cells and diseased tubular cells play a key role in the rescue mechanism.


Initial scaffold thickness affects the emergence of a geometrical and mechanical equilibrium in engineered cardiovascular tissues.
In situ cardiovascular tissue-engineering can potentially address the shortcomings of the current replacement therapies, in particular, their inability to grow and remodel. In native tissues, it is widely accepted that physiological growth and remodelling occur to maintain a homeostatic mechanical state to conserve its function, regardless of changes in the mechanical environment. A similar homeostatic state should be reached for tissue-engineered (TE) prostheses to ensure proper functioning. For in situ tissue-engineering approaches obtaining such a state greatly relies on the initial scaffold design parameters. In this study, it is investigated if the simple scaffold design parameter initial thickness, influences the emergence of a mechanical and geometrical equilibrium state in in vitro TE constructs, which resemble thin cardiovascular tissues such as heart valves and arteries. Towards this end, two sample groups with different initial thicknesses of myofibroblast-seeded polycaprolactone-bisurea constructs were cultured for three weeks under dynamic loading conditions, while tracking geometrical and mechanical changes temporally using non-destructive ultrasound imaging. A mechanical equilibrium was reached in both groups, although at different magnitudes of the investigated mechanical quantities. Interestingly, a geometrically stable state was only established in the thicker constructs, while the thinner constructs' length continuously increased. This demonstrates that reaching geometrical and mechanical stability in TE constructs is highly dependent on functional scaffold design.


A simple algorithm for identifying negated findings and diseases in discharge summaries.
Narrative reports in medical records contain a wealth of information that may augment structured data for managing patient information and predicting trends in diseases. Pertinent negatives are evident in text but are not usually indexed in structured databases. The objective of the study reported here was to test a simple algorithm for determining whether a finding or disease mentioned within narrative medical reports is present or absent. We developed a simple regular expression algorithm called NegEx that implements several phrases indicating negation, filters out sentences containing phrases that falsely appear to be negation phrases, and limits the scope of the negation phrases. We compared NegEx against a baseline algorithm that has a limited set of negation phrases and a simpler notion of scope. In a test of 1235 findings and diseases in 1000 sentences taken from discharge summaries indexed by physicians, NegEx had a specificity of 94.5% (versus 85.3% for the baseline), a positive predictive value of 84.5% (versus 68.4% for the baseline) while maintaining a reasonable sensitivity of 77.8% (versus 88.3% for the baseline). We conclude that with little implementation effort a simple regular expression algorithm for determining whether a finding or disease is absent can identify a large portion of the pertinent negatives from discharge summaries.


Metonitazene in the United States-Forensic toxicology assessment of a potent new synthetic opioid using liquid chromatography mass spectrometry.
Metonitazene is considered a new psychoactive substance (NPS) and emerging potent synthetic opioid, causing increased public health concern beginning in 2020. Metonitazene joins a growing list of new synthetic opioids (NSOs) contributing to deaths among people who use drugs in the United States and other parts of the world. Metonitazene (a 2-benzylbenzimidazole analogue) first appeared in mid-2020 in the recreational drug supply and subsequently began proliferating in death investigation casework towards the end of 2020. Screening and metabolite discovery were performed by liquid chromatography quadrupole time-of-flight mass spectrometry. Quantitative confirmation was performed by liquid chromatography tandem quadrupole mass spectrometry. Metonitazene was confirmed in 20 authentic forensic postmortem cases with an average concentration in blood at 6.3 ± 7.5 ng/ml (median: 3.8 ng/ml, range: 0.5-33 ng/ml, n = 18) and in urine at 15 ± 13 ng/ml (median: 11 ng/ml, range: 0.6-46 ng/ml, n = 14). Metonitazene was the only opioid identified in 30% of cases but was also found in combination with fentanyl (55%) and NPS benzodiazepines, opioids, and hallucinogens (45%). Medical examiners included metonitazene as a drug responsible for the cause of death, and the manner of death was always ruled to be an accident. The metabolism of metonitazene was found to be similar to that of isotonitazene, a closely related analogue. Toxicology laboratories and death investigators should ensure that metonitazene is included in forensic testing protocols, all while remaining vigilant for subsequent NSOs to emerge.


Astrogliosis: An integral player in the pathogenesis of Alzheimer's disease.
Alzheimer's disease is the main cause of dementia in the elderly and begins with a subtle decline in episodic memory followed by a more general decline in overall cognitive abilities. Though the exact trigger for this cascade of events remains unknown the presence of the misfolded amyloid-beta protein triggers reactive gliosis, a prominent neuropathological feature in the brains of Alzheimer's patients. The cytoskeletal and morphological changes of astrogliosis are its evident features, while changes in oxidative stress defense, cholesterol metabolism, and gene transcription programs are less manifest. However, these latter molecular changes may underlie a disruption in homeostatic regulation that keeps the brain environment balanced. Astrocytes in Alzheimer's disease show changes in glutamate and GABA signaling and recycling, potassium buffering, and in cholinergic, purinergic, and calcium signaling. Ultimately the dysregulation of homeostasis maintained by astrocytes can have grave consequences for the stability of microcircuits within key brain regions. Specifically, altered inhibition influenced by astrocytes can lead to local circuit imbalance with farther reaching consequences for the functioning of larger neuronal networks. Healthy astrocytes have a role in maintaining and modulating normal neuronal communication, synaptic physiology and energy metabolism, astrogliosis interferes with these functions. This review considers the molecular and functional changes occurring during astrogliosis in Alzheimer's disease, and proposes that astrocytes are key players in the development of dementia.


Two new genera of songbirds represent endemic radiations from the Shola Sky Islands of the Western Ghats, India.
A long-standing view of Indian biodiversity is that while rich in species, there are few endemics or in-situ radiations within the subcontinent. One exception is the Western Ghats biodiversity hotspot, an isolated mountain range with many endemic species. Understanding the origins of the montane-restricted species is crucial to illuminate both taxonomic and environmental history. With evidence from genetic, morphometric, song, and plumage data, we show that two songbird lineages endemic to the Western Ghats montane forest each have diversified into multiple distinct species. Historically labeled as single species of widespread Asian genera, these two lineages are highly divergent and do not group with the taxa in which they were previously classified but rather are distinct early divergences in larger Asian clades of flycatchers and babblers. Here we designated two new genera, the Western Ghats shortwings as Sholicola and the laughingthrushes as Montecincla, and evaluated species-limits to reflect distinct units by revising six previously named taxa and describing one novel species. Divergence dating showed that both these montane groups split from their Himalayan relatives during the Miocene, which is coincident with a shift towards arid conditions that fragmented the previously contiguous humid forest across peninsular India and isolated these lineages in the Western Ghats. Furthermore, these two genera showed congruent patterns of diversification across the Western Ghats Sky Islands, coincident with other climatic changes. Our study reveals the existence of two independent endemic radiations in the high montane Western Ghats or Shola Sky Islands with coincident divergence times, highlighting the role of climate in the diversification of these ancient lineages. The endemic and highly divergent nature of these previously unrecognized species underscores the dearth of knowledge about the biogeography of the Asian tropics, even for comparatively well-known groups such as birds. The substantial increase in the diversity of this region underscores the need for more rigorous systematic analysis to inform biodiversity studies and conservation efforts.


Economic analysis for clinical practice--the case of 31 national consensus guidelines in the Netherlands.
Evidence on the cost-effectiveness of health interventions in the development of practice guidelines has become of interest in many countries. Challenges are the quality of economic data, the use of cost-effectiveness criteria, and the consensus process. Our paper aims to assess the quality and use of economic information in the formulation of consensus guidelines in a Dutch pilot programme and to recommend improvements. Retrospective qualitative review of economic evaluations and formulated recommendations, using a checklist based on international standards. The national programme to support the development of guidelines with economic analysis in multidisciplinary consensus groups run from 1998 to 2002. It has included 31 medical guidelines, addressing 23 conditions across seven International Classification of Diseases (ICD)-disease groups. Experts in health technology assessment have participated in the guidelines groups. Economic information in all guidelines varies by all criteria in the level of evidence used. Information on quality-adjusted life years gained is limited as is statistical analysis in most studies. Highest cost-effectiveness ratios reported are between Euros 20,000 and Euros 30,000. However, there is no uniformity in the definitions of acceptable cost-effectiveness ratios. Economic recommendations can be included in guidelines. Interaction between clinicians and health economists promotes a balance between medical and economic arguments. Among panellists there appears to be agreement on the level of the cost-effectiveness ratios that is acceptable. It is recommended that economic analysis is used to strengthen the evidence-base of guidelines. An evidence-grading system should include the quality of economic evaluation. Roles of policymakers and providers need to be defined.


Clinical assessment in ischaemic cardiomyopathy.
Despite the trend of decreasing death rates attributable to ischaemic heart disease and stroke, the prevalence of heart failure and the resultant death rates in the United States have almost tripled between 1974 and 1994 [1]. Coronary artery disease is the commonest cause of heart failure in developed countries, accounting for up to 60% of cases. Advances in medical therapy, particularly the use of angiotensin-converting enzyme inhibitors and beta-blockers, have served to reduce morbidity and mortality in patients with left ventricular (LV) dysfunction due to coronary artery disease [2-5]. However, these improvements have been modest, and despite these therapies, patients with severe ischaemic cardiomyopathy continue to have a high mortality when treated medically. It is increasingly clear that the impaired LV function in these patients is not always an irreversible process. Traditionally, these observations have been made following demonstrable improvements in systolic function after coronary revascularization procedures. Diagnostic testing to evaluate the presence and extent of viable myocardium has therefore become an important component of the clinical assessment of patients with chronic coronary artery disease and LV dysfunction.