Oregon physicians' perceptions of patients who request assisted suicide and their families.
In 1997, the Oregon Death with Dignity Act was enacted, allowing a physician to prescribe a lethal dose of medication for a competent, terminally ill patient who requests one. In 2000, we conducted single, semistructured, in-depth, face-to-face interviews with 35 Oregon physicians who received a request for a lethal prescription. The interviews focused on physicians' perceptions of patients who requested assisted suicide, the reasons for the request, and the reactions of their families. The interviews were audiotaped, transcribed, and analyzed using qualitative techniques. Physicians described requesting patients as having strong and vivid personalities characterized by determination and inflexibility. These individuals wanted to control the timing and manner of death and to avoid dependence on others. These preferences reflected long-standing coping and personality traits. Physicians perceived that these patients viewed living as purposeless and too effortful, and that they were ready for death. The requests, which were forceful and persistent, could occur at any point after diagnosis of the terminal illness, and were paralleled by refusal of medical interventions including palliative treatments. Many family members were reluctant to support these requests until they recognized the strength of the preference.


Theileria annulata in CD5(+) macrophages and B1 B cells.
Theileria parasites infect and transform bovine leukocytes. We have analyzed laboratory-established Theileria sp.-infected leukocyte lines and observed that transformed macrophages express CD5. Low-level expression of CD5 by macrophages was further confirmed on three independent Theileria annulata clinical isolates from Tunisia. Interestingly, the fourth CD5(+) clinical isolate (MB2) was morphologically different, expressed surface immunoglobulin M (IgM) and BoLA class II, and had rearranged Ig light-chain genes. To demonstrate that MB2 did indeed contain CD5(+) B cells, individual clonal lines were obtained by limiting dilution, and CD5 expression and Ig gene rearrangement were confirmed. This suggests that in natural infections T. annulata can invade and transform CD5(+) B cells.


Spatially distributed dendritic resonance selectively filters synaptic input.
An important task performed by a neuron is the selection of relevant inputs from among thousands of synapses impinging on the dendritic tree. Synaptic plasticity enables this by strenghtening a subset of synapses that are, presumably, functionally relevant to the neuron. A different selection mechanism exploits the resonance of the dendritic membranes to preferentially filter synaptic inputs based on their temporal rates. A widely held view is that a neuron has one resonant frequency and thus can pass through one rate. Here we demonstrate through mathematical analyses and numerical simulations that dendritic resonance is inevitably a spatially distributed property; and therefore the resonance frequency varies along the dendrites, and thus endows neurons with a powerful spatiotemporal selection mechanism that is sensitive both to the dendritic location and the temporal structure of the incoming synaptic inputs.


Expression of Fap amyloids in Pseudomonas aeruginosa, P. fluorescens, and P. putida results in aggregation and increased biofilm formation.
The fap operon, encoding functional amyloids in Pseudomonas (Fap), is present in most pseudomonads, but so far the expression and importance for biofilm formation has only been investigated for P. fluorescens strain UK4. In this study, we demonstrate the capacity of P. aeruginosa PAO1, P. fluorescens Pf-5, and P. putida F1 to express Fap fibrils, and investigated the effect of Fap expression on aggregation and biofilm formation. The fap operon in all three Pseudomonas species conferred the ability to express Fap fibrils as shown using a recombinant approach. This Fap overexpression consistently resulted in highly aggregative phenotypes and in increased biofilm formation. Detailed biophysical investigations of purified fibrils confirmed FapC as the main fibril monomer and supported the role of FapB as a minor, nucleating constituent as also indicated by bioinformatic analysis. Bioinformatics analysis suggested FapF and FapD as a potential β-barrel membrane pore and protease, respectively. Manipulation of the fap operon showed that FapA affects monomer composition of the final amyloid fibril, and that FapB is an amyloid protein, probably a nucleator for FapC polymerization. Our study highlights the fap operon as a molecular machine for functional amyloid formation.


Association of copeptin with myocardial infarct size and myocardial function after ST segment elevation myocardial infarction.
To investigate the relationship between circulating plasma copeptin values and infarct size as well as myocardial function at baseline and 4 months after mechanical reperfusion for ST segment elevation myocardial infarction (STEMI). Prospective observational cohort study. University Hospital of Innsbruck. 54 patients with acute STEMI. Correlation of plasma copeptin with infarct size as well as left ventricular ejection fraction (LVEF) and remodelling. Participants underwent contrast enhanced cardiac MRI at baseline and 4 months thereafter. Blood samples were drawn 2 days after the onset of symptoms. Copeptin values were determined by an immunofluorescent assay. Copeptin concentrations (median 10.4 pmol/l, IQR 6.0-14.4) were associated with early and chronic infarct size (r=0.388, p=0.004 at baseline; r=0.385, p=0.011 at follow-up) and inversely related to LVEF at both times (r=-0.484, p<0.001 at baseline; r=-0.461, p<0.001 at follow-up). Patients with adverse remodelling showed higher baseline copeptin values compared to patients without remodelling (p=0.02). Receiver operating characteristic analysis indicated a cut-off value of 16.7 pmol/l for copeptin to best identify patients with future adverse remodelling. Increased copeptin values 2 days after STEMI are associated with larger acute and chronic infarct sizes. Moreover, elevated copeptin concentrations at baseline were associated with myocardial function and remodelling 4 months post-STEMI. These findings strengthen the role of copeptin as a biomarker of adverse outcome after STEMI.


Performance of a high-throughput next-generation sequencing method for analysis of HIV drug resistance and viral load.
To evaluate the performance of a high-throughput research assay for HIV drug resistance testing based on whole genome next-generation sequencing (NGS) that also quantifies HIV viral load. Plasma samples (n = 145) were obtained from HIV-positive MSM (HPTN 078). Samples were analysed using clinical assays (the ViroSeq HIV-1 Genotyping System and the Abbott RealTime HIV-1 Viral Load assay) and a research assay based on whole-genome NGS (veSEQ-HIV). HIV protease and reverse transcriptase sequences (n = 142) and integrase sequences (n = 138) were obtained using ViroSeq. Sequences from all three regions were obtained for 100 (70.4%) of the 142 samples using veSEQ-HIV; results were obtained more frequently for samples with higher viral loads (93.5% for 93 samples with >5000 copies/mL; 50.0% for 26 samples with 1000-5000 copies/mL; 0% for 23 samples with <1000 copies/mL). For samples with results from both methods, drug resistance mutations (DRMs) were detected in 33 samples using ViroSeq and 42 samples using veSEQ-HIV (detection threshold: 5.0%). Overall, 146 major DRMs were detected; 107 were detected by both methods, 37 were detected by veSEQ-HIV only (frequency range: 5.0%-30.6%) and two were detected by ViroSeq only. HIV viral loads estimated by veSEQ-HIV strongly correlated with results from the Abbott RealTime Viral Load assay (R2 = 0.85; n = 142). The NGS-based veSEQ-HIV method provided results for most samples with higher viral loads, was accurate for detecting major DRMs, and detected mutations at lower levels compared with a method based on population sequencing. The veSEQ-HIV method also provided HIV viral load data.


Does Hypohydration Really Impair Endurance Performance? Methodological Considerations for Interpreting Hydration Research.
The impact of alterations in hydration status on human physiology and performance responses during exercise is one of the oldest research topics in sport and exercise nutrition. This body of work has mainly focussed on the impact of reduced body water stores (i.e. hypohydration) on these outcomes, on the whole demonstrating that hypohydration impairs endurance performance, likely via detrimental effects on a number of physiological functions. However, an important consideration, that has received little attention, is the methods that have traditionally been used to investigate how hypohydration affects exercise outcomes, as those used may confound the results of many studies. There are two main methodological limitations in much of the published literature that perhaps make the results of studies investigating performance outcomes difficult to interpret. First, subjects involved in studies are generally not blinded to the intervention taking place (i.e. they know what their hydration status is), which may introduce expectancy effects. Second, most of the methods used to induce hypohydration are both uncomfortable and unfamiliar to the subjects, meaning that alterations in performance may be caused by this discomfort, rather than hypohydration per se. This review discusses these methodological considerations and provides an overview of the small body of recent work that has attempted to correct some of these methodological issues. On balance, these recent blinded hydration studies suggest hypohydration equivalent to 2-3% body mass decreases endurance cycling performance in the heat, at least when no/little fluid is ingested.


The efficacy of flapless implant surgery on soft-tissue profile comparing immediate loading implants to delayed loading implants: A comparative clinical study.
To assess the efficacy of flapless implant surgery on soft-tissue profile and to compare the clinical outcomes of flapless implant therapy on immediate loading (IL) implants to delayed loading (DL) implants. The study sample consisted of 20 patients who were partially edentulous in the anterior maxillary region. They were divided into two groups. In group I (IL) 10 implants were placed and immediately provisionalized and restored with a metal ceramic crown on the 14th day. In group II (DL) 10 implants were placed and loaded after 4 months. Single-piece implants were used for the IL group and two-piece implants were used for the DL group. All soft tissue parameters i.e., modified plaque index (mPI), modified bleeding index (mBI), papillary index (PPI), marginal level of soft tissue (ML) and width of keratinized mucosa (WKM) were recorded at baseline, Day 60, Day 120 and Day 180. The success rate in group I was found to be 80%, which was lower than the success rate in group II which was found to be 90%. On comparison, there is no statistically significant difference in success rate between the two study groups. There was no statistically significant difference between the groups over time in parameters like mPI, mBI, ML and WKM. The mean PPI score in group II showed a significant increase from when compared to group I. The results of this study indicated that flapless implant surgery using either immediately loading implants or DL implants, demonstrate enhancement of implant esthetics.


Efficacy comparison of trimetazidine with therapeutic alternatives in stable angina pectoris: a network meta-analysis.
To compare the antianginal efficacy of trimetazidine with that of other agents with no influence on heart rate. Medline and Embase databases were searched for blinded, randomized, controlled trials assessing the effects of non-heart-rate-lowering antianginal treatments on exercise tolerance and/or clinical criteria in stable angina patients. All relevant trimetazidine trials including the VASCO trial, the results of which are published herein, were included. A Bayesian network meta-analysis on the summary data was performed. Comparator antianginal agents were considered as a group and in agent/class subgroups. Trials involving β-blockers, non-dihydropyridine calcium channel blockers, and ivabradine were excluded. 218 trials totaling 19,028 patients were included in at least 1 network analysis. Effects of trimetazidine were statistically significant compared with placebo for exercise tolerance and clinical criteria. Transposition of results into seconds for clinical interpretation of exercise tolerance parameters showed a mean improvement of +46 s (95% credibility interval: 28; 66) for total exercise duration, +55 s (35; 77) for 1-mm ST segment depression (T1), and +54 s (24; 84) for time to onset of angina, in favor of trimetazidine. Differences between trimetazidine and active comparators were not significant when exercise tolerance and clinical criteria were analyzed, with +7 s (-12; 28) for total exercise duration, -1 s (-23; 22) for T1, +8 s (-22; 40) for time to onset of angina, and -0.28 (-1.17; 0.64) attacks per week for trimetazidine compared with antianginal agents as a group. Trimetazidine efficacy was comparable to that of other non-heart-rate-lowering antianginal treatments in patients with stable angina pectoris.


Improving the throughput of automated holographic optical tweezers.
The purpose of this work is to introduce three improvements to automated holographic-optical-tweezers systems that increase the number and speed of particles that can be manipulated simultaneously. First, we address path planning by solving a bottleneck assignment problem, which can reduce total move time by up to 30% when compared with traditional assignment problem solutions. Next, we demonstrate a new strategy to identify and remove undesired (e.g., misshapen or agglomerated) particles. Finally, we employ a controller that combines both closed- and open-loop automation steps, which can increase the overall loop rate and average particle speeds while also utilizing necessary process monitoring checks to ensure that particles reach their destinations. Using these improvements, we show fast reconfiguration of 100 microspheres simultaneously with a closed-loop control rate of 6, and 10 Hz by employing both closed- and open-loop steps. We also demonstrate the closed-loop assembly of a large pattern in a continuously flowing microchannel-based particle-delivery system. The proposed approach provides a promising path toward automatic and scalable assembly of microgranular structures.


Molecular imprinting at walls of silica nanotubes for TNT recognition.
This paper reports the molecular imprinting at the walls of highly uniform silica nanotubes for the recognition of 2,4,6-trinitrotoluene (TNT). It has been demonstrated that TNT templates were efficiently imprinted into the matrix of silica through the strong acid-base pairing interaction between TNT and 3-aminopropyltriethoxysilane (APTS). TNT-imprinted silica nanotubes were synthesized by the gelation reaction between APTS and tetraethylorthosilicate (TEOS), selectively occurring at the porous walls of APTS-modified alumina membranes. The removal of the original TNT templates leaves the imprinted cavities with covalently anchored amine groups at the cavity walls. A high density of recognition sites with molecular selectivity to the TNT analyte was created at the wall of silica nanotubes. Furthermore, most of these recognition sites are situated at the inside and outside surfaces of tubular walls and in the proximity of the two surfaces due to the ultrathin wall thickness of only 15 nm, providing a better site accessibility and lower mass-transfer resistance. Therefore, greater capacity and faster kinetics of uptaking target species were achieved. The silica nanotube reported herein is an ideal form of material for imprinting various organic or biological molecules toward applications in chemical/biological sensors and bioassay.


Nifedipine in the treatment of hypertensive episodes in the coronary care unit.
The effectiveness of nifedipine for the treatment of acute hypertensive episodes in patients already taking chronic calcium-channel blocker therapy is unknown. We report our experience with 43 consecutive patients who received nifedipine for acute hypertensive episodes in the coronary care unit. Of the 43 patients (24 men, 19 women), 23 (53 percent) were taking chronic (greater than 2 mo) calcium-channel blocker therapy. Nifedipine 10 mg capsules were chewed and swallowed with repeat doses given at hourly intervals if necessary. Target BP was 140/90 mm Hg, which was achieved in 31 of 43 patients (72 percent). In patients already taking calcium-channel blockers, target BP was achieved in 18 of 23 patients (78 percent). Response in patients not taking chronic calcium-channel blockers was observed in 13 of 20 patients (65 percent). Overall, adverse effects occurred in 16 of 43 patients (37 percent): 11 of 23 patients (48 percent) taking calcium-channel blockers, and 5 of 20 patients (25 percent) not taking calcium-channel blockers. Nifedipine is equally effective in lowering BP in patients taking calcium-channel blockers as it is in patients not taking them. Although associated with a higher incidence of adverse effects in patients already taking calcium-channel blockers, these effects were not considered serious. Nifedipine is an effective agent in acute hypertensive episodes, even in patients receiving chronic calcium-channel blocker therapy.


Kinetic studies and biochemical pathway analysis of anaerobic poly-(R)-3-hydroxybutyric acid synthesis in Escherichia coli.
Poly-(R)-3-hydroxybutyric acid (PHB) was synthesized anaerobically in recombinant Escherichia coli. The host anaerobically accumulated PHB to more than 50% of its cell dry weight during cultivation in either growth or nongrowth medium. The maximum specific PHB production rate during growth-associated synthesis was approximately 2.3 +/- 0.2 mmol of PHB/g of residual cell dry weight/h. The by-product secretion profiles differed significantly between the PHB-synthesizing strain and the control strain. PHB production decreased acetate accumulation for both growth and nongrowth-associated PHB synthesis. For instance under nongrowth cultivation, the PHB-synthesizing culture produced approximately 66% less acetate on a glucose yield basis as compared to a control culture. A theoretical biochemical network model was used to provide a rational basis to interpret the experimental results like the fermentation product secretion profiles and to study E. coli network capabilities under anaerobic conditions. For example, the maximum theoretical carbon yield for anaerobic PHB synthesis in E. coli is 0.8. The presented study is expected to be generally useful for analyzing, interpreting, and engineering cellular metabolisms.


Evaluation of the predicted error of the soil moisture retrieval from C-band SAR by comparison against modelled soil moisture estimates over Australia.
The Sentinel-1 will carry onboard a C-band radar instrument that will map the European continent once every four days and the global land surface at least once every twelve days with finest 5 × 20 m spatial resolution. The high temporal sampling rate and operational configuration make Sentinel-1 of interest for operational soil moisture monitoring. Currently, updated soil moisture data are made available at 1 km spatial resolution as a demonstration service using Global Mode (GM) measurements from the Advanced Synthetic Aperture Radar (ASAR) onboard ENVISAT. The service demonstrates the potential of the C-band observations to monitor variations in soil moisture. Importantly, a retrieval error estimate is also available; these are needed to assimilate observations into models. The retrieval error is estimated by propagating sensor errors through the retrieval model. In this work, the existing ASAR GM retrieval error product is evaluated using independent top soil moisture estimates produced by the grid-based landscape hydrological model (AWRA-L) developed within the Australian Water Resources Assessment system (AWRA). The ASAR GM retrieval error estimate, an assumed prior AWRA-L error estimate and the variance in the respective datasets were used to spatially predict the root mean square error (RMSE) and the Pearson's correlation coefficient R between the two datasets. These were compared with the RMSE calculated directly from the two datasets. The predicted and computed RMSE showed a very high level of agreement in spatial patterns as well as good quantitative agreement; the RMSE was predicted within accuracy of 4% of saturated soil moisture over 89% of the Australian land mass. Predicted and calculated R maps corresponded within accuracy of 10% over 61% of the continent. The strong correspondence between the predicted and calculated RMSE and R builds confidence in the retrieval error model and derived ASAR GM error estimates. The ASAR GM and Sentinel-1 have the same basic physical measurement characteristics, and therefore very similar retrieval error estimation method can be applied. Because of the expected improvements in radiometric resolution of the Sentinel-1 backscatter measurements, soil moisture estimation errors can be expected to be an order of magnitude less than those for ASAR GM. This opens the possibility for operationally available medium resolution soil moisture estimates with very well-specified errors that can be assimilated into hydrological or crop yield models, with potentially large benefits for land-atmosphere fluxes, crop growth, and water balance monitoring and modelling.


The psychiatric and psychological sequelae of vaccine-induced immune thrombotic thrombocytopenia (VITT).
This review paper explores the potential psychiatric and psychological sequelae of vaccine-induced immune thrombotic thrombocytopenia, also called vaccine-induced immune thrombocytopenia, and thrombosis (VITT). In the absence of any literature to date we have extrapolated data from similar conditions, particularly data pertaining to the critical care population. We discuss both the direct and indirect effects of thrombosis, likely psychiatric and psychological challenges during recovery, and ethical issues around vaccination. We have also suggested a comprehensive guide to the psychiatric assessment and management of patients presenting with VITT with the aim of early identification of problems and maximizing rehabilitation potential and quality of life.


Testosterone replacement therapy and hospitalization rates in men with COPD.
Testosterone deficiency is common in men with chronic obstructive pulmonary disease (COPD) and may exacerbate their condition. Research suggests that testosterone replacement therapy (TRT) may have a beneficial effect on respiratory outcomes in men with COPD. To date, however, no large-scale nationally representative studies have examined this association. The objective of the study was to assess whether TRT reduced the risk of respiratory hospitalizations in middle-aged and older men with COPD. We conducted two retrospective cohort studies. First, using the Clinformatics Data Mart-a database of one of the largest commercially insured populations in the United States-we examined 450 men, aged 40-63 years, with COPD who initiated TRT between 2005 and 2014. Second, using the national 5% Medicare database, we examined 253 men, aged ≥66 years, with COPD who initiated TRT between 2008 and 2013. We used difference-in-differences (DID) statistical modeling to compare pre- versus post-respiratory hospitalization rates in TRT users versus matched TRT nonusers over a parallel time period. DID analyses showed that TRT users had a greater relative decrease in respiratory hospitalizations compared with nonusers. Specifically, middle-aged TRT users had a 4.2% greater decrease in respiratory hospitalizations compared with nonusers (-2.4 decrease vs. 1.8 increase; p = 0.03); and older TRT users had a 9.1% greater decrease in respiratory hospitalizations compared with nonusers (-0.8 decrease vs. 8.3 increase; p = 0.04). These findings suggest that TRT may slow disease progression in patients with COPD. Future studies should examine this association in larger cohorts of patients, with particular attention to specific biological pathways.


Prospective evaluation of multidetector computed tomography for extremity vascular trauma.
Multidetector computed tomographic angiography (MDCTA) is increasingly being used for the assessment of extremity vascular injury. However, to date, there are only retrospective series and a single small prospective study evaluating its efficacy. Therefore, the objective of this study was to prospectively evaluate the ability of MDCTA to detect arterial injury in the injured upper and lower extremities. After institutional review board approval, all trauma patients aged 16 years or older admitted to a Level I trauma center who sustained extremity trauma and underwent initial evaluation with a 64-channel MDCTA from March 2009 to June 2010 were prospectively enrolled. The sensitivity and specificity of MDCTA were tested against an aggregate gold standard of operative intervention, conventional angiography, and clinical follow-up. During the 20-month study period, 635 patients with extremity trauma underwent a structured clinical examination. Hard signs of vascular injury was observed in 5.5% of patients with a 97.1% incidence of clinically significant injury requiring operative intervention. Eighty-three percent of patients had no signs of vascular injury with no missed injuries detected during follow-up. Eighty-nine MDCTAs were performed in the remaining 73 patients (11.5%) with soft signs. The mechanism of injury was penetrating in 69.9% (42 gunshot wound, 5 stab wound, and 4 shotgun). There were 24 positive studies, 23 of which were confirmed at operation (5 brachial artery injuries, 2 radial, 1 ulnar, 1 external iliac, 2 common femoral, 5 proximal superficial femoral, 2 distal superficial femoral, 4 popliteal, and 1 posterior tibial artery injury). A left posterior tibial artery occlusion was managed nonoperatively. There were 58 negative studies with clinical follow-up available in 100%, for a mean of 10.6 days ± 11.7 days (median, 6 days; range, 1-41 days). MDCTA was nondiagnostic in seven patients (9.6%), five secondary to artifact from retained missile fragments (3 shotgun and 2 gunshot wound), and two secondary to technical errors in reformatting. In the absence of artifact, MDCTA achieved 100% sensitivity and 100% specificity in detecting all clinically significant arterial injuries. Physical examination is critical in the decision-making process for the injured extremity and can accurately reduce unnecessary imaging. If imaging is required, MDCTA is a sensitive and a specific noninvasive modality for arterial evaluation and may replace conventional angiography as the diagnostic modality of choice for the evaluation of the acutely injured extremity.


Antifungal Activity of Propolis Against Yeasts Isolated From Blood Culture: In Vitro Evaluation.
Due to the failure of available antifungal agents in the treatment of candidemia and the toxic activities of these drugs, a lot of researches are being conducted to develop new nontoxic and effective antifungal agents for optimal control of fungal pathogens. The aim of this study is to evaluate the in vitro antifungal activity of propolis against yeasts isolated from the blood cultures of intensive care unit patients. Seventy-six strains were included in this study. The in vitro antifungal activity of propolis, fluconazole (FLU), and itraconazole (ITR) was investigated by the microdilution broth methods (CLSI guidelines M27-A3 for yeast). The propolis sample was collected from Kayseri, Turkey. Of the 76 isolates, 33 were identified as Candida albicans while 37 were C. parapsilosis, three were C. tropicalis, and three were identified as C. glabrata. The geometric mean range for MIC (μg/ml) with regard to all isolates was 0.077 to 3 μg/ml for FLU and ITR, and 0.375 to 0.70 μg/ml for propolis. It was shown that propolis had significant antifungal activity against all Candida strains and the MIC range of propolis was determined as 0185 to 3 μg/ml. This study demonstrated that propolis had significant antifungal activity against yeasts isolated from blood culture compared with FLU and ITR. The propolis MIC in azole-resistant strains such as C. glabrata was found lower than the FLU MIC.


Competitions for smoking cessation.
Competitions might encourage people to undertake and/or reinforce behaviour change, including smoking cessation. Competitions involve individuals or groups having the opportunity to win a prize following successful cessation, either through direct competition or by entry into a lottery or raffle. To determine whether competitions lead to higher long-term smoking quit rates. We also aimed to examine the impact on the population, the costs, and the unintended consequences of smoking cessation competitions. This review has merged two previous Cochrane reviews. Here we include studies testing competitions from the reviews 'Competitions and incentives for smoking cessation' and 'Quit & Win interventions for smoking cessation'. We updated the evidence by searching the Cochrane Tobacco Addiction Group Specialized Register in June 2018. We considered randomized controlled trials (RCTs), allocating individuals, workplaces, groups within workplaces, or communities to experimental or control conditions. We also considered controlled studies with baseline and post-intervention measures in which participants were assigned to interventions by the investigators. Participants were smokers, of any age and gender, in any setting. Eligible interventions were contests, competitions, lotteries, and raffles, to reward cessation and continuous abstinence in smoking cessation programmes. For this update, data from new studies were extracted independently by two review authors. The primary outcome measure was abstinence from smoking at least six months from the start of the intervention. We performed meta-analyses to pool study effects where suitable data were available and where the effect of the competition component could be separated from that of other intervention components, and report other findings narratively. Twenty studies met our inclusion criteria. Five investigated performance-based reward, where groups of smokers competed against each other to win a prize (N = 915). The remaining 15 used performance-based eligibility, where cessation resulted in entry into a prize draw (N = 10,580). Five of these used Quit & Win contests (N = 4282), of which three were population-level interventions. Fourteen studies were RCTs, and the remainder quasi-randomized or controlled trials. Six had suitable abstinence data for a meta-analysis, which did not show evidence of effectiveness of performance-based eligibility interventions (risk ratio (RR) 1.16, 95% confidence interval (CI) 0.77 to 1.74, N = 3201, I2 = 57%). No trials that used performance-based rewards found a beneficial effect of the intervention on long-term quit rates.The three population-level Quit & Win studies found higher smoking cessation rates in the intervention group (4% to 16.9%) than the control group at long-term follow-up, but none were RCTs and all had important between-group differences in baseline characteristics. These studies suggested that fewer than one in 500 smokers would quit because of the contest.Reported unintended consequences in all sets of studies generally related to discrepancies between self-reported smoking status and biochemically-verified smoking status. More serious adverse events were not attributed to the competition intervention.Using the GRADE system we rated the overall quality of the evidence for smoking cessation as 'very low', because of the high and unclear risk of bias associated with the included studies, substantial clinical and methodological heterogeneity, and the limited population investigated. At present, it is impossible to draw any firm conclusions about the effectiveness, or a lack of it, of smoking cessation competitions. This is due to a lack of well-designed comparative studies. Smoking cessation competitions have not been shown to enhance long-term cessation rates. The limited evidence suggesting that population-based Quit & Win contests at local and regional level might deliver quit rates above baseline community rates has not been tested adequately using rigorous study designs. It is also unclear whether the value or frequency of possible cash reward schedules influence the success of competitions. Future studies should be designed to compensate for the substantial biases in the current evidence base.


Readministration of the MMPI-2 following defensive invalidation in a military job applicant sample.
Job applicants whose response style on the Minnesota Multiphasic Personality Inventory-2 (MMPI-2; Butcher, Dahlstrom, Graham, Tellegen, & Kaemmer) is excessively defensive create a dilemma for psychologists working in personnel selection settings. Clinical guidelines recommend the profile be considered uninterpretable, but the absence of usable testing data could lead to the elimination of otherwise qualified candidates. Readministering the MMPI-2 with altered instructions to reduce defensive responding has been suggested as an alternative. This option has lacked empirical support until recently. One study (Butcher, Morfitt, Rouse, & Holden, 1997) evaluated the effects of altered instructions on retest validity in a civilian job applicant sample, with the majority of participants obtaining valid and normal profiles on retest. The purpose of this study was to determine if these results would be replicated in a military job applicant sample. Participants were 97 military personnel who completed the MMPI-2 as part of application for selection to instructor duty. Forty-seven participants had obtained invalid profiles and retook the MMPI-2 after receiving instructions intended to reduce defensiveness. The results showed that 83% of retested participants obtained valid profiles on the second MMPI-2. The second test results were very similar in profile to those obtained from a comparison group of 50 participants whose initial MMPI-2 results were valid. The findings are discussed in terms of study limitations and future research directions.


Artificial visual stimuli for animal experiments: An experimental evaluation in a prey capture context with common marmosets (Callithrix jacchus).
Experimenters often use images of real objects to simulate interactions between animal subjects or visual stimuli on a touchscreen to test animal cognition. However, the degree to which nonhuman animals recognize 2-D images as representing the corresponding real objects remains debated. The common marmoset monkey (Callithrix jacchus) has been described as a species that spontaneously shows natural behaviors to 2-D images, for example, grasping behaviors to insects and fear responses to snakes. In this study, we tested 10 monkeys with their favorite food item (crickets), 2-D images (a photo and videos of a cricket), and a 3-D plastic model to reevaluate marmoset's spontaneous responses to 2-D images and to explore which artificial visual stimuli can motivate spontaneous interactions. The monkeys showed grasping behavior to the real cricket and the 3-D plastic model, but to none of the 2-D images. Our experiment suggests that depth information is the most important factor eliciting predatory behavior from the marmosets, and, therefore, a stimulus produced by a 3-D printer could be a good alternative when a spontaneous interaction or a convincing stimulus is required. Furthermore, this work serves as a cautionary tale for those using 2-D image presentations with marmosets, and perhaps other animal species. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Learning objectives for medical student education--guidelines for medical schools: report I of the Medical School Objectives Project.
Many observers of medicine have expressed concerns that new doctors are not as well prepared as they should be to meet society's expectations of them. To assist medical schools in their efforts to respond to these concerns, in January 1996 the Association of American Medical Colleges (AAMC) established the Medical School Objectives Project (MSOP). The goal for the first phase of the project--which has been completed and is reported in this article--was to develop a consensus within the medical education community on the attributes that medical students should possess at the time of graduation, and to set forth learning objectives that can guide each medical school as it establishes objectives for its own program. Later reports will focus on the implementation phase of the MSOP. In this report, each of the four attributes agreed upon by a wide spectrum of medical educators is stated and explained, and then the learning objectives associated with the school's instilling of that attribute are stated. The first of the four attributes is that physicians must be altruistic. There are seven learning objectives, including the objective that before graduation, the student can demonstrate compassionate treatment of patients and respect for their privacy and dignity. The second attribute is that physicians must be knowledgeable; one of the six learning objectives is that the student can demonstrate knowledge of the normal structure and function of the body and of each of its major organ systems. The third attribute is that physicians must be skillful; one of the eleven learning objectives is that the student have knowledge about relieving pain and ameliorating the suffering of patients. The last attribute is that physicians must be dutiful; one of the six learning objectives is that the student have knowledge of the epidemiology of common maladies within a defined population, and the systematic approaches useful in reducing the incidence and prevalence of those maladies. The report ends by stating that (1) if a school's curriculum is shaped by the set of learning objectives presented in the report, the graduates will be well prepared to assume the limited patient care responsibilities expected of new residents and also will have begun to achieve the attributes needed to practice contemporary medicine; (2) schools should feel a sense of urgency in responding to the intent of the report; and (3) it is important to measure the outcomes of learning objectives, and better assessment methods should be developed, particularly ones to assess outcomes related to attitudes and values.


Toward a holistic and risk-based management of European river basins.
The European Union Water Framework Directive (WFD) requires a good chemical and ecological status of European surface waters by 2015. Integrated, risk-based management of river basins is presumed to be an appropriate approach to achieve that goal. The approach of focusing on distinct hazardous substances in surface waters together with investment in best available technology for treatment of industrial and domestic effluents was successful in significantly reducing excessive contamination of several European river basins. The use of the concept of chemical status in the WFD is based on this experience and focuses on chemicals for which there is a general agreement that they should be phased out. However, the chemical status, based primarily on a list of 33 priority substances and 8 priority hazardous substances, considers only a small portion of possible toxicants and does not address all causes of ecotoxicological stress in general. Recommendations for further development of this concept are 1) to focus on river basin-specific toxicants, 2) to regularly update priority lists with a focus on emerging toxicants, 3) to consider state-of-the-art mixture toxicity concepts and bioavailability to link chemical and ecological status, and 4) to add a short list of priority effects and to develop environmental quality standards for these effects. The ecological status reflected by ecological quality ratios is a leading principle of the WFD. While on the European scale the improvement of hydromorphological conditions and control of eutrophication are crucial to achieve a good ecological status, on a local and regional scale managers have to deal with multiple pressures. On this scale, toxic pollution may play an important role. Strategic research is necessary 1) to identify dominant pressures, 2) to predict multistressor effects, 3) to develop stressor- and type-specific metrics of pressures, and 4) to better understand the ecology of recovery. The concept of reference conditions to define the ecological status is hard to apply and tends to ignore the fact that ecosystems can be highly dynamic. A better understanding of ecosystem responses to changes as well as early warning systems and concepts sensitive to various stressors to discriminate disturbances from natural variation are required. Because ecosystems are closely interconnected, an integrated monitoring, diagnosis, and stressors-based management of the whole water, sediment, groundwater, soil, and air system is required considering land use and the interaction with a changing climate. Extending this holistic approach beyond a consideration of existing pressures by anticipating on future ones to use and protect the aquatic environment in a sustainable way is one of the big challenges.


Development of a polymer endovascular prosthesis and its implantation in porcine arteries.
A polyethylene-terephthalate braided mesh stent has been developed for application in the (coronary) arterial tree. In vitro measurements showed that the radial pressure delivered by this device was in the same range as that of a stainless steel stent. Hysteresis-like behavior, however, occurred after constraining the polyester stent for a period of only 15 minutes on a delivery system for percutaneous implantation. This implies that the polymer stent must be mounted on this delivery system immediately before the placement procedure, and that either a diameter in the unconstrained condition must be selected, which is considerably larger than the diameter of the target vessel, or stent expansion has to be enhanced by balloon expansion. Taking into account the results obtained during the in vitro studies, we investigated the angiographic patency and histologic features after implantation of this polyester stent in peripheral arteries of pigs. In four animals eight stents were placed. Except for heparin during the implantation procedure only, antithrombotic or antiplatelet drugs were not administered. After 4 weeks repeat angiography was performed. Angiography revealed that five of the six correctly placed stents were patent. At autopsy, two additional patent stents proved to be located in the aortic bifurcation, probably due to failure of the delivery system. Quantitative assessment showed that the mean luminal diameters of the site of stent placement were 3.3 +/- 0.2 mm before, 3.2 +/- 0.2 mm immediately after, and 3.1 +/- 0.3 mm at 4 weeks after implantation. Histology demonstrated an inflammatory reaction of variable severity around the stent fibers. Quantitative histologic measurements showed that the thickness of the neointima was 114 +/- 38 mum after 4 weeks. In conclusion, polyester stents can be constructed with mechanical properties similar to stainless steel stents. Hysteresis-like behavior of polyester stents, however, influences the selection of the nominal stent diameter as well as the forces exerted to the vessel wall. After implantation in porcine peripheral arteries, five of six correctly placed stents were patent at 4 weeks. The extent of neointimal proliferation was similar to that observed after placement of metal stents in swine, despite the presence of a more pronounced inflammatory reaction.


Self-limited plasmonic welding of silver nanowire junctions.
Nanoscience provides many strategies to construct high-performance materials and devices, including solar cells, thermoelectrics, sensors, transistors, and transparent electrodes. Bottom-up fabrication facilitates large-scale chemical synthesis without the need for patterning and etching processes that waste material and create surface defects. However, assembly and contacting procedures still require further development. Here, we demonstrate a light-induced plasmonic nanowelding technique to assemble metallic nanowires into large interconnected networks. The small gaps that form naturally at nanowire junctions enable effective light concentration and heating at the point where the wires need to be joined together. The extreme sensitivity of the heating efficiency on the junction geometry causes the welding process to self-limit when a physical connection between the wires is made. The localized nature of the heating prevents damage to low-thermal-budget substrates such as plastics and polymer solar cells. This work opens new avenues to control light, heat and mass transport at the nanoscale.


Chromosome 3p Loss-Orchestrated VHL, HIF, and Epigenetic Deregulation in Clear Cell Renal Cell Carcinoma.
Clear cell renal cell carcinoma (ccRCC) is the most common renal cell carcinoma subtype, and metastatic ccRCC is associated with 5-year survival rates of 10% to 20%. Genetically, ccRCC originates from sequential losses of multiple tumor suppressor genes. Remarkably, chromosome 3p loss occurs in more than 90% of sporadic ccRCCs. This results in concurrent one-copy loss of four tumor suppressor genes that are also mutated individually at high frequency in ccRCC (ie, VHL, 80%; PBRM1, 29% to 46%; BAP1, 6% to 19%; and SETD2, 8% to 30%). Pathogenically, 3p loss probably represents the first genetic event that occurs in sporadic ccRCC and the second genetic event in VHL-mutated hereditary ccRCC. VHL constitutes the substrate recognition module of the VCB-Cul2 E3 ligase that degrades HIF1/2α, whereas PBRM1, BAP1, and SETD2 are epigenetic modulators that regulate gene transcription. Because 3p loss and VHL inactivation are nearly universal truncal events in ccRCC, the resulting HIF1/2 signaling overdrive and accompanied tumor hypervascularization probably underlie the therapeutic benefits observed with vascular endothelial growth factor receptor inhibitors, including sorafenib, sunitinib, pazopanib, axitinib, bevacizumab, cabozantinib, and lenvatinib. Furthermore, recent marked advances in ccRCC genomics, transcriptomics, proteomics, metabolomics, molecular mechanisms, mouse models, prognostic and predictive biomarkers, and clinical trials have rendered invaluable translational insights concerning precision kidney cancer therapeutics. With an armamentarium encompassing 13 drugs that exploit seven unique therapeutic mechanisms (ie, cytokines, vascular endothelial growth factor receptor, mTORC1, cMET/AXL, fibroblast growth factor receptor, programmed cell death-1 and programmed death-ligand 1, and cytotoxic T-cell lymphocyte associated-4) to treat metastatic renal cell carcinoma, one of the imminent clinical questions concerning care of patients with metastatic ccRCC is how a personalized treatment strategy, through rationally combining and sequencing different therapeutic modalities, can be formulated to offer the best clinical outcome for individual patients. Here, we attempt to integrate recent discoveries of immediate translational impacts and discuss future translational challenges and opportunities.


Amplifying genetic logic gates.
Organisms must process information encoded via developmental and environmental signals to survive and reproduce. Researchers have also engineered synthetic genetic logic to realize simpler, independent control of biological processes. We developed a three-terminal device architecture, termed the transcriptor, that uses bacteriophage serine integrases to control the flow of RNA polymerase along DNA. Integrase-mediated inversion or deletion of DNA encoding transcription terminators or a promoter modulates transcription rates. We realized permanent amplifying AND, NAND, OR, XOR, NOR, and XNOR gates actuated across common control signal ranges and sequential logic supporting autonomous cell-cell communication of DNA encoding distinct logic-gate states. The single-layer digital logic architecture developed here enables engineering of amplifying logic gates to control transcription rates within and across diverse organisms.


High-Mobility Group Box 1 Promotes Hepatocellular Carcinoma Progression through miR-21-Mediated Matrix Metalloproteinase Activity.
Liver inflammation plays a critical role in hepatocellular carcinoma (HCC) etiology. Damage-associated molecular patterns (DAMP), such as high-mobility group box 1 (HMGB1), and dysregulated miRNAs involved in inflammatory disease states, such as miR-21, may participate in the link between inflammation and cancer. We sought to determine the role of HMGB1 signaling in HCC tumor progression. We first document the concordant expression increase of HMGB1 and miR-21 in HCC cell lines and primary HCC tumor samples and subsequently show that HMGB1 stimulation results in overexpression of miR-21. These changes were found to be dependent on the IL6/STAT3 signaling axis. Invasion and migration of HCC cells in vitro were inhibited by both STAT3 and miR-21 antagonists, suggesting a role for this pathway in HCC tumor progression. We verified that HMGB1-induced expression of miR-21 in HCC provides a posttranscriptional repression of the matrix metalloproteinase (MMP) inhibitors RECK and TIMP3, which are known to impact HCC progression and metastases. Finally, we found that inhibition of miR-21 in murine HMGB1-overexpressing HCC xenografts led to reduced tumor MMP activity through released repression of the miR-21 targets RECK and TIMP3, which ultimately impeded tumor progression. The prototypical DAMP, HMGB1, is released during liver inflammation and provides a favorable environment for HCC growth. HMGB1 signaling increases miR-21 expression to mediate the enhanced activity of MMPs through RECK and TIMP3. These findings provide a novel mechanism for HMGB1-mediated HCC progression through the IL6/Stat3-miR-21 axis.


A palmitoylation cycle dynamically regulates partitioning of the GABA-synthesizing enzyme GAD65 between ER-Golgi and post-Golgi membranes.
GAD65, the smaller isoform of the enzyme glutamic acid decarboxylase, synthesizes GABA for fine-tuning of inhibitory neurotransmission. GAD65 is synthesized as a soluble hydrophilic protein but undergoes a hydrophobic post-translational modification and becomes anchored to the cytosolic face of Golgi membranes. A second hydrophobic modification, palmitoylation of Cys30 and Cys45 in GAD65, is not required for the initial membrane anchoring but is crucial for post-Golgi trafficking of the protein to presynaptic clusters. The mechanism by which palmitoylation directs targeting of GAD65 through and out of the Golgi complex is unknown. Here, we show that prior to palmitoylation, GAD65 anchors to both ER and Golgi membranes. Palmitoylation, however, clears GAD65 from the ER-Golgi, targets it to the trans-Golgi network and then to a post-Golgi vesicular pathway. FRAP analyses of trafficking of GAD65-GFP reveal a rapid and a slow pool of protein replenishing the Golgi complex. The rapid pool represents non-palmitoylated hydrophobic GAD65-GFP, which exchanges rapidly between the cytosol and ER/Golgi membranes. The slow pool represents palmitoylation-competent GAD65-GFP, which replenishes the Golgi complex via a non-vesicular pathway and at a rate consistent with a depalmitoylation step. We propose that a depalmitoylation-repalmitoylation cycle serves to cycle GAD65 between Golgi and post-Golgi membranes and dynamically control levels of enzyme directed to the synapse.


Infrastructure expansion challenges sustainable development in Papua New Guinea.
The island of New Guinea hosts the third largest expanse of tropical rainforest on the planet. Papua New Guinea-comprising the eastern half of the island-plans to nearly double its national road network (from 8,700 to 15,000 km) over the next three years, to spur economic growth. We assessed these plans using fine-scale biophysical and environmental data. We identified numerous environmental and socioeconomic risks associated with these projects, including the dissection of 54 critical biodiversity habitats and diminished forest connectivity across large expanses of the island. Key habitats of globally endangered species including Goodfellow's tree-kangaroo (Dendrolagus goodfellowi), Matchie's tree kangaroo (D. matschiei), and several birds of paradise would also be bisected by roads and opened up to logging, hunting, and habitat conversion. Many planned roads would traverse rainforests and carbon-rich peatlands, contradicting Papua New Guinea's international commitments to promote low-carbon development and forest conservation for climate-change mitigation. Planned roads would also create new deforestation hotspots via rapid expansion of logging, mining, and oil-palm plantations. Our study suggests that several planned road segments in steep and high-rainfall terrain would be extremely expensive in terms of construction and maintenance costs. This would create unanticipated economic challenges and public debt. The net environmental, social, and economic risks of several planned projects-such as the Epo-Kikori link, Madang-Baiyer link, Wau-Malalaua link, and some other planned projects in the Western and East Sepik Provinces-could easily outstrip their overall benefits. Such projects should be reconsidered under broader environmental, economic, and social grounds, rather than short-term economic considerations.


Stereotactic radiosurgery as the primary treatment for new and recurrent paragangliomas: is open surgical resection still the treatment of choice?
Paragangliomas (PGs) or glomus tumors are rare, and publications comparing treatment alternatives are few. We sought to analyze our experience with stereotactic radiosurgery (SRS), review the literature, and develop treatment guidelines. We retrospectively examined the outcomes of 41 PGs in 36 patients treated with SRS at Stanford. Our data from medical records, telephone interviews, and imaging studies were combined with previously reported SRS data and compared to results following other treatments. With a median clinical follow-up of 4.8 years (3.9 years radiographic), local control was 100%. Complications included increase in preexistent vertigo in one patient and transient cranial neuropathies in two patients. Published surgical series describe a lower local control rate as well as more frequent and severe complications. Published radiation therapy (RT) series document a slightly lower local control rate than SRS, but SRS can be delivered more quickly and conveniently. Open surgery and other combinations of treatments appear to be required for several subpopulations of PG patients. We feel that SRS should be the primary treatment for most new and recurrent PGs. Even some very large PGs are appropriate for SRS. RT remains an appropriate option in some centers, especially those where SRS is not available. PGs occurring in the youngest patients, catecholamine secreting PGs, and PGs causing rapidly progressing neurologic deficits may be more appropriate for open resection. Metastatic PGs may benefit from combinations of chemotherapy and SRS or RT. Treatment guidelines are proposed.


The future of WRRF modelling - outlook and challenges.
The wastewater industry is currently facing dramatic changes, shifting away from energy-intensive wastewater treatment towards low-energy, sustainable technologies capable of achieving energy positive operation and resource recovery. The latter will shift the focus of the wastewater industry to how one could manage and extract resources from the wastewater, as opposed to the conventional paradigm of treatment. Debatable questions arise: can the more complex models be calibrated, or will additional unknowns be introduced? After almost 30 years using well-known International Water Association (IWA) models, should the community move to other components, processes, or model structures like 'black box' models, computational fluid dynamics techniques, etc.? Can new data sources - e.g. on-line sensor data, chemical and molecular analyses, new analytical techniques, off-gas analysis - keep up with the increasing process complexity? Are different methods for data management, data reconciliation, and fault detection mature enough for coping with such a large amount of information? Are the available calibration techniques able to cope with such complex models? This paper describes the thoughts and opinions collected during the closing session of the 6th IWA/WEF Water Resource Recovery Modelling Seminar 2018. It presents a concerted and collective effort by individuals from many different sectors of the wastewater industry to offer past and present insights, as well as an outlook into the future of wastewater modelling.


Hypoxia-induced in vivo sickling of transgenic mouse red cells.
To develop an animal model for sickle cell anemia, we have created transgenic mice that express a severe naturally occurring human sickling hemoglobin, Hb S Antilles. Due to its low solubility and oxygen affinity, Hb S Antilles has a greater propensity to cause red cell sickling than Hb S. To make transgenic animals that express a high level of Hb S Antilles, the erythroid-specific DNAse I hypersensitive site II from the human beta-globin cluster was linked independently to the human alpha 2-globin gene and to the beta S Antilles gene. Embryos were injected with both constructs simultaneously and seven transgenic mice were obtained, three of which contained both the human alpha and the human beta S Antilles transgene. After crossing the human transgenes into the mouse beta-thalassemic background a transgenic mouse line was derived in which approximately half the beta-globin chains in the murine red cells were human beta S Antilles. Deoxygenation of the transgenic red cells in vitro resulted in extensive sickling. An increase of in vivo sickling was achieved by placing these transgenic mice in a low oxygen environment. This murine model for red cell sickling should help to advance our understanding of sickle cell disease and may provide a model to test therapeutic interventions.


Fibroblast-specific protein 1/S100A4-positive cells prevent carcinoma through collagen production and encapsulation of carcinogens.
Stromal restraints to cancer are critical determinants of disease but they remain incompletely understood. Here, we report a novel mechanism for host surveillance against cancer contributed by fibroblast-specific protein 1 (FSP1)+ /S100A4+ fibroblasts. Mechanistic studies of fibrosarcoma formation caused by subcutaneous injection of the carcinogen methylcholanthrene (MCA) had suggested that IFN-γ receptor signaling may restrict MCA diffusion by inducing expression of collagen (foreign body reaction). We tested the hypothesis that this reaction encapsulated MCA and limited carcinogenesis by determining whether its ability to induce fibrosarcomas was impaired in the absence of proliferating fibroblasts. We found that FSP1+ /S100A4+ fibroblasts accumulated around the carcinogen where they produced collagens, encapsulating MCA and protecting epithelial cells from DNA damage. Ablation of these cells at the site of MCA injection by local administration of ganciclovir in FSP-TK transgenic mice altered tumor morphology to an epithelial phenotype, indicating that, in the absence of encapsulating fibroblasts, MCA targeted epithelial cells. Notably, we showed that destruction of the fibrous capsule around the MCA by local injection of collagenase induced rapid tumor development in mice that were otherwise durably tumor free. Our findings demonstrate that the FSP1+ /S100A4+ fibroblasts prevent epithelial malignancy and that collagen encapsulation of carcinogens protects against tumor development. Together, this study provides a novel mechanism for host surveillance against cancer.


[Interval for access to treatment for breast cancer in the Federal District, Brazil].
To analyze the time between the first symptom and treatment in patients treated for breast cancer in public hospitals in the Federal District. This was a cross-sectional analysis. We interviewed 250 women diagnosed with breast cancer treated in six hospitals of the State Department of Health of the Federal District from November 2009 to January 2011. The time intervals studied were the time between the detection of the symptoms and treatment subdivided into intervals until and after the first medical appointment. The variables were: age, menopausal status, color, educational level, average monthly household income, origin, reason for the initial consultation, staging, tumor size, laterality, metastasis to axillary lymph nodes, neoadjuvant chemotherapy, and type of surgery. The Mann-Whtney test was used to assess the association of these variables with the time intervals until treatment. The mean age was 52 years, with a predominance of white women (57.6%), from the Federal District (62.4%), with a family income of up to 2 minimum wages (78%), and up to four years of schooling (52.4%). The staging of the disease ranged from II to IV in 78.8% of the women. The time between the first symptom and treatment was 229 days (median). After detection of the first symptom, 52.9% of the women attended a consultation within 30 days and 88.8% took more than 90 days to start treatment. Women with elementary school education had a greater delay to the start of treatment (p=0.049). There was a significant delay to start treatment of women with breast cancer in public hospitals of the Federal District, suggesting that efforts should be made to reduce the time needed to schedule medical appointments and to diagnose and treat these patients.


Staged stent-assisted angioplasty for symptomatic intracranial vertebrobasilar artery stenosis.
Medically refractory symptomatic vertebrobasilar atherosclerotic disease has a poor prognosis. Studies have shown that longer (> or = 10 mm), eccentric, high-grade (> 70%) stenoses portend increased procedure-related morbidity. The authors reviewed their experience to determine whether a staged procedure consisting of angioplasty followed by delayed (> or = 1 month later) repeated angioplasty and stent placement reduces the morbidity associated with endovascular treatment of symptomatic basilar and/or intracranial vertebral artery (VA) stenoses. The authors retrospectively reviewed the medical records in a consecutive series of eight patients who underwent planned stent-assisted angioplasty for medically refractory, symptomatic atherosclerotic disease of the intracranial posterior circulation between February 1999 and January 2002. Staged stent-assisted angioplasty was planned for these patients because the extent and degree of stenosis of the VA and/or basilar artery (BA) lesion portended an excessive procedure-related risk. The degree of stenosis, recent onset of symptoms (unstable plaque), vessel tortuosity, and lesion length and morphological feaures were contributing factors in determining procedure-related risk. Patient records were analyzed for location and degree of stenosis, preprocedural regimen of antiplatelet and/or anticoagulation agents, devices used, procedure-related complications, and clinical and radiographic outcomes. Among the patients in whom staged stent-assisted angioplasty was planned, vessel dissection, which necessitated immediate stent placement, occurred during passage of the balloon in one of them. In a second patient, the stent could not be maneuvered through the tortuous VA. In a third patient, the VA and BAs remained widely patent after angioplasty alone, and therefore stent placement was not required. Significant complications among the eight patients included transient aphasia and hemiparesis in one and a groin hematoma that necessitated surgical intervention in another; there was no permanent neurological morbidity. The mean stenosis before treatment was 78%, which fell to 54% after angioplasty, and the mean residual stenosis after stent placement was 30%. At the last follow-up examination, none of the treated patients had further symptoms attributable to the treated stenosis. The novel combination of initial angioplasty followed by delayed endoluminal stent placement may reduce the neurological morbidity associated with endovascular treatment of long, high-grade stenotic lesions. Attempting to cross high-grade stenoses with higher-profile devices such as stents may result in an embolic shower. Furthermore, neointimal proliferation and scar formation after angioplasty result in a thickened fibrous layer, which may be protective during delayed stent deployment. Larger-scale studies involving multiple centers are needed to elucidate further the lesion morphological characteristics and patient population most likely to benefit from staged procedures.


The clinical significance of simultaneous infection with hepatitis G virus in patients with chronic hepatitis C.
Hepatitis G virus (HGV) is a recently discovered member of the flavivirus family that has been associated with acute and chronic hepatitis. HGV infection has been reported to coexist in 10-20% of patients with chronic hepatitis C. The significance of simultaneous infection with HGV and hepatitis C virus (HCV) remains to be clarified, as do the effects on HGV of therapeutic interventions such as interferon treatment or liver transplantation. 1) to examine the frequency of HGV infection in the settings of liver transplantation and interferon therapy for hepatitis C; and 2) to compare HGV RNA levels before and after liver transplantation or interferon treatment. Pre-treatment sera were available in 65 patients with chronic hepatitis C treated with interferon; pretransplant sera were available in 49 patients transplanted for end stage liver disease associated with chronic hepatitis C. Information collected included age, sex, risk factors for hepatitis, concurrent liver disease, patient and allograft survival, biochemical response to interferon, histological activity index, and degree of fibrosis/cirrhosis. HCV genotyping was performed by sequencing the NS-5 region. HGV quantitation was performed using a research-based branched DNA (bDNA) assay with a set of probes directed at the 5' untranslated region. HGV was detected in 10 of 49 patients (20%) before transplant and in 13 of 65 patients (20%) treated with interferon. There was a female predominance among HGV-positive compared with HGV-negative transplant patients (80% vs 20%; p < 0.01), but such a difference was not observed in the interferon-treated group. Hepatic iron concentration was lower in hepatic explants from patients who were HGV-positive than in those who were HGV-negative (318 +/- 145 microg/g dry weight vs 1497 +/- 2202 microg/g dry weight; p = 0.02). HCV exposure after 1980 was more common in the HGV-positive patients than in those who were HGV-negative for the entire study population (10 of 20 [50%] vs 16 of 66 [24%]; p = 0.03), as well as for the nontransplant subgroup (8 of 12 [67%] vs 12 of 39 [31%]; p = 0.03). HGV RNA levels declined at 1 yr after transplant in seven of eight patients. Among nine patients tested during or after interferon treatment, HGV RNA levels declined from pretreatment levels in all and disappeared in three. Among patients with chronic hepatitis C treated with either interferon or liver transplantation, the frequency of coinfection with HGV is about 20%. HGV may be a more recent virus in the US than HCV. Coinfection with HGV does not appear to affect the likelihood of response to interferon in patients with hepatitis C. Finally, HGV RNA levels appear to decline after both liver transplantation and interferon therapy, suggesting possible suppression by increased HCV replication in the former case, and a possible drug treatment effect in the latter.


Stem cells: to be born great, achieve greatness, or have greatness thrust upon them?
Induced pluripotent stem cells (iPSCs) have opened new doors in providing an ethical, patient-specific cell source towards tissue engineering. Developing these therapies involves the production of reprogrammed iPSCs, expanding them while maintaining pluripotency, then differentiating them into functional tissues. To bring these therapies to the clinic, efficient and GMP-compliant manufacturing methods are required. In this Research Highlight, we describe recent innovations to several aspects of the pluripotent cell therapy pipeline.


Effectiveness of a Question Prompt List Intervention for Older Patients Considering Major Surgery: A Multisite Randomized Clinical Trial.
Poor preoperative communication can have serious consequences, including unwanted treatment and postoperative conflict. To compare the effectiveness of a question prompt list (QPL) intervention vs usual care on patient engagement and well-being among older patients considering major surgery. This randomized clinical trial used a stepped-wedge design to randomly assign patients to a QPL intervention (n = 223) or usual care (n = 223) based on the timing of their visit with 1 of 40 surgeons at 5 US study sites. Patients were 60 years or older with at least 1 comorbidity and an oncologic or vascular (cardiac, neurosurgical, or peripheral vascular) problem that could be treated with major surgery. Family members were also enrolled (n = 263). The study dates were June 2016 to November 2018. Data analysis was by intent-to-treat. A brochure of 11 questions to ask a surgeon developed by patient and family stakeholders plus an endorsement letter from the surgeon were sent to patients before their outpatient visit. Primary patient engagement outcomes included the number and type of questions asked during the surgical visit and patient-reported Perceived Efficacy in Patient-Physician Interactions scale assessed after the surgical visit. Primary well-being outcomes included (1) the difference between patient's Measure Yourself Concerns and Well-being (MYCaW) scores reported after surgery and scores reported after the surgical visit and (2) treatment-associated regret at 6 to 8 weeks after surgery. Of 1319 patients eligible for participation, 223 were randomized to the QPL intervention and 223 to usual care. Among 446 patients, the mean (SD) age was 71.8 (7.1) years, and 249 (55.8%) were male. On intent-to-treat analysis, there was no significant difference between the QPL intervention and usual care for all patient-reported primary outcomes. The difference in MYCaW scores for family members was greater in usual care (effect estimate, 1.51; 95% CI, 0.28-2.74; P = .008). When the QPL intervention group was restricted to patients with clear evidence they reviewed the QPL, a nonsignificant increase in the effect size was observed for questions about options (odds ratio, 1.88; 95% CI, 0.81-4.35; P = .16), expectations (odds ratio, 1.59; 95% CI, 0.67-3.80; P = .29), and risks (odds ratio, 2.41; 95% CI, 1.04-5.59; P = .04) (nominal α = .01). The results of this study were null related to primary patient engagement and well-being outcomes. Changing patient-physician communication may be difficult without addressing clinician communication directly. ClinicalTrials.gov identifier: NCT02623335.


Supervised Learning Classifiers for Electrical Impedance-based Bladder State Detection.
Urinary Incontinence affects over 200 million people worldwide, severely impacting the quality of life of individuals. Bladder state detection technology has the potential to improve the lives of people with urinary incontinence by alerting the user before voiding occurs. To this end, the objective of this study is to investigate the feasibility of using supervised machine learning classifiers to determine the bladder state of 'full' or 'not full' from electrical impedance measurements. Electrical impedance data was obtained from computational models and a realistic experimental pelvic phantom. Multiple datasets with increasing complexity were formed for varying noise levels in simulation. 10-Fold testing was performed on each dataset to classify 'full' and 'not full' bladder states, including phantom measurement data. Support vector machines and k-Nearest-Neighbours classifiers were compared in terms of accuracy, sensitivity, and specificity. The minimum and maximum accuracies across all datasets were 73.16% and 100%, respectively. Factors that contributed most to misclassification were the noise level and bladder volumes near the threshold of 'full' or 'not full'. This paper represents the first study to use machine learning for bladder state detection with electrical impedance measurements. The results show promise for impedance-based bladder state detection to support those living with urinary incontinence.


In vitro procoagulant activity induced in endothelial cells by chemotherapy and antiangiogenic drug combinations: modulation by lower-dose chemotherapy.
One of the emerging problems concerning the use of antiangiogenic drugs, when used in combination with certain chemotherapy regimens, is enhanced rates and severity of adverse clotting events. For as yet unknown reasons, certain drugs and particular combinations can induce an elevated incidence of thromboembolic events in treated cancer patients [e.g., SU5416, a vascular endothelial cell growth factor receptor-2 (VEGFR-2) antagonist, when combined with gemcitabine and cisplatin (CDDP)]. Such results highlight the need to develop assays capturing the essence of enhanced clot formation under such combination treatment and which may have predictive potential as well. Here, we report the possibility of such an assay (i.e., the ratio of tissue factor over tissue factor pathway inhibitor expression or activity in cultured human endothelial cells calculated as a coagulation index). A marked increase in coagulation index was observed after exposure to SU5416 and the CDDP/gemcitabine chemotherapy combination in contrast to either of these treatments used alone. Substitution of SU5416 with any one of ZD6474, SU6668, IMC-1121, a monoclonal antibody to VEGFR-2, or an antibody to VEGF (bevacizumab) did not cause a marked increase in the coagulation index, nor did the combination of SU5416 with 5-fluorouracil and leucovorin. Finally, we noted that reducing the concentrations of gemcitabine and CDDP (i.e., use of "metronomic dosing" in vitro) significantly attenuated the coagulation index increase induced by these drugs, suggesting that use of low-dose chemotherapy regimens might be an approach to consider for reducing the incidence of adverse clotting events associated with chemotherapy alone or in conjunction with antiangiogenic drug combination therapies.


Paediatric European Risperidone Studies (PERS): context, rationale, objectives, strategy, and challenges.
In children and adolescents with conduct disorder (CD), pharmacotherapy is considered when non-pharmacological interventions do not improve symptoms and functional impairment. Risperidone, a second-generation antipsychotic is increasingly prescribed off-label in this indication, but its efficacy and tolerability is poorly studied in CD, especially in young people with normal intelligence. The Paediatric European Risperidone Studies (PERS) include a series of trials to assess short-term efficacy, tolerability and maintenance effects of risperidone in children and adolescents with CD and normal intelligence as well as long-term tolerability in a 2-year pharmacovigilance. In addition to its core studies, secondary PERS analyses will examine moderators of drug effects. As PERS is a large-scale academic project involving a collaborative network of expert centres from different countries, it is expected that results will lead to strengthen the evidence base for the use of risperidone in CD and improve standards of care. Challenging issues faced by the PERS consortium are described to facilitate future developments in paediatric neuropsychopharmacology.


Mechanical loading by fluid shear stress enhances IGF-1 receptor signaling in osteoblasts in a PKCzeta-dependent manner.
Maintenance of optimal bone physiology requires the coordinated activity of osteoclasts that resorb old bone and osteoblasts that deposit new bone. Mechanical loading of bone and the resulting movement of interstitial fluid within the spaces surrounding bone cells is thought to play a key role is maintaining optimal bone mass. One way in which fluid movement may promote bone formation is by enhancing osteoblast survival. We have shown previously that application of fluid flow to osteoblasts in vitro confers a protective effect by inhibiting osteoblast apoptosis (Pavalko et al., 2003, J. Cell Physiol., 194: 194-205). To investigate the cellular mechanisms that regulate the response of osteoblasts to fluid shear stress, we have examined the possible interaction between fluid flow and growth factors in MC3T3-E1 osteoblast-like cells. We found that insulin-like growth factor-I (IGF-I) was significantly more effective at preventing TNF-alpha-induced apoptosis when cells were first subjected to mechanical loading by exposure to either unidirectional or oscillatory fluid flow compared to cells that were maintained in static culture. Additionally, downstream signaling in response to treatment with IGF-I, including ERK and Akt activation, was enhanced in cells that were subjected to fluid flow, compared to cells maintained in static culture. Furthermore, we found that PKC activity is essential for fluid shear stress sensitization of IGF-IR, since a specific inhibitor of PCKzeta function blocked the flow-enhanced IGF-I-activated Akt and ERK phosphorylation. Together, our results suggest that fluid shear stress may regulate IGF-I signaling in osteoblasts in a PKC-zeta-dependent manner.


Interleukin 2 therapy: current role in surgical oncological practice.
The use of recombinant interleukin 2 (rIL-2) in clinical practice has opened up new and beneficial avenues in the treatment of certain malignant diseases. Although rIL-2 can stimulate a range of host antitumour defence mechanisms, only 30-40 per cent of patients who are treated will respond to such therapy as assessed by a reduction in tumour volume. The effect of rIL-2-based treatment schedules on delaying progression of disease and on overall survival in comparison with standard current treatments and chemotherapeutic regimens is not clear. Randomized clinical trials are required to evaluate precisely the role of rIL-2 in various therapeutic combinations and to ascertain the optimum therapeutic regimens for individual tumour types. Studies currently under way should provide more insight into the possible beneficial effects of immunotherapy with rIL-2. More basic research is required to ascertain how rIL-2 may produce its antitumour effects and why the therapeutic results obtained in humans have been so selective and less beneficial than those in experimental animals.


Ca2+/calmodulin-dependent kinase II triggers cell membrane injury by inducing complement factor B gene expression in the mouse heart.
Myocardial Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibition improves cardiac function following myocardial infarction (MI), but the CaMKII-dependent pathways that participate in myocardial stress responses are incompletely understood. To address this issue, we sought to determine the transcriptional consequences of myocardial CaMKII inhibition after MI. We performed gene expression profiling in mouse hearts with cardiomyocyte-delimited transgenic expression of either a CaMKII inhibitory peptide (AC3-I) or a scrambled control peptide (AC3-C) following MI. Of the 8,600 mRNAs examined, 156 were substantially modulated by MI, and nearly half of these showed markedly altered responses to MI with CaMKII inhibition. CaMKII inhibition substantially reduced the MI-triggered upregulation of a constellation of proinflammatory genes. We studied 1 of these proinflammatory genes, complement factor B (Cfb), in detail, because complement proteins secreted by cells other than cardiomyocytes can induce sarcolemmal injury during MI. CFB protein expression in cardiomyocytes was triggered by CaMKII activation of the NF-kappaB pathway during both MI and exposure to bacterial endotoxin. CaMKII inhibition suppressed NF-kappaB activity in vitro and in vivo and reduced Cfb expression and sarcolemmal injury. The Cfb-/- mice were partially protected from the adverse consequences of MI. Our findings demonstrate what we believe is a novel target for CaMKII in myocardial injury and suggest that CaMKII is broadly important for the genetic effects of MI in cardiomyocytes.


Tetrahydrocannabinol Does Not Reduce Pain in Patients With Chronic Abdominal Pain in a Phase 2 Placebo-controlled Study.
Delta-9-tetrahydrocannabinol (THC) is the most abundant cannabinoid from the plant Cannabis sativa. There is only equivocal evidence that THC has analgesic effects. We performed a phase 2 controlled trial to evaluate the analgesic efficacy, pharmacokinetics, safety, and tolerability of an oral tablet containing purified THC in patients with chronic abdominal pain. Sixty-five patients with chronic abdominal pain for 3 months or more (numeric rating scale scores of 3 or more) after surgery or because of chronic pancreatitis were randomly assigned to groups given the THC tablet or identical matching placebos for 50-52 days. Subjects in the THC group were given the tablet first in a step-up phase (3 mg 3 times daily for 5 days and then 5 mg 3 times daily for 5 days), followed by a stable dose phase (8 mg 3 times daily until days 50-52). Preceding and during the entire study period, patients were asked to continue taking their medications (including analgesics) according to prescription. Patients reported any additional pain medications in a diary. Efficacy and safety assessments were conducted preceding medication intake (day 1), after 15 days, and at 50-52 days. Plasma samples were collected on study days 1, 15, and 50-52; mean plasma concentration curves of THC and 11-OH-THC were plotted. The primary end point was pain relief, which was measured by a visual analogue scale (VAS) of the mean pain (VAS mean scores) on the basis of information from patient diaries. Secondary end points included pain and quality of life (determined from patient questionnaires), pharmacokinetics, and safety. At days 50-52, VAS mean scores did not differ significantly between the THC and placebo groups (F1,46 = 0.016; P = .901). Between the start and end of the study, VAS mean scores decreased by 1.6 points (40%) in the THC group compared with 1.9 points (37%) in the placebo group. No differences were observed in secondary outcomes. Oral THC was generally well-absorbed. Seven patients in the THC group stopped taking the tablets because of adverse events, compared with 2 patients in the placebo group. All (possibly) related adverse events were mild or moderate. In a phase 2 study, we found no difference between a THC tablet and a placebo tablet in reducing pain measures in patients with chronic abdominal pain. THC, administered 3 times daily, was safe and well-tolerated during a 50-day to 52-day treatment period. ClinicalTrials.gov number: NCT01562483 and NCT01551511.


Relationship between mechanical properties and bone mineral density of human femoral bone retrieved from patients with osteoarthritis.
The objective of this study was to analyse retrieved human femoral bone samples using three different test methods, to elucidate the relationship between bone mineral density and mechanical properties. Human femoral heads were retrieved from 22 donors undergoing primary total hip replacement due to hip osteoarthritis and stored for a maximum of 24 hours postoperatively at + 6 °C to 8 °C.Analysis revealed an average structural modulus of 232±130 N/mm(2) and ultimate compression strength of 6.1±3.3 N/mm(2) with high standard deviations. Bone mineral densities of 385±133 mg/cm(2) and 353±172 mg/cm(3) were measured using thedual energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT), respectively. Ashing resulted in a bone mineral density of 323±97 mg/cm(3). In particular, significant linear correlations were found between DXA and ashing with r = 0.89 (p < 0.01, n = 22) and between structural modulus and ashing with r = 0.76 (p < 0.01, n = 22).Thus, we demonstrated a significant relationship between mechanical properties and bone density. The correlations found can help to determine the mechanical load capacity of individual patients undergoing surgical treatments by means of noninvasive bone density measurements.


Injury reports in a dental school: a two-year overview.
As teaching institutions, it is vital for dental schools to collect data on accidental injuries to identify potential problems, improve the quality of care of patients, and educate future practitioners about risk management. Our data reveal important trends concerning such injuries. These data were compiled over a two-year period (2001-03) from accident reports at one dental school. We categorized the accidents as follows: source (instrument causing the injury), recipient of injury, time of day, location within the dental school where the injury occurred, and body part injured. The population examined in this study consisted of predoctoral and postdoctoral dental students, staff, faculty, and patients of the dental school. The majority of injuries occurred in the predoctoral clinic toward the middle to the end of the scheduled clinic periods. The instrument most likely involved was a needle, and the body part most commonly injured was a finger. The collection and analysis of injury data may be used to identify trends that will aid in the prediction and prevention of these injuries and, at a national level, serve as a benchmark that other dental schools can employ to assess their relative frequency of injury.


Conducting microhelices from self-assembly of protein fibrils.
Herein we utilize insulin to prepare amyloid based chiral helices with either right or left handed helicity. We demonstrate that the helices can be utilized as structural templates for the conducting polymer alkoxysulfonate poly(ethylenedioxythiophene) (PEDOT-S). The chirality of the helical assembly is transferred to PEDOT-S as demonstrated by polarized optical microscopy (POM) and Circular Dichroism (CD). Analysis of the helices by conductive atomic force microscopy (c-AFM) shows significant conductivity. In addition, the morphology of the template structure is stabilized by PEDOT-S. These conductive helical structures represent promising candidates in our quest for THz resonators.


Ten different Polycomb group genes are required for spatial control of the abdA and AbdB homeotic products.
Mutations in genes of the Polycomb (Pc) group cause abnormal segmental development due to ectopic expression of the homeotic products of the Antennapedia and bithorax complexes. Here the requirements for Pc group genes in controlling the abdA and AbdB products of the bithorax complex are described. Embryos containing mutations in the genes Polycomb (Pc), extra sex combs (esc), Enhancer of zeste [E(z)], polyhomeotic (ph), Sex comb on midleg (Scm), Polycomb-like (Pcl), Sex comb extra (Sce), Additional sex combs (Asx), Posterior sex combs (Psc) and pleiohomeotic (pho) were examined. In every case, both abdA and AbdB are expressed outside of their normal domains along the anterior-posterior (A-P) axis, consistent with these Pc group products acting in a single pathway or molecular complex. The earliest detectable ectopic expression is highest in the parasegments immediately adjacent to the normal expression boundary. Surprisingly, in the most severe Pc group mutants, the earliest ectopic AbdB is distributed in a pair-rule pattern. At all stages, ectopic abdA in the epidermis is highest along the anterior edges of the parasegments, in a pattern that mimics the normal abdA cell-specific pattern. These examples of highly patterned mis-expression show that Pc group mutations do not cause indiscriminate activation of homeotic products. We suggest that the ectopic expression patterns result from factors that normally activate abdA and AbdB only in certain parasegments, but that in Pc group mutants these factors gain access to regulatory DNA in all parasegments.


Cardiovascular responses to caffeine by gender and pubertal stage.
Caffeine use is on the rise among children and adolescents. Previous studies from our laboratory reported gender differences in the effects of caffeine in adolescents. The purpose of this study was to test the hypotheses that gender differences in cardiovascular responses to caffeine emerge after puberty and that cardiovascular responses to caffeine differ across the phases of the menstrual cycle. To test these hypotheses, we examined heart rate and blood pressure before and after administration of placebo and 2 doses of caffeine (1 and 2 mg/kg) in prepubertal (8- to 9-year-olds; n = 52) and postpubertal (15- to 17-year-olds; n = 49) boys (n = 54) and girls (n = 47) by using a double-blind, placebo-controlled, dose-response design. There was an interaction between gender and caffeine dose, with boys having a greater response to caffeine than girls. In addition, we found interactions between pubertal phase, gender, and caffeine dose, with gender differences present in postpubertal, but not in prepubertal, participants. Finally, we found differences in responses to caffeine across the menstrual cycle in post-pubertal girls, with decreases in heart rate greater in the midluteal phase and blood pressure increases greater in the midfollicular phase of the menstrual cycle. These data suggest that gender differences in response to caffeine emerge after puberty. Future research will determine the extent to which these gender differences are mediated by physiological factors, such as steroid hormones, or psychosocial factors, such as more autonomy and control over beverage purchases.


Identification and evaluation of children with autism spectrum disorders.
Autism spectrum disorders are not rare; many primary care pediatricians care for several children with autism spectrum disorders. Pediatricians play an important role in early recognition of autism spectrum disorders, because they usually are the first point of contact for parents. Parents are now much more aware of the early signs of autism spectrum disorders because of frequent coverage in the media; if their child demonstrates any of the published signs, they will most likely raise their concerns to their child's pediatrician. It is important that pediatricians be able to recognize the signs and symptoms of autism spectrum disorders and have a strategy for assessing them systematically. Pediatricians also must be aware of local resources that can assist in making a definitive diagnosis of, and in managing, autism spectrum disorders. The pediatrician must be familiar with developmental, educational, and community resources as well as medical subspecialty clinics. This clinical report is 1 of 2 documents that replace the original American Academy of Pediatrics policy statement and technical report published in 2001. This report addresses background information, including definition, history, epidemiology, diagnostic criteria, early signs, neuropathologic aspects, and etiologic possibilities in autism spectrum disorders. In addition, this report provides an algorithm to help the pediatrician develop a strategy for early identification of children with autism spectrum disorders. The accompanying clinical report addresses the management of children with autism spectrum disorders and follows this report on page 1162 [available at www.pediatrics.org/cgi/content/full/120/5/1162]. Both clinical reports are complemented by the toolkit titled "Autism: Caring for Children With Autism Spectrum Disorders: A Resource Toolkit for Clinicians," which contains screening and surveillance tools, practical forms, tables, and parent handouts to assist the pediatrician in the identification, evaluation, and management of autism spectrum disorders in children.


Volume changes of extremely large and giant intracranial aneurysms after treatment with flow diverter stents.
This study assessed volume changes of unruptured large and giant aneurysms (greatest diameter >20 mm) after treatment with flow diverter (FD) stents. Clinical audit of the cases treated in a single institution, over a 5-year period. Demographic and clinical data were retrospectively collected from the hospital records. Aneurysm volumes were measured by manual outlining at sequential slices using computerised tomography (CT) or magnetic resonance (MR) angiography data. The audit included eight patients (seven females) with eight aneurysms. Four aneurysms involved the cavernous segment of the internal carotid artery (ICA), three the supraclinoid ICA and one the basilar artery. Seven patients presented with signs and symptoms of mass effect and one with seizures. All but one aneurysm was treated with a single FD stent; six aneurysms were also coiled (either before or simultaneously with FD placement). Minimum follow-up time was 6 months (mean 20 months). At follow-up, three aneurysms decreased in size, three were unchanged and two increased. Both aneurysms that increased in size showed persistent endosaccular flow at follow-up MR; in one case, failure was attributed to suboptimal position of the stent; in the other case, it was attributed to persistence of a side branch originating from the aneurysm (similar to the endoleak phenomenon of aortic aneurysms). At follow-up, five aneurysms were completely occluded; none of these increased in volume. Complete occlusion of the aneurysms leads, in most cases, to its shrinkage. In cases of late aneurysm growth or regrowth, consideration should be given to possible endoleak as the cause.


Sex Hormone-Binding Globulin Levels in Young Men Are Associated With Nonalcoholic Fatty Liver Disease in Midlife.
Cross-sectional data note lower levels of testosterone and sex hormone-binding globulin (SHBG) levels in men with nonalcoholic fatty liver disease (NAFLD). Whether sex hormone levels in young men are predictive of later risk of NAFLD is not known. Among men in the prospective population-based multicenter Coronary Artery Risk Development in Young Adults study (mean age 50; n = 837), we assessed whether testosterone and SHBG levels measured at study year 10 (median age 35 years) were associated with prevalent NAFLD at study year 25. NAFLD was defined using noncontrast abdominal computed tomography (CT) scan after excluding other causes of hepatic steatosis. The association of testosterone and SHBG with prevalent NAFLD was assessed by logistic regression. Total testosterone levels in young men were inversely associated with subsequent prevalent NAFLD on unadjusted analysis (odds ratio [OR] 0.64, 95% confidence interval 0.53-0.7, P < 0.001), although no longer significant after adjustment for year 10 metabolic covariates as well as change in metabolic covariates from years 10 to 25 (OR 0.99, 95% confidence interval 0.76-1.27). In contrast, there was a significant inverse association of SHBG with prevalent NAFLD, independent of testosterone and metabolic covariates (OR 0.68, OR 0.51-0.92, P = 0.013). On formal mediation testing, visceral adiposity was found to explain ∼41.0% (95% confidence interval 27%-73%) of the association of lower SHBG with prevalent NAFLD. Lower levels of SHBG in young men are associated with increase in prevalent NAFLD in middle age, independent of comprehensive metabolic risk factors. SHBG may provide a novel marker of NAFLD risk in young men.


Predicting neonatal intubation competency in trainees.
Pediatric residency training programs are graduating residents who are not competent in neonatal intubation, a vital skill needed for any pediatrician involved in delivery room resuscitations. However, a precise definition of competency during training is lacking. The objective of this study was to more precisely define the trajectory toward competency in neonatal intubation for pediatric residents, as a framework for later evaluating complementary training tools. This is a retrospective single-center observational study of resident-performed neonatal intubations at Duke University Medical Center between 2005 and 2013. Using a Bayesian statistical model, intubation competency was defined when the resident attained a 75% likelihood of intubating their next patient successfully. A total of 477 unique intubation attempts by 105 residents were analyzed. The path to proficiency was defined by a categorical or milestone learning event after which all learners move toward competency in a similar manner. In our cohort, 4 cumulative successes were needed to achieve competency. Only 24 of 105 (23%) achieved competency during the study period. Residents who failed their first 2 opportunities, compared with those successful on their first 2 opportunities, needed nearly double the intubation exposure to achieve competency. Bayesian statistics may be useful to more precisely describe neonatal intubation competency in residents. Achieving competency in neonatal intubation appears to be a categorical or milestone learning event whose timing varies between residents. The current educational environment does not provide adequate procedural exposure to achieve competency for most residents.


X-ray computed tomography for quality inspection of agricultural products: A review.
The quality of agricultural products relates to the internal structure, which has long been a matter of interest in agricultural scientists. However, inspection methods of the opaque nature of internal information on agricultural products are usually destructive and require sample separation or preparation. X-ray computed tomography (X-ray CT) technology is one of the important nondestructive testing (NDT) technologies without sample separation and preparation. In this study, X-ray CT technology is used to obtain two-dimensional slice images and three-dimensional tomographic images of samples. The purpose of the review was to provide an overview of the working principle of X-ray CT technology, image processing, and analysis. This review aims to focus on the development of the agricultural products (e.g., wheat, maize, rice, apple, beef) and its applications (e.g., internal quality evaluation, microstructure observation, mechanical property measurement, and others) using CT scanner. This paper covers the aspects regarding the advantages and disadvantages of NDT technology, especially the unique advantages and limitations of X-ray CT technology on the quality inspection of agricultural products. Future prospects of X-ray CT technology are also put forward to become indispensable to the quality evaluation and product development on agricultural products.