Elucidating the impact of A-site cation change on photocatalytic H2 and O2 evolution activities of perovskite-type LnTaON2 (Ln = La and Pr).
Transition metal (oxy)nitrides with perovskite-type structures have been regarded as one of the promising classes of inorganic semiconductor materials that can be used in solar water splitting systems for the production of hydrogen as a renewable and storable energy carrier. The performance of transition metal (oxy)nitrides in solar water splitting is strongly influenced by the crystal structure-related dynamics of photogenerated charge carriers. Here, we have systematically assessed the influence of A-site cation exchange on the visible-light-induced photocatalytic H2 and O2 evolution activities, photoanodic response, and dynamics of photogenerated charge carriers of perovskite-type LnTaON2 (Ln = La and Pr). The structural refinement results reveal the orthorhombic Imma and Pnma structures for LaTaON2 and PrTaON2, respectively; the latter has a more distorted crystal structure from the ideal cubic perovskite due to the smaller size of Pr3+ cations. Compared with LaTaON2, PrTaON2 exhibits lower photocatalytic H2 and O2 gas evolution activities and photoanodic response owing to an excessive amount of intrinsic defects associated with anionic vacancies and reduced tantalum species stemming from a long high-temperature nitridation process under reductive NH3 atmosphere. Transient absorption signals evidence the faster decay of photogenerated electrons (holes) in Pt (CoOx)-loaded LaTaON2 than that in Pt (CoOx)-loaded PrTaON2, consistent with the photocatalytic and photoelectrochemical performance of the two photocatalysts. This study suggests that in addition to selecting a suitable A-site cation, it is prerequisite to synthesize LnTaON2 (Ln = La and Pr) crystals with a low defect density to improve their photo-conversion efficiency for solar water splitting.


Mercury cycling in stream ecosystems. 3. Trophic dynamics and methylmercury bioaccumulation.
Trophic dynamics (community composition and feeding relationships) have been identified as important drivers of methylmercury (MeHg) bioaccumulation in lakes, reservoirs, and marine ecosystems. The relative importance of trophic dynamics and geochemical controls on MeHg bioaccumulation in streams, however, remains poorly characterized. MeHg bioaccumulation was evaluated in eight stream ecosystems across the United States (Oregon, Wisconsin, and Florida) spanning large ranges in climate, landscape characteristics, atmospheric Hg deposition, and stream chemistry. Across all geographic regions and all streams, concentrations of total Hg (THg) in top predator fish and forage fish, and MeHg in invertebrates, were strongly positively correlated to concentrations of filtered THg (FTHg), filtered MeHg (FMeHg), and dissolved organic carbon (DOC); to DOC complexity (as measured by specific ultraviolet absorbance); and to percent wetland in the stream basins. Correlations were strongest for nonurban streams. Although regressions of log[Hg] versus delta15N indicate that Hg in biota increased significantly with increasing trophic position within seven of eight individual streams, Hg concentrations in top predator fish (including cutthroat, rainbow, and brown trout; green sunfish; and largemouth bass) were not strongly influenced by differences in relative trophic position. Slopes of log[Hg] versus delta15N, an indicator of the efficiency of trophic enrichment, ranged from 0.14 to 0.27 for all streams. These data suggest that, across the large ranges in FTHg (0.14-14.2 ng L(-1)), FMeHg (0.023-1.03 ng L(-1)), and DOC (0.50-61.0 mg L(-1)) found in this study, Hg contamination in top predatorfish in streams likely is dominated by the amount of MeHg available for uptake at the base of the food web rather than by differences in the trophic position of top predator fish.


[What is a nociceptor?].
Nociceptors can be defined as sensory receptors that are activated by noxious stimuli that damage or threaten the body's integrity. Nociceptors belong to the slowly conducting afferent A delta and C fibres. They are classified according to their responses to mechanical, thermal, and chemical stimuli. In the skin, high-threshold mechano-nociceptors (HTMs) and mechano-heat nociceptors of A and C fibres (AMHs and CMHs) are frequently found. CMHs are usually called polymodal C fibres (CPMs) if they also show chemosensitive properties. Sensations of sharp pain are evoked by intraneural microstimulation of nociceptive A delta fibres, whereas stimulation of C fibres causes dull pain sensations. NOCICEPTORS OF DEEP TISSUES AND VISCERA: Slowly conducting afferents of deep tissues (muscles, joints) are primarily classified according to their mechanosensitivity. High-threshold afferents in somatic and visceral tissues are specifically activated by noxious mechanical stimuli. Many visceral afferents, however, are already activated by peristaltic contractions encoding the stimulus intensity over a wide range. High proportions of somatic and visceral nociceptors can be excited or sensitised by various irritants and inflammatory mediators such as capsaicin, bradykinin, prostaglandins, leukotrienes, serotonin, histamine, and free radicals. As a special class of nociceptors, mechano-insensitive or "silent" afferents have been found in nearly all tissues. Silent afferents become mechanosensitive only after long noxious stimulation, e.g., during an inflammation. "Free nerve endings", which are regarded as the morphological correlatives of nociceptors, usually consist of bundles of unmyelinated fibres. With electron microscopy varicose segments of the sensory axon are visible that are characterised by free areas of axolemma, accumulations of mitochondria and vesicles, and a modified axoplasm. These presumptive receptive sites are periodically arranged along the whole course of the sensory endings at a length of up to several hundred microns. Additionally, the fine sensory endings are branched, forming tree-like structures, and frequently innervate different types of tissues. Studies correlating structure and function of articular afferents provide evidence for a close relationship between topographical and functional properties of sensory endings. High-threshold afferents (nociceptors) seem to terminate in structures of dense connective tissue. Proportions of nociceptors contain neuropeptides such as substance P and calcitonin gene-related peptide, which are released from the activated nociceptive terminals and cause neurogenic inflammation, including precapillary vasodilatation and postcapillary plasma extravasation. Experimental and clinical progress has been achieved in using the nociceptor as a target for chemical anti-nociception and treatment of pain. Substances that act directly or indirectly on the nociceptor are steroidal and non-steroidal analgesics, capsaicin analogs, bradykinin antagonists, opioids, and (in the trigeminal system) 5-hydroxytryptamine agonists.


Hippocampal-prefrontal theta-gamma coupling during performance of a spatial working memory task.
Cross-frequency coupling supports the organization of brain rhythms and is present during a range of cognitive functions. However, little is known about whether and how long-range cross-frequency coupling across distant brain regions subserves working memory. Here we report that theta-slow gamma coupling between the hippocampus and medial prefrontal cortex (mPFC) is augmented in a genetic mouse model of cognitive dysfunction. This increased cross-frequency coupling is observed specifically when the mice successfully perform a spatial working memory task. In wild-type mice, increasing task difficulty by introducing a long delay or by optogenetically interfering with encoding, also increases theta-gamma coupling during correct trials. Finally, epochs of high hippocampal theta-prefrontal slow gamma coupling are associated with increased synchronization of neurons within the mPFC. These findings suggest that enhancement of theta-slow gamma coupling reflects a compensatory mechanism to maintain spatial working memory performance in the setting of increased difficulty.


Cognitive function and dental care utilization among community-dwelling older adults.
We sought to investigate the relationship between varying levels of cognitive function and dental care utilization. Using data obtained from the National Health and Nutrition Examination Survey (1999-2002), we performed weighted descriptive and multivariate logistic regression analyses on 1984 individuals with at least 1 tooth and who were 60 years and older. Multivariate analyses suggested that level of cognitive function was associated with dental care utilization. At a higher level of cognitive functioning, individuals were more likely to have had more frequent dental visits. In addition, a higher level of socioeconomic status, healthy lifestyle, and worse self-rated oral health-related symptoms were more likely to indicate a higher frequency of dental care utilization. By contrast, poorer oral health status as determined by clinical examinations was negatively associated with frequency of dental visits. The results suggest that community-dwelling older adults with low cognitive function are at risk for less frequent use of dental care. Oral health serves as a mediating factor between cognitive function and dental care utilization. There is a great need to improve oral health awareness and education among older adults, caregivers, and health care professionals.


All-optical RF spectrum analyzer with a 5 THz bandwidth based on CMOS-compatible high-index doped silica waveguides.
We report an all-optical radio-frequency (RF) spectrum analyzer with a bandwidth greater than 5 THz, based on a 50 cm long spiral waveguide in a CMOS-compatible high-index doped silica platform. By carefully mapping out the dispersion profile of the waveguides for different thicknesses, we identify the optimal design to achieve near-zero dispersion in the C-band. To demonstrate the capability of the RF spectrum analyzer, we measure the optical output of a femtosecond fiber laser with an ultrafast optical RF spectrum in the terahertz regime.


Dentate granule cell recruitment of feedforward inhibition governs engram maintenance and remote memory generalization.
Memories become less precise and generalized over time as memory traces reorganize in hippocampal-cortical networks. Increased time-dependent loss of memory precision is characterized by an overgeneralization of fear in individuals with post-traumatic stress disorder (PTSD) or age-related cognitive impairments. In the hippocampal dentate gyrus (DG), memories are thought to be encoded by so-called 'engram-bearing' dentate granule cells (eDGCs). Here we show, using rodents, that contextual fear conditioning increases connectivity between eDGCs and inhibitory interneurons (INs) in the downstream hippocampal CA3 region. We identify actin-binding LIM protein 3 (ABLIM3) as a mossy-fiber-terminal-localized cytoskeletal factor whose levels decrease after learning. Downregulation of ABLIM3 expression in DGCs was sufficient to increase connectivity with CA3 stratum lucidum INs (SLINs), promote parvalbumin (PV)-expressing SLIN activation, enhance feedforward inhibition onto CA3 and maintain a fear memory engram in the DG over time. Furthermore, downregulation of ABLIM3 expression in DGCs conferred conditioned context-specific reactivation of memory traces in hippocampal-cortical and amygdalar networks and decreased fear memory generalization at remote (i.e., distal) time points. Consistent with the observation of age-related hyperactivity of CA3, learning failed to increase DGC-SLIN connectivity in 17-month-old mice, whereas downregulation of ABLIM3 expression was sufficient to restore DGC-SLIN connectivity, increase PV+ SLIN activation and improve the precision of remote memories. These studies exemplify a connectivity-based strategy that targets a molecular brake of feedforward inhibition in DG-CA3 and may be harnessed to decrease time-dependent memory generalization in individuals with PTSD and improve memory precision in aging individuals.


Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload.
Fibroblasts, which are the most numerous cell type in the heart, interact with cardiomyocytes in vitro and affect their function; however, they are considered to play a secondary role in cardiac hypertrophy and failure. Here we have shown that cardiac fibroblasts are essential for the protective and hypertrophic myocardial responses to pressure overload in vivo in mice. Haploinsufficiency of the transcription factor-encoding gene Krüppel-like factor 5 (Klf5) suppressed cardiac fibrosis and hypertrophy elicited by moderate-intensity pressure overload, whereas cardiomyocyte-specific Klf5 deletion did not alter the hypertrophic responses. By contrast, cardiac fibroblast-specific Klf5 deletion ameliorated cardiac hypertrophy and fibrosis, indicating that KLF5 in fibroblasts is important for the response to pressure overload and that cardiac fibroblasts are required for cardiomyocyte hypertrophy. High-intensity pressure overload caused severe heart failure and early death in mice with Klf5-null fibroblasts. KLF5 transactivated Igf1 in cardiac fibroblasts, and IGF-1 subsequently acted in a paracrine fashion to induce hypertrophic responses in cardiomyocytes. Igf1 induction was essential for cardioprotective responses, as administration of a peptide inhibitor of IGF-1 severely exacerbated heart failure induced by high-intensity pressure overload. Thus, cardiac fibroblasts play a pivotal role in the myocardial adaptive response to pressure overload, and this role is partly controlled by KLF5. Modulation of cardiac fibroblast function may provide a novel strategy for treating heart failure, with KLF5 serving as an attractive target.


A linear mixed-model approach to study multivariate gene-environment interactions.
Different exposures, including diet, physical activity, or external conditions can contribute to genotype-environment interactions (G×E). Although high-dimensional environmental data are increasingly available and multiple exposures have been implicated with G×E at the same loci, multi-environment tests for G×E are not established. Here, we propose the structured linear mixed model (StructLMM), a computationally efficient method to identify and characterize loci that interact with one or more environments. After validating our model using simulations, we applied StructLMM to body mass index in the UK Biobank, where our model yields previously known and novel G×E signals. Finally, in an application to a large blood eQTL dataset, we demonstrate that StructLMM can be used to study interactions with hundreds of environmental variables.


STD and HIV risk factors among U.S. young adults: variations by gender, race, ethnicity and sexual orientation.
STDs, including HIV, disproportionately affect individuals who have multiple minority identities. Understanding differences in STD risk factors across racial, ethnic and sexual minority groups, as well as genders, is important for tailoring public health interventions. Data from Waves 3 (2001-2002) and 4 (2007-2008) of the National Longitudinal Study of Adolescent Health were used to develop population-based estimates of STD and HIV risk factors among 11,045 young adults (mean age, 29 at Wave 4), by gender, race and ethnicity, and sexual orientation (heterosexual, mixed-oriented, gay). Regression analyses were conducted to examine associations between risk factors and young adults' characteristics. Overall, sexual-minority women in each racial or ethnic group had a higher prevalence of sexual risk behaviors-including a history of multiple partners, forced sex and incarceration-than their heterosexual counterparts. Mixed-oriented women in each racial or ethnic group were more likely than heterosexual white women to have received an STD diagnosis (odds ratios, 1.8-6.4). Black men and sexual-minority men also appeared to be at heightened risk. Gay men in all racial and ethnic groups were significantly more likely than heterosexual white men to report having received an STD diagnosis (2.3-8.3); compared with heterosexual white men, mixed-oriented black men had the highest odds of having received such a diagnosis (15.2). Taking account of multiple minority identities should be an important part of future research and intervention efforts for STD and HIV prevention.


Malaria haplotype frequency estimation.
We present a Bayesian approach for estimating the relative frequencies of multi-single nucleotide polymorphism (SNP) haplotypes in populations of the malaria parasite Plasmodium falciparum by using microarray SNP data from human blood samples. Each sample comes from a malaria patient and contains one or several parasite clones that may genetically differ. Samples containing multiple parasite clones with different genetic markers pose a special challenge. The situation is comparable with a polyploid organism. The data from each blood sample indicates whether the parasites in the blood carry a mutant or a wildtype allele at various selected genomic positions. If both mutant and wildtype alleles are detected at a given position in a multiply infected sample, the data indicates the presence of both alleles, but the ratio is unknown. Thus, the data only partially reveals which specific combinations of genetic markers (i.e. haplotypes across the examined SNPs) occur in distinct parasite clones. In addition, SNP data may contain errors at non-negligible rates. We use a multinomial mixture model with partially missing observations to represent this data and a Markov chain Monte Carlo method to estimate the haplotype frequencies in a population. Our approach addresses both challenges, multiple infections and data errors.


Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297.
Gemcitabine is generally considered to constitute first-line therapy for pancreatic cancer. To determine whether the addition of fluorouracil (5-FU) improves on the results from single-agent gemcitabine, the Eastern Cooperative Oncology Group (ECOG) compared gemcitabine plus bolus 5-FU with gemcitabine alone for patients with advanced pancreatic carcinoma. This trial involved patients with biopsy-proven, advanced carcinoma of the pancreas not amenable to surgical resection. Patients were randomized to receive either gemcitabine alone (1,000 mg/m(2)/wk) weekly for 3 weeks of every 4 or to receive gemcitabine (1,000 mg/m(2)/wk) followed by 5-FU (600 mg/m(2)/wk) weekly on the same schedule. The primary end point of the trial was survival, with secondary end points of time to progression and response rate. Of 327 patients enrolled over 18 months, 322 were eligible. Overall, the median survival was 5.4 months for gemcitabine alone and 6.7 months for gemcitabine plus 5-FU (P =.09). Progression-free survival for gemcitabine alone was 2.2 months, compared with 3.4 months for gemcitabine plus 5-FU (P =.022). Objective responses were uncommon and were observed in only 5.6% of patients treated with gemcitabine and 6.9% of patients treated with gemcitabine plus 5-FU. Most toxicities were hematologic or gastrointestinal; no significant differences were noted between the two treatment arms. 5-FU, administered in conjunction with gemcitabine, did not improve the median survival of patients with advanced pancreatic carcinoma compared with single-agent gemcitabine. Further studies with other combinations of gemcitabine and 5-FU are not compelling, and clinical trial resources should address other combinations and novel agents.


Stable chirped black solitary waves in dispersive media withintensity-dependent gain and loss.
We examine the stationary propagation of a black solitary wave in a fiber laser or in a fiber transmission system with periodically distributed amplifiers and saturable absorbers that is governed by the Ginzburg-Landau equation. An analytical solution of the chirped black solitary wave to the Ginzburg-Landau equation that includes the nonlinear saturation effect is obtained for what we believe to be the first time. The stability analyses reveal that the stationary propagation of the chirped black solitary wave can be stable when the saturation effect of nonlinear gain or loss is taken into account, whereas the chirped black solitary-wave solution of the Ginzburg-Landau equation that does not include the nonlinear saturation of gain or loss is found to be unstable. The criterion for the stable or unstable propagation of the chirped black solitary wave in the presence of the nonlinear gain or loss saturation is presented. Also, it is shown that two identical chirped black solitary waves launched in parallel will attract each other and may develop into a bound state of two parallel chirped black solitary waves. This is in contrast to the behavior of conventional black solitons of an unperturbed system, in which the two black solitons launched in parallel repel each other and distance themselves during propagation.


Technology development.
In technology development significant advances are as often the result of a series of evolutionary steps as they are of breakthroughs. This is illustrated by the examples of the steam engine and the computer. Breakthroughs, such as the transistor, are relatively rare, and are often the result of the introduction of new knowledge coming from a quite different area. Technology development is often difficult to predict because of its complexity; practical considerations may far outweigh apparent scientific advantages, and cultural factors enter in at many levels. In a large technological organization problems exist in bringing scientific knowledge to bear on development, but much can be done to obviate these difficulties.


Surfactant protein-A inhibits Aspergillus fumigatus-induced allergic T-cell responses.
The pulmonary surfactant protein (SP)-A has potent immunomodulatory activities but its role and regulation during allergic airway inflammation is unknown. We studied changes in SP-A expression in the bronchoalveolar lavage (BAL) using a murine model of single Aspergillus fumigatus (Af) challenge of sensitized animals. SP-A protein levels in the BAL fluid showed a rapid, transient decline that reached the lowest values (25% of controls) 12 h after intranasal Af provocation of sensitized mice. Decrease of SP-A was associated with influx of inflammatory cells and increase of IL-4 and IL-5 mRNA and protein levels. Since levels of SP-A showed a significant negative correlation with these BAL cytokines (but not with IFN-gamma), we hypothesized that SP-A exerts an inhibitory effect on Th2-type immune responses. To study this hypothesis, we used an in vitro Af-rechallenge model. Af-induced lymphocyte proliferation of cells isolated from sensitized mice was inhibited in a dose-dependent manner by addition of purified human SP-A (0.1-10 microg/ml). Flow cytometric studies on Af-stimulated lymphocytes indicated that the numbers of CD4+ (but not CD8+) T cells were significantly increased in the parental population and decreased in the third and fourth generation in the presence of SP-A. Further, addition of SP-A to the tissue culture inhibited Af-induced IL-4 and IL-5 production suggesting that SP-A directly suppressed allergen-stimulated CD4+ T cell function. We speculate that a transient lack of this lung collectin following allergen exposure of the airways may significantly contribute to the development of a T-cell dependent allergic immune response.


Mutant Mice With Calcium-Sensing Receptor Activation Have Hyperglycemia That Is Rectified by Calcilytic Therapy.
The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor that plays a pivotal role in extracellular calcium homeostasis. The CaSR is also highly expressed in pancreatic islet α- and β-cells that secrete glucagon and insulin, respectively. To determine whether the CaSR may influence systemic glucose homeostasis, we characterized a mouse model with a germline gain-of-function CaSR mutation, Leu723Gln, referred to as Nuclear flecks (Nuf). Heterozygous- (CasrNuf/+) and homozygous-affected (CasrNuf/Nuf) mice were shown to have hypocalcemia in association with impaired glucose tolerance and insulin secretion. Oral administration of a CaSR antagonist compound, known as a calcilytic, rectified the glucose intolerance and hypoinsulinemia of CasrNuf/+ mice and ameliorated glucose intolerance in CasrNuf/Nuf mice. Ex vivo studies showed CasrNuf/+ and CasrNuf/Nuf mice to have reduced pancreatic islet mass and β-cell proliferation. Electrophysiological analysis of isolated CasrNuf/Nuf islets showed CaSR activation to increase the basal electrical activity of β-cells independently of effects on the activity of the adenosine triphosphate (ATP)-sensitive K+ (KATP) channel. CasrNuf/Nuf mice also had impaired glucose-mediated suppression of glucagon secretion, which was associated with increased numbers of α-cells and a higher α-cell proliferation rate. Moreover, CasrNuf/Nuf islet electrophysiology demonstrated an impairment of α-cell membrane depolarization in association with attenuated α-cell basal KATP channel activity. These studies indicate that the CaSR activation impairs glucose tolerance by a combination of α- and β-cell defects and also influences pancreatic islet mass. Moreover, our findings highlight a potential application of targeted CaSR compounds for modulating glucose metabolism.


Multiscattering-enhanced optical biosensor: multiplexed, non-invasive and continuous measurements of cellular processes.
The continuous measurement of uptake or release of biomarkers provides invaluable information for understanding and monitoring the metabolism of cells. In this work, a multiscattering-enhanced optical biosensor for the multiplexed, non-invasive, and continuous detection of hydrogen peroxide (H2O2), lactate and glucose is presented. The sensing scheme is based on optical monitoring of the oxidation state of the metalloprotein cytochrome c (cyt c). The analyte of interest is enzymatically converted into H2O2 leading to an oxidation of the cyt c. Contact microspotting is used to prepare nanoliter-sized sensing spots containing either pure cyt c, a mixture of cyt c with glucose oxidase (GOx) to detect glucose, or a mixture of cyt c with lactate oxidase (LOx) to detect lactate. The sensing spots are embedded in a multiscattering porous medium that enhances the optical signal. We achieve limits of detection down to 240 nM and 110 nM for lactate and glucose, respectively. A microfluidic embodiment enables multiplexed and crosstalk-free experiments on living organisms. As an example, we study the uptake of exogenously supplied glucose by the green algae Chlamydomonas reinhardtii and simultaneously monitor the stress-related generation of H2O2. This multifunctional detection scheme provides a powerful tool to study biochemical processes at cellular level.


Occlusion, Orthodontic treatment, and temporomandibular disorders: a review.
A review of the current literature regarding the interaction of morphologic and functional occlusal factors relative to TMD indicates that there is a relatively low association of occlusal factors in characterizing TMD. Skeletal anterior open bite, overjets greater than 6 to 7 mm, retruded cuspal position/intercuspal position slides greater than 4 mm, unilateral lingual crossbite, and five or more missing posterior teeth are the five occlusal features that have been associated with specific diagnostic groups of TMD conditions. The first three factors often are associated with TMJ arthropathies and may be the result of osseous or ligamentous changes within the temporomandibular articulation. With regard to the relationship of orthodontic treatment to TMD, the current literature indicates that orthodontic treatment performed during adolescence generally does not increase or decrease the odds of developing TMD later in life. There is no elevated risk of TMD associated with any particular type of orthodontic mechanics or with extraction protocols. Although a stable occlusion is a reasonable orthodontic treatment goal, not achieving a specific gnathologically ideal occlusion does not result in TMD signs and symptoms. Thus, according to the existing literature, the relationship of TMD to occlusion and orthodontic treatment is minor. Signs and symptoms of TMD occur in healthy individuals and increase with age, particularly during adolescence; thus, TM disorders that originate during various types of dental treatment may not be related to the treatment but may be a naturally occurring phenomenon.


Cost-utility analysis of adjuvant goserelin (Zoladex) and adjuvant chemotherapy in premenopausal women with breast cancer.
Increased health care costs have made it incumbent on health-care facilities and physicians to demonstrate both clinical and cost efficacy when recommending treatments. Though studies have examined the cost-effectiveness of adjuvant goserelin with radiotherapy for locally advanced prostate cancer, few have compared the cost-effectiveness of adjuvant goserelin to adjuvant chemotherapy alone in premenopausal breast cancer. In this retrospective study at one hospital, the records of 152 patients with stage Ia to IIIa ER + breast cancer who received goserelin or chemotherapy were reviewed. Survival analysis was assessed by the Kaplan-Meier method. Patients were interviewed to evaluate their quality of life using the European Organization for Research and Treatment Quality of Life questionnaire (EORTC-QLQ-C30, version 4.0), and to obtain the utility value by the standard gamble (SG) and visual scale (VS) methods. Total medical cost was assessed from the (National Health Insurance) NHI payer's perspective. Survival at 11 years was significantly better in the groserelin group (P < 0.0012). The lifetime lost was lower in the goserelin group (42 months vs. 66 months). The quality adjusted survival (QAS) of patients who received goserelin was longer (122.5 ± 6.3 vs. 112.2 ± 6.7 months). Total expenses of goserelin were more than cyclophosphamide, methotrexate, 5-fluorouracil (CMF) or 5-fluorouracil, epirubicin, cyclophosphamide (FEC) chemotherapy regimes, but less than docetaxel, epirubicin (TE) or docetaxel, epirubicin, cyclophosphamide (TEC) regimes. The quality-adjusted life-year was higher in the goserelin group. Goserelin therapy results in better survival and higher utility-weighted life-years, and is more cost-effective than TC or TEC chemotherapy.


Focal hypersteatosis: a pseudolesion in patients with liver steatosis.
We aimed to describe ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) findings of focal hypersteatosis (FHS). We retrospectively reviewed our database for patients with hypersteatosis. Over a 5-year period (February 2005 to September 2010) a total of 17 321 patients underwent abdominal CT scan and 28 patients were determined to have FHS. All patients had US, CT, and MRI studies. Size, area, and density measurements were performed on CT images. Fat signal percentage (FSP) was measured on T1-weighted in- and out-of-phase gradient-echo images. FHS was defined based on MRI findings, as an area of greater signal drop on out-of phase images compared with the rest of the fatty liver. The period prevelance of focal hypersteatosis was measured as 0.16% over the 5-year period. Cancer was the most common diagnosis (22 of 28 patients, 78.5%), with the breast (32.1%) and colorectal (25%) cancers predominating. FHS was seen in segment 4 (n=26, 92.8%), segment 8 (n=1, 3.6%), and segment 3 (n=1, 3.6%). Shape was nodular in 21 patients (75%), while triangular or amorphous in the remaining 7 patients (25%). FHS was hyperechoic and isoechoic in 5 (17.9%) and 23 (82.1%) patients, respectively. FHS was hypodense on CT of all patients relative to fatty liver. On MRI, the FHS was hyperintense on T1-weighted in-phase images in 17 patients (60.7%). Median liver parenchymal FSP was 21.5% (range, 10%-41.4%) and median FSP of hypersteatotic area was 32.5% (range, 19%-45%). Focal hypersteatosis is a pseudolesion that can be observed in patients with liver steatosis. It appears hypodense on CT and mostly isoechoic on US relative to fatty liver. It may mimic metastasis in cancer patients with steatosis, due to nodular shape and atypical location. MRI should be used for correct diagnosis in patients with equivocal findings on CT to avoid biopsy.


The economics of faking ecstasy.
In this paper, we develop a signaling model of rational lovemaking. In the act of lovemaking, a man and a woman send each other possibly deceptive signals about their true state of ecstasy. For example, if one of the partners is not in ecstasy, then he or she may decide to fake it. The model predicts that (1) a higher cost of faking lowers the probability of faking; (2) middle-aged and old men are more likely to fake than young men; (3) young and old women are more likely to fake than middle-aged women; and (4) love, formally defined as a mixture of altruism and demand for togetherness, increases the likelihood of faking. The predictions are tested with data from the 2000 Orgasm Survey. Besides supporting the model's predictions, the data also reveal an interesting positive relationship between education and the tendency to fake in both men and women.


Metagenomic profiling of ticks: Identification of novel rickettsial genomes and detection of tick-borne canine parvovirus.
Across the world, ticks act as vectors of human and animal pathogens. Ticks rely on bacterial endosymbionts, which often share close and complex evolutionary links with tick-borne pathogens. As the prevalence, diversity and virulence potential of tick-borne agents remain poorly understood, there is a pressing need for microbial surveillance of ticks as potential disease vectors. We developed a two-stage protocol that includes 16S-amplicon screening of pooled samples of hard ticks collected from dogs, sheep and camels in Palestine, followed by shotgun metagenomics on individual ticks to detect and characterise tick-borne pathogens and endosymbionts. Two ticks isolated from sheep yielded an abundance of reads from the genus Rickettsia, which were assembled into draft genomes. One of the resulting genomes was highly similar to Rickettsia massiliae strain MTU5. Analysis of signature genes showed that the other represents the first genome sequence of the potential pathogen Candidatus Rickettsia barbariae. Ticks from a dog and a sheep yielded draft genome sequences of Coxiella strains. A sheep tick yielded sequences from the sheep pathogen Anaplasma ovis, while Hyalomma ticks from camels yielded sequences belonging to Francisella-like endosymbionts. From the metagenome of a dog tick from Jericho, we generated a genome sequence of a canine parvovirus. Here, we have shown how a cost-effective two-stage protocol can be used to detect and characterise tick-borne pathogens and endosymbionts. In recovering genome sequences from an unexpected pathogen (canine parvovirus) and a previously unsequenced pathogen (Candidatus Rickettsia barbariae), we demonstrate the open-ended nature of metagenomics. We also provide evidence that ticks can carry canine parvovirus, raising the possibility that ticks might contribute to the spread of this troublesome virus.


147 fs, 51 MHz soliton fiber laser at 1.56 microm with a fiber-connector-type SWNT/P3HT saturable absorber.
We fabricated a fiber-connector-type saturable absorber in which SWNTs and P3HT (poly-3-hexylthiophene) were coated on the fiber connector end. This saturable absorber allowed us to realize a short laser cavity length. We used a soliton cavity configuration to generate the shortest pulse (147 fs) at the highest repetition rate (51 MHz) yet obtained with carbon nanotubes (CNT) related saturable absorbers.


Particle size analysis of turbid media with a single optical fiber in contact with the medium to deliver and detect white light.
Wavelength-dependent elastic-scattering spectra of highly scattering media measured with only a single fiber for both light delivery and collection are presented. White light is used as a source, and oscillations of the detected light intensities are seen as a function of wavelength. The maximum and minimum of the oscillations can be used to determine scatterer size for monodisperse distributions of spheres when the refractive indices are known. In addition, several properties of the probe relevant to tissue diagnosis are examined and discussed including the effects of absorption, a broad distribution of scatterers, and the depth probed.


Pharmacokinetics of pars plana intravitreal injections versus microcannula suprachoroidal injections of bevacizumab in a porcine model.
To compare the pharmacokinetics and tissue response between intravitreal and microcannulation injections into the suprachoroidal space using bevacizumab. Sixty-two pigs were studied. Either a pars plana intravitreal bevacizumab or a viscoelastic-enhanced microcannula suprachoroidal injection was performed with either 1.25 mg (group 1) or 3 mg (group 2). In group 1, six animals were euthanatized at 0.5, 7, 30, 60, 90, and 120 days after injection (n = 36). In group 2, six animals were euthanatized at 0.5, 7, 14, and 32 days (n = 24). Eyes were enucleated, dissected, and snap-frozen, or they were fixed for histology. Analysis of drug tissue levels was performed at two separate laboratories using masked specimens. Both laboratories were confirmatory. Intravitreal bevacizumab pharmacokinetics demonstrated a gradual decline in tissue levels over 30 to 60 days in both groups 1 and 2. In addition, suprachoroidal bevacizumab tissue levels declined rapidly and were not measurable at or beyond 7 days. Vitreitis and granulomatous vasculitis were noted in 7 of 30 intravitreal injection eyes. Immunohistology suggested a distinctive drug distribution. Direct intravitreal injection of bevacizumab has a more sustained pharmacologic profile than does a similar dose delivered to the suprachoroidal space. Intravitreal injections distributed more to the inner retina, whereas suprachoroidal delivery occurred primarily at the choroid, retinal pigment epithelium, and photoreceptor outer segments. Sustained release formulation of larger biological molecules should be considered to optimize suprachoroidal delivery. Inflammation from injections is granulomatous, seen only with intravitreal injections, and may result from either an altered immune response or a dose-related effect.


Scrapie epidemic in a fully PrP-genotyped sheep flock.
In scrapie-affected sheep flocks, host PrP genotype plays a vital role in determining which sheep will succumb to scrapie and the incubation period. Consequently, within-flock scrapie dynamics is best understood within the context of the genotype profile of the flock. Here we describe a 17 month epidemic of scrapie in a commercially farmed flock of 230 genotyped Texel sheep. At the start of the study, 70% of the sheep were of three genotypes only: ARR/ARQ, ARH/ARQ and ARQ/ARQ. Only 15% of sheep encoded the disease-associated VRQ allele and only a single sheep (0.4%) was of the most susceptible VRQ/VRQ genotype. For susceptible genotypes there was a marked deficit (P<0.025) of older animals (> or =3 years), implying that some cases of scrapie had occurred previously. In the ensuing 17 months, 18 sheep of known genotype were confirmed positive for the disease: seven VRQ/ARQ, six VRQ/ARH, two VRQ/ARR, three ARQ/ARQ. Median ages at death were 2.7, 2.8, 4.2 and 3.8 years respectively. Mortality rates were 55, 86, 13 and 3% respectively. Survival analysis revealed a highly significant effect of genotype on survivorship, but no difference between VRQ/ARQ and VRQ/ARH, or between VRQ/ARR and ARQ/ARQ. There was no difference in the survivorship of middle- and older-age cohorts of susceptible sheep. Scrapie risk group (as defined by PrP genotype) was not associated with submission as a scrapie suspect but later found to be negative, or with dying of unknown causes on the farm.


Effects of learning climate and registered nurse staffing on medication errors.
Despite increasing recognition of the significance of learning from errors, little is known about how learning climate contributes to error reduction. The purpose of this study was to investigate whether learning climate moderates the relationship between error-producing conditions and medication errors. A cross-sectional descriptive study was done using data from 279 nursing units in 146 randomly selected hospitals in the United States. Error-producing conditions included work environment factors (work dynamics and nurse mix), team factors (communication with physicians and nurses' expertise), personal factors (nurses' education and experience), patient factors (age, health status, and previous hospitalization), and medication-related support services. Poisson models with random effects were used with the nursing unit as the unit of analysis. A significant negative relationship was found between learning climate and medication errors. It also moderated the relationship between nurse mix and medication errors: When learning climate was negative, having more registered nurses was associated with fewer medication errors. However, no relationship was found between nurse mix and medication errors at either positive or average levels of learning climate. Learning climate did not moderate the relationship between work dynamics and medication errors. The way nurse mix affects medication errors depends on the level of learning climate. Nursing units with fewer registered nurses and frequent medication errors should examine their learning climate. Future research should be focused on the role of learning climate as related to the relationships between nurse mix and medication errors.


Genetic diversity of high performance cultivars of upland and irrigated Brazilian rice.
The objective of this study was to analyze the diversity and discrimination of high-performance Brazilian rice cultivars using microsatellite markers. Twenty-nine rice cultivars belonging to EMBRAPA Arroz e Feijão germplasm bank in Brazil were genotyped by 24 SSR markers to establish their structure and genetic discrimination. It was demonstrated that the analyzed germplasm of rice presents an expressive and significant genetic diversity with low heterogeneity among the cultivars. All 29 cultivars were differentiated genetically, and were organized into two groups related to their upland and irrigated cultivation systems. These groups showed a high genetic differentiation, with greater diversity within the group that includes the cultivars for irrigated system. The genotyping data of these cultivars, with the morphological e phenotypical data, are valuable information to be used by rice breeding programs to develop new improved cultivars.


Iron, copper, zinc, and manganese transport and regulation in pathogenic Enterobacteria: correlations between strains, site of infection and the relative importance of the different metal transport systems for virulence.
For all microorganisms, acquisition of metal ions is essential for survival in the environment or in their infected host. Metal ions are required in many biological processes as components of metalloproteins and serve as cofactors or structural elements for enzymes. However, it is critical for bacteria to ensure that metal uptake and availability is in accordance with physiological needs, as an imbalance in bacterial metal homeostasis is deleterious. Indeed, host defense strategies against infection either consist of metal starvation by sequestration or toxicity by the highly concentrated release of metals. To overcome these host strategies, bacteria employ a variety of metal uptake and export systems and finely regulate metal homeostasis by numerous transcriptional regulators, allowing them to adapt to changing environmental conditions. As a consequence, iron, zinc, manganese, and copper uptake systems significantly contribute to the virulence of many pathogenic bacteria. However, during the course of our experiments on the role of iron and manganese transporters in extraintestinal Escherichia coli (ExPEC) virulence, we observed that depending on the strain tested, the importance of tested systems in virulence may be different. This could be due to the different set of systems present in these strains, but literature also suggests that as each pathogen must adapt to the particular microenvironment of its site of infection, the role of each acquisition system in virulence can differ from a particular strain to another. In this review, we present the systems involved in metal transport by Enterobacteria and the main regulators responsible for their controlled expression. We also discuss the relative role of these systems depending on the pathogen and the tissues they infect.


Identification of an immunodominant epitope on RNA polymerase III recognized by systemic sclerosis sera: application to enzyme-linked immunosorbent assay.
To characterize an immunodominant epitope on RNA polymerase III (RNAP III) recognized by systemic sclerosis (SSc) sera and to develop an enzyme-linked immunosorbent assay (ELISA) for the detection of serum anti-RNAP I/III antibodies. RNAP III-specific subunits RPC62 and RPC155 were generated in a bacterial expression system as a series of recombinant fragments. Reactivities to these recombinant fragments were examined by immunoblots and/or ELISA in 16 SSc sera containing anti-RNAP I/III antibodies, 89 SSc sera lacking anti-RNAP I/III antibodies, 61 systemic lupus erythematosus (SLE) sera, and 61 healthy control sera. Anti-RNAP I/III-positive SSc sera recognized several distinct epitopes on RPC62 and RPC155 in various combinations, but the fragment encoding amino acids at positions 732-1166 of RPC155 was recognized by all 11 anti-RNAP I/III-positive SSc sera tested. Carboxyl- and amino-terminal deletion studies showed that at least 130 amino acids at positions 891-1020 of RPC155 were necessary for the antibody binding, but strong reactivity required an additional amino-terminal extension. When a purified recombinant fragment containing the immunodominant epitope was used as the antigen source in an ELISA, elevated antibody reactivity was detected in all 16 anti-RNAP I/III-positive SSc sera, but in no anti-RNAP I/III-negative SSc, SLE, or healthy control sera, representing a sensitivity of 100% and a specificity of 100%. A major epitope commonly recognized by SSc sera containing anti-RNAP I/III antibodies was identified on RPC155. The ELISA using a recombinant fragment expressing the immunodominant epitope should be a valuable tool for routine screening for anti-RNAP I/III antibodies in clinical diagnostic laboratories.


Cloning and analysis of genomic differences unique to Burkholderia pseudomallei by comparison with B. thailandensis.
Melioidosis is an infectious disease caused by Burkholderia pseudomallei. Genomic subtractive hybridisation was performed with the closely related avirulent species B. thailandensis to identify virulence genes of B. pseudomallei. The subtractive hybridisation products were highly specific for B. pseudomallei. Sequence analysis revealed a number of putative virulence factors, as well as apparently novel sequences of unknown function. The subtracted library contained DNA regions of relatively low G + C mol% content, which were distributed throughout the B. pseudomallei genome. The distribution of subtracted sequences amongst a collection of 22 B. pseudomallei isolates was found to be variable, with the exception of three strains which almost universally lacked the subtracted sequences. These three strains also differed in that they were highly haemolytic, indicating a possible separate virotype.


The DNA glycosylase AlkD uses a non-base-flipping mechanism to excise bulky lesions.
Threats to genomic integrity arising from DNA damage are mitigated by DNA glycosylases, which initiate the base excision repair pathway by locating and excising aberrant nucleobases. How these enzymes find small modifications within the genome is a current area of intensive research. A hallmark of these and other DNA repair enzymes is their use of base flipping to sequester modified nucleotides from the DNA helix and into an active site pocket. Consequently, base flipping is generally regarded as an essential aspect of lesion recognition and a necessary precursor to base excision. Here we present the first, to our knowledge, DNA glycosylase mechanism that does not require base flipping for either binding or catalysis. Using the DNA glycosylase AlkD from Bacillus cereus, we crystallographically monitored excision of an alkylpurine substrate as a function of time, and reconstructed the steps along the reaction coordinate through structures representing substrate, intermediate and product complexes. Instead of directly interacting with the damaged nucleobase, AlkD recognizes aberrant base pairs through interactions with the phosphoribose backbone, while the lesion remains stacked in the DNA duplex. Quantum mechanical calculations revealed that these contacts include catalytic charge-dipole and CH-π interactions that preferentially stabilize the transition state. We show in vitro and in vivo how this unique means of recognition and catalysis enables AlkD to repair large adducts formed by yatakemycin, a member of the duocarmycin family of antimicrobial natural products exploited in bacterial warfare and chemotherapeutic trials. Bulky adducts of this or any type are not excised by DNA glycosylases that use a traditional base-flipping mechanism. Hence, these findings represent a new model for DNA repair and provide insights into catalysis of base excision.


Role of endotoxemia in causing renal dysfunction in cirrhosis.
Renal failure is a challenging problem in patients with cirrhosis since mortality increases with worsening renal function, hence the inclusion of serum creatinine in calculating the Model for End-Stage Liver Disease score for liver transplant evaluation. Among the various causes, infection is the leading etiology of mortality associated with cirrhosis. Bacterial infection frequently precipitates renal failure in patients with cirrhosis with the reported prevalence around 34%. Patients with cirrhosis are at increased risk of infections due to impaired immunity and increased gut permeability leading to bacterial translocation in the setting of portal hypertension. One of the most feared complications of severely decompensated liver and renal failure is hepatorenal syndrome, of which liver transplant may be the only available treatment. Furthermore, in those with spontaneous bacterial peritonitis and urinary tract infection, progressive renal failure occurs despite resolution of infection. Thus, the effects of endotoxemia on renal function in cirrhosis have become a major focus of research. The mechanisms of the damaging effects of endotoxin on renal function are complex but, in essence, involve dysregulated inflammation, circulatory dysfunction, poor clearance of endotoxin burden, as well as vasomotor nephropathy. In this article, we will review the mechanisms of endotoxemia-induced renal dysfunction in the setting of cirrhosis through the effects on renal blood flow, renal vascular endothelium, glomerular filtration rate, and tubular function.


Ofloxacin versus standard therapy in treatment of community-acquired pneumonia requiring hospitalization. Pneumonia Study Group.
Community-acquired pneumonia occurs 3 to 4 million times per year in the United States, accounting for about 500,000 hospitalizations annually. Empiric treatment is usually instituted because of a lack of early organism-specific diagnostic tests. This study compared empiric therapy with ofloxacin to standard antibiotic regimens (usually a beta-lactam with or without a macrolide) for patients hospitalized for community-acquired pneumonia. Therapy was administered to 298 patients (146 receiving ofloxacin and 152 receiving standard therapy); 227 patients (ofloxacin, 109; standard treatment, 118) were evaluable for treatment efficacy. The most common pyogenic respiratory pathogens were Haemophilus influenzae (30 isolates) and Streptococcus pneumoniae (24 isolates). There was evidence of infection with either Mycoplasma pneumoniae (38 patients), Chlamydia pneumoniae (40 patients), or a Legionella sp. (8 patients) in a total of 79 patients (35%). The clinical success rates were similar in both groups among evaluable patients (92%, ofloxacin; 87%, standard therapy) and among patients with atypical respiratory pathogens (88%, ofloxacin; 81%, standard therapy). The mean numbers (+/- the standard deviations) of intravenous doses of antibiotics were 7.5 +/- 8.0 in the ofloxacin group and 18.4 +/- 18.5 in the standard therapy group (P < 0.001); the mean number of oral doses of ofloxacin per patient was 19.7 +/- 11.2, compared with 30.2 +/- 16.0 oral antibiotic doses in the standard therapy group (P < 0.001). All treatments were well tolerated and associated with no significant clinical or laboratory abnormalities. The findings of this study indicate that ofloxacin is active against traditional bacterial pathogens as well as the major atypical respiratory pathogens. When given as monotherapy for the empiric treatment of community-acquired pneumonia, ofloxacin is as effective as standard antimicrobial therapy.


Freezability prediction of boar ejaculates assessed by functional sperm parameters and sperm proteins.
The objective of this work was to look for useful predictive indicators of the potentially "good" or "poor" ability of a boar ejaculate to sustain cryopreservation by assessing both the conventional sperm quality parameters (Study 1) and the immunolabeling of three proteins involved in the physiology of the sperm cell: GLUT3, HSP90AA1 and Cu/ZnSOD (Study 2). Study 1 was carried out in three different steps during the cryopreservation process of the sperm-rich fraction of 29 Piétrain boar ejaculates (17 degrees C, 5 degrees C, and 240min postthaw). These ejaculates were clustered based on sperm quality parameters analyzed at 240min postthaw, obtaining 16 good freezability ejaculates (GFEs) and 13 poor freezability ejaculates (PFEs). The sperm linearity (LIN) and the straightforward (STR) indexes at 5 degrees C showed higher hyperactivated movement in the PFEs than in the GFEs, which suggests that analyzing these sperm kinematic parameters could be a useful tool for predicting the potential freezability of an ejaculate. This statement was demonstrated by grouping the 29 ejaculates into two clusters (A and B) based on LIN and STR values assessed after 30 min at 5 degrees C, which resulted in around 72% of coincidence with the GFE and PFE groups. Study 2, performed at 17 degrees C and 240 min postthaw, revealed no differences between GFEs and PFEs in the immunolabeling of the three proteins within a same step, in terms of location and reactivity, although reactivity was generally weaker at 240 min postthaw in both groups. Additional studies on Western blot are currently being carried out with the objective to quantify the expression of the three proteins in GFEs and PFEs in the three steps of the cryopreservation process.


Very low levels of 25-hydroxyvitamin D are not associated with immunologic changes or clinical outcome in South African patients with HIV-associated cryptococcal meningitis.
Vitamin D deficiency is associated with impaired immune responses and increased susceptibility to a number of intracellular pathogens in individuals infected with human immunodeficiency virus (HIV). It is not known whether such an association exists with Cryptococcus neoformans. Levels of 25-hydroxyvitamin D (25[OH]D) were measured in 150 patients with cryptococcal meningitis (CM) and 150 HIV-infected controls in Cape Town, South Africa, and associations between vitamin D deficiency and CM were examined. The 25-hydroxyvitamin D levels and cryptococcal notifications were analyzed for evidence of reciprocal seasonality. Associations between 25(OH)D levels and disease severity, immune responses, and microbiological clearance were investigated in the patients with CM. Vitamin D deficiency (plasma 25[OH]D ≤50 nmol/L) was present in 74% of patients. Vitamin D deficiency was not associated with CM (adjusted odds ratio, 0.93 [95% confidence interval, .6-1.6]; P = .796). Levels of 25(OH)D showed marked seasonality, but no reciprocal seasonality was seen in CM notifications. No significant associations were found between 25(OH)D levels and fungal burden or levels of tumor necrosis factor α, interferon γ, interleukin 6, soluble CD14, or neopterin in cerebrospinal fluid. Rates of fungal clearance did not vary according to vitamin D status. Vitamin D deficiency does not predispose to the development of CM, or lead to impaired immune responses or microbiological clearance in HIV-infected patients with CM.


A Convolutional Neural Network Smartphone App for Real-Time Voice Activity Detection.
This paper presents a smartphone app that performs real-time voice activity detection based on convolutional neural network. Real-time implementation issues are discussed showing how the slow inference time associated with convolutional neural networks is addressed. The developed smartphone app is meant to act as a switch for noise reduction in the signal processing pipelines of hearing devices, enabling noise estimation or classification to be conducted in noise-only parts of noisy speech signals. The developed smartphone app is compared with a previously developed voice activity detection app as well as with two highly cited voice activity detection algorithms. The experimental results indicate that the developed app using convolutional neural network outperforms the previously developed smartphone app.


Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection.
The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood although apoptosis has been proposed as a key mechanism. We now show that caspase-3-mediated apoptosis accounts for the death of only a small fraction of CD4 T cells corresponding to those that are both activated and productively infected. The remaining over 95% of quiescent lymphoid CD4 T cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis corresponds to an intensely inflammatory form of programmed cell death in which cytoplasmic contents and pro-inflammatory cytokines, including IL-1β, are released. This death pathway thus links the two signature events in HIV infection-CD4 T-cell depletion and chronic inflammation-and creates a pathogenic vicious cycle in which dying CD4 T cells release inflammatory signals that attract more cells to die. This cycle can be broken by caspase 1 inhibitors shown to be safe in humans, raising the possibility of a new class of 'anti-AIDS' therapeutics targeting the host rather than the virus.


How adolescents perceive their communities: a qualitative study that explores the relationship between health and the physical environment.
The Well-Being of Adolescents in Vulnerable Environments (WAVE) study was conducted among adolescents aged 15-19 years in Baltimore, Ibadan, Johannesburg, New Delhi, and Shanghai to examine perceived factors related to their health. A preliminary analysis of the data, unexpectedly, revealed that the influence of the physical environment on adolescent health was a dominant theme across every site examined. To explore this further, this paper analyzed the specific components of the physical environment that were perceived to influence health, and how they contributed to various health outcomes across sites. Researchers in each site conducted in-depth interviews among adolescents; community mapping and focus groups among adolescents; a Photovoice methodology, in which adolescents were trained in photography and took photos of the meaning of 'health' in their communities; and key informant interviews among adults who work with young people. A total 529 participants from across the sites were included in the analysis. Findings showed that while there was surprising uniformity in how adolescents characterized their physical environment, perceived health outcomes related to the physical environment varied by site and gender. In Baltimore and Johannesburg, vacant homes and the lack of recreation facilities were perceived to impact on sexual and reproductive health problems for girls, while among boys they contributed to drugs and violence. In Shanghai, New Delhi, and Ibadan, garbage and trash observed in their communities were perceived to have a higher impact on infectious and chronic diseases. As the world continues to urbanize, our study points to a strong need to examine how the physical aspects of a living environment contribute to the health of adolescents. Specific aspects, such as housing, safety, garbage, and recreational spaces must all be examined as possible pathways for making improvements to health of adolescents, particularly among those living in poor urban environments.


Schlieren systems with coherent illumination for quantitative measurements.
Schlieren systems with a coherent light source were investigated by the Fourier optics technique. The imaging properties of the systems with various cutoff filters were studied. Systems with a graded piecewise linear filter and a Gaussian step function convolution (graded) filter are considered, demonstrating that the image can be approximated by the geometrical-optics theory of conventional schlieren systems. A nonlinear phase contribution was estimated, allowing for the measurement of strong phase objects. Within the framework of linear approximation the results are described by the phase derivative point-spread function, introduced in this paper as the schlieren point-spread function. In addition, modification of the Lopez cutoff filter is proposed, demonstrating its superiority over the piecewise linear and the Gaussian step convolution filters. Simulations of coherent schlieren imaging as well as phase derivative measurements were performed. Finally, the imaging properties of the schlieren systems with the different filters are compared.


Pharmacokinetics of a single inhalation of hydrogen gas in pigs.
The benefits of inhaling hydrogen gas (H2) have been widely reported but its pharmacokinetics have not yet been sufficiently analyzed. We developed a new experimental system in pigs to closely evaluate the process by which H2 is absorbed in the lungs, enters the bloodstream, and is distributed, metabolized, and excreted. We inserted and secured catheters into the carotid artery (CA), portal vein (PV), and supra-hepatic inferior vena cava (IVC) to allow repeated blood sampling and performed bilateral thoracotomy to collapse the lungs. Then, using a hydrogen-absorbing alloy canister, we filled the lungs to the maximum inspiratory level with 100% H2. The pig was maintained for 30 seconds without resuming breathing, as if they were holding their breath. We collected blood from the three intravascular catheters after 0, 3, 10, 30, and 60 minutes and measured H2 concentration by gas chromatography. H2 concentration in the CA peaked immediately after breath holding; 3 min later, it dropped to 1/40 of the peak value. Peak H2 concentrations in the PV and IVC were 40% and 14% of that in the CA, respectively. However, H2 concentration decay in the PV and IVC (half-life: 310 s and 350 s, respectively) was slower than in the CA (half-life: 92 s). At 10 min, H2 concentration was significantly higher in venous blood than in arterial blood. At 60 min, H2 was detected in the portal blood at a concentration of 6.9-53 nL/mL higher than at steady state, and in the SVC 14-29 nL/mL higher than at steady state. In contrast, H2 concentration in the CA decreased to steady state levels. This is the first report showing that inhaled H2 is transported to the whole body by advection diffusion and metabolized dynamically.


Participation in the Supplemental Nutrition Assistance Program and Dietary Behaviors: Role of Community Food Environment.
The United States Department of Agriculture's Supplemental Nutrition Assistance Program (SNAP) is the country's largest nutrition assistance program for low-income populations. Although SNAP has been shown to reduce food insecurity, research findings on the diet quality of program participants are inconsistent. This study evaluated whether the community food environment is a potential moderator of the association between SNAP participation and eating behaviors. This cross-sectional study used participant data from a telephone survey of 2,211 households in four cities in New Jersey. Data were collected from two cross-sectional panels from 2009 to 2010 and 2014. Food outlet data were purchased from commercial sources and classified as supermarkets, small grocery stores, convenience stores, or limited service restaurants. Analysis is limited to 983 respondents (588 SNAP participants) with household incomes below 130% of the federal poverty level. Eating behaviors were assessed as frequency of consumption of fruit, vegetables, salad, and sugar-sweetened beverages. Interaction and stratified analyses using gamma regression determined the differences in the association between SNAP participation and eating behaviors by the presence or absence of food outlets adjusted for covariates. SNAP participation was associated with a higher frequency of consuming sugar-sweetened beverages (P<0.05) when respondents lived within ¼ to ½ mile of a small grocery store, supermarket, and limited service restaurant. SNAP participants who did not live close to a convenience store reported a lower frequency of sugar-sweetened beverage consumption (P=0.01), and those living more than ½ mile away from a supermarket reported a lower frequency of fruit consumption (P=0.03). The findings from this study suggest that the community food environment may play a role in moderating the association between SNAP participation and eating behaviors. Although SNAP participation is associated with some unhealthy behaviors, this association may only hold true when respondents live in certain food environments.


Z/I1 Hybrid Virulence Plasmids Carrying Antimicrobial Resistance genes in S. Typhimurium from Australian Food Animal Production.
Knowledge of mobile genetic elements that capture and disseminate antimicrobial resistance genes between diverse environments, particularly across human-animal boundaries, is key to understanding the role anthropogenic activities have in the evolution of antimicrobial resistance. Plasmids that circulate within the Enterobacteriaceae and the Proteobacteria more broadly are well placed to acquire resistance genes sourced from separate niche environments and provide a platform for smaller mobile elements such as IS26 to assemble these genes into large, complex genomic structures. Here, we characterised two atypical Z/I1 hybrid plasmids, pSTM32-108 and pSTM37-118, hosting antimicrobial resistance and virulence associated genes within endemic pathogen Salmonella enterica serovar Typhimurium 1,4,[5],12:i:-, sourced from Australian swine production facilities during 2013. We showed that the plasmids found in S. Typhimurium 1,4,[5],12:i:- are close relatives of two plasmids identified from Escherichia coli of human and bovine origin in Australia circa 1998. The older plasmids, pO26-CRL125 and pO111-CRL115, encoded a putative serine protease autotransporter and were host to a complex resistance region composed of a hybrid Tn21-Tn1721 mercury resistance transposon and composite IS26 transposon Tn6026. This gave a broad antimicrobial resistance profile keyed towards first generation antimicrobials used in Australian agriculture but also included a class 1 integron hosting the trimethoprim resistance gene dfrA5. Genes encoding resistance to ampicillin, trimethoprim, sulphonamides, streptomycin, aminoglycosides, tetracyclines and mercury were a feature of these plasmids. Phylogenetic analyses showed very little genetic drift in the sequences of these plasmids over the past 15 years; however, some alterations within the complex resistance regions present on each plasmid have led to the loss of various resistance genes, presumably as a result of the activity of IS26. These alterations may reflect the specific selective pressures placed on the host strains over time. Our studies suggest that these plasmids and variants of them are endemic in Australian food production systems.


New application of the CRISPR-Cas9 system for site-specific exogenous gene doping analysis.
The increased potential for gene doping since the introduction of gene therapy presents the need to develop antidoping assays. We therefore aimed to develop a quick and simple method for the detection of specifically targeted exogenous doping genes utilizing an in vitro clustered regularly interspaced short palindromic repeats-CRISPR associated protein 9 (CRISPR-Cas9) system. A human erythropoietin (hEPO) is a drug frequently used for doping in athletes, and gene doping using gene transfer techniques may be attempted. Therefore, we selected hEPO gene as a model of exogenous doping gene, and complemental single guide RNA (sgRNA) was designed to specifically bind to the four exon-exon junctions in the hEPO cDNA. For the rapid reaction of CRISPR-Cas9, further optimization was performed using an open-source program (CRISPOR) that avoids TT and GCC motifs before the protospacer adjacent motif (PAM) domain and predicts the efficiency of the sgRNA. We optimized the in vitro Cas9 assay and dual use of sgRNA for double cleavage and identified the limit of detection (LOD) of the 1.25 nM of the double cleavage method. We expect that the improved CRISPR-Cas9 method can be used for antidoping analysis of gene doping.


Pollensomes as Natural Vehicles for Pollen Allergens.
Olive (Olea europaea) pollen constitutes one of the most important allergen sources in the Mediterranean countries and some areas of the United States, South Africa, and Australia. Recently, we provided evidence that olive pollen releases nanovesicles of respirable size, named generically pollensomes, during in vitro germination. Olive pollensomes contain allergens, such as Ole e 1, Ole e 11, and Ole e 12, suggesting a possible role in allergy. The aim of this study was to assess the contribution of pollensomes to the allergic reaction. We show that pollensomes exhibit allergenic activity in terms of patients' IgE-binding capacity, human basophil activation, and positive skin reaction in sensitized patients. Furthermore, allergen-containing pollensomes have been isolated from three clinically relevant nonphylogenetically related species: birch (Betula verrucosa), pine (Pinus sylvestris), and ryegrass (Lolium perenne). Most interesting, pollensomes were isolated from aerobiological samples collected with an eight-stage cascade impactor collector, indicating that pollensomes secretion is a naturally occurring phenomenon. Our findings indicate that pollensomes may represent widespread vehicles for pollen allergens, with potential implications in the allergic reaction.


Review: neuromuscular synaptic vulnerability in motor neurone disease: amyotrophic lateral sclerosis and spinal muscular atrophy.
Amid the great diversity of neurodegenerative conditions, there is a growing body of evidence that non-somatic (that is, synaptic and distal axonal) compartments of neurones are early and important subcellular sites of pathological change. In this review we discuss experimental data from human patients, animal models and in vitro systems showing that neuromuscular synapses are targeted in different forms of motor neurone disease (MND), including amyotrophic lateral sclerosis and spinal muscular atrophy. We highlight important developments revealing the heterogeneous nature of vulnerability in populations of lower motor units in MND and examine how progress in our understanding of the molecular pathways underlying MND may provide insights into the regulation of synaptic vulnerability and pathology. We conclude that future experiments developing therapeutic approaches specifically targeting neuromuscular synaptic vulnerability are likely to be required to prevent or delay disease onset and progression in human MND patients.


Pyoderma Gangrenosum after Fat Grafting in Alloplastic Breast Reconstruction: An Unusual Outcome.
Pyoderma gangrenosum (PG) is a rare and painful inflammatory skin disorder that has been recently associated with breast surgery. It is commonly mistaken for postoperative ischemia or wound infection and does not show response to antibiotics or debridement. We describe the first case of post-surgical PG (PSPG) after alloplastic breast reconstruction involving fat grafting. A 47-year-old woman underwent bilateral mastectomy and 2-stage alloplastic breast reconstruction, with fat grafting from the abdomen. Two days post-surgery, she developed bilateral erythema with tender grouped pustules that progressed rapidly into necrotic ulcerations. She did not respond to antibiotics and serial debridement. Subsequent biopsy confirmed a diagnosis of PG. She was started on steroid therapy and responded well. She was discharged on a steroid regimen, local wound care, and eventually a T-cell inhibitor. Over the next 12 months, her wounds healed without surgical intervention. PSPG has been observed in a variety of reconstructive breast surgeries, but never reported in the setting of fat grafting. As PG involves subcutaneous fat, fat grafting may accelerate and exacerbate the course of disease. Treatment for PSPG includes systemic steroid therapy or other immunomodulatory agents (or both). Surgical management remains controversial, as serial debridement and reconstruction have shown to exacerbate and stimulate disease progression. A long-term follow-up is recommended to monitor for wound healing. Delayed diagnosis of PG in breast reconstruction patients can lead to severe morbidity and disfigurement. This is first case of PSPG following fat grafting in the literature.


Sex- and structure-specific differences in antioxidant responses to methylmercury during early development.
Methylmercury (MeHg) is a ubiquitous environmental contaminant and neurotoxin, particularly hazardous to developing and young individuals. MeHg neurotoxicity during early development has been shown to be sex-dependent via disturbances in redox homeostasis, a key event mediating MeHg neurotoxicity. Therefore, we investigated if MeHg-induced changes in key systems of antioxidant defense are sex-dependent. C57BL/6J mice were exposed to MeHg during the gestational and lactational periods, modeling human prenatal and neonatal exposure routes. Dams were exposed to 5ppm MeHg via drinking water from early gestational period until postnatal day 21 (PND21). On PND21 a pair of siblings (a female and a male) from multiple (5-6) litters were euthanized and tissue samples were taken for analysis. Cytoplasmic and nuclear extracts were isolated from fresh cerebrum and cerebellum and used to determine thioredoxin (Trx) and glutathione (GSH) levels, as well as thioredoxin reductase (TrxR) and glutathione peroxidase (GPx) activities. The remaining tissue was used for mRNA analysis. MeHg-induced antioxidant response was not uniform for all the analyzed antioxidant molecules, and sexual dimorphism in response to MeHg treatment was evident for TrxR, Trx and GPx. The pattern of response, namely a decrease in males and an increase in females, may impart differential and sex-specific susceptibility to MeHg. GSH levels were unchanged in MeHg treated animals and irrespective of sex. Trx was reduced only in nuclear extracts from male cerebella, exemplifying a structure-specific response. Results from the gene expression analysis suggest posttranscriptional mechanism of sex-specific regulation of the antioxidant response upon MeHg treatment. The study demonstrates for the first time sex-and structure-specific changes in the response of the thioredoxin system to MeHg neurotoxicity and suggests that these differences in antioxidant responses might impart differential susceptibility to developmental MeHg exposure.


Effect of Season, Location, Filleting Regime and Storage on Water-Holding Properties of Farmed Atlantic Salmon (Salmo salar L.).
The effect of season, localization, filleting regime and storage on water-holding properties of Atlantic salmon (Salmo salar L.) was investigated. Salmon was sampled at two different slaughter facilities (in the north and south of Norway) in autumn and spring and divided in pre- and post-rigor groups, which were sampled before and after filleting. This gave a total of 16 groups that were analyzed for water-holding capacity (WHC), water content and pH. In addition, a storage trial was performed to assess the effect of all the design variables on drip loss and the composition of the drip loss during up to 18 days of storage. WHC was significantly affected by both rigor status and filleting, while water content was affected by localization and filleting. In addition, post-rigor filleting gave significantly decreased drip loss compared to pre-rigor filleting. However, storage time had the highest impact on the drip loss. Based on this, it is concluded that pre-rigor filleted salmon have excellent water-holding properties and a great potential for early processing (pre-rigor processing). It was however difficult to find a clear connection between the drip loss and the water-holding capacity of the muscle.


[Oral low-dose magnesium gluconate preventing pregnancy induced hypertension].
To study the effects of oral low-dose magnesium gluconate in prevention of pregnancy induced hypertension (PIH) and its mechanism. A prospective randomized double-blind study was carried out in 51 pregnant women as treatment group (including 22 cases as treatment group 1 and 29 cases as treatment group 2) and 51 pregnant women as controls (including 28 cases as controls group 1 and 23 cases as control group 2). Low-dose magnesium gluconate (3 g/day) or placebo was given from the 28th week of gestation to delivery consecutively. 4% of the pregnant women developed PIH after magnesium gluconate treatment, which was substantially lower than that in the control group (16%) (P < 0.05). In the treatment group 2, women showed higher concentration of 6-keto-prostaglandin F1 alpha (PGF1a) and 6-keto-/thromboxane B2(TXB2) (P/T) ratio than that of the control group 2. Moreover, TXB2 level was lower than that in the control group 2. In the treatment group 1 women showed higher ratio of P/T than that of the control group 1. There were no significant differences of serum magnesium concentration among all groups. Low-dose magnesium gluconate may efficiently prevent PIH in high risk women. The mechanism of action of magnesium gluconate probably involves to keep the balance of PGI2 and TXA2, but not associates with serum magnesium level.


Diagnosis and Treatment of a Swainson's Toucan (Ramphastos ambiguus swainsonii) With Rhinosinusitis.
A female Swainson's toucan (Ramphastos ambiguus swainsonii) was presented for examination with a 2-year history of mucoid nasal discharge and abnormal growth of the rhamphotheca. Nasal cytologic examination and culture results were consistent with mixed aerobic and anaerobic bacterial rhinitis. Radiographic and computed tomographic imaging demonstrated a deviated septum of the nasal diverticulum and multiple soft tissue densities in the caudal aspects of the maxillary and mandibular infraorbital diverticula of the infraorbital sinus. Results of rhinoscopy and biopsy confirmed bacterial rhinitis. Treatment included multiple nasal lavages with saline, gentamicin, and amphotericin B and systemic ciprofloxacin and tobramycin nebulizations for several weeks. Repeat radiographic imaging 4 years later showed resolution of most soft tissue opacities previously observed within the maxillary and mandibular diverticula but persistence of 3 areas of soft tissue, dense material within the maxillary sinus diverticulum. A sinus trephination procedure was performed through the maxillary bone for sinoscopy and sample collection and topical treatment. Results of aerobic bacterial cultures from the granulomas were negative. Biopsy results were consistent with keratin granulomas without bacterial or fungal infection. Two and a half years after trephination, the surgical site was fully healed with no recurrence of the nasal discharge. This is the first report, to our knowledge, of sinus trephination in a toucan and describes the advanced diagnostic and medical and surgical treatment of chronic rhinitis in this case.


Starvation in human pregnancy: hypoglycemia, hypoinsulinemia, and hyperketonemia.
In women fasted during the second trimester of pregnancy, concentrations of glucose and insulin in the plasma fell to a greater extent and ketone acid concentrations in the blood rose more rapidly than in nonpregnant controls. Nitrogen excretion in the urine, particularly ammonia, was increased in the pregnant group. Continuous glucose utilization by the conceptus may exaggerate and accelerate the metabolic consequences of starvation.


Electrical modulation of the complex refractive index in mid-infrared quantum cascade lasers.
We have demonstrated an integrated three terminal device for the modulation of the complex refractive index of a distributed feedback quantum cascade laser (QCL). The device comprises an active region to produce optical gain vertically stacked with a control region made of asymmetric coupled quantum wells (ACQW). The optical mode, centered on the gain region, has a small overlap also with the control region. Owing to the three terminals an electrical bias can be applied independently on both regions: on the laser for producing optical gain and on the ACQW for tuning the energy of the intersubband transition. This allows the control of the optical losses at the laser frequency as the absorption peak associated to the intersubband transition can be electrically brought in and out the laser transition. By using this function a laser modulation depth of about 400 mW can be achieved by injecting less than 1 mW in the control region. This is four orders of magnitude less than the electrical power needed using direct current modulation and set the basis for the realisation of electrical to optical transducers.


Excess mortality according to group of causes in the first year of the COVID-19 pandemic in Brazil.
To estimate excess mortality by cause of death in Brazil and states in 2020. We estimated the expected number of deaths considering a linear trend analysis with the number of deaths between 2015 and 2019 for each group of causes and each federative unit. We calculated standardized mortality ratios (SMR) and 95% confidence intervals for each SMR assuming a Poisson distribution. We performed the analyses in the R program, version 4.1.3. We observed a 19% excess in deaths in 2020 (SMR=1.19; 95%CI=1.18-1.20). The Infectious and Parasitic Diseases group stood out among the defined causes (SMR=4.80; 95%CI 4.78-4.82). The ill-defined causes showed great magnitude in this period (SMR=6.08; 95%CI 6.06-6.10). Some groups had lower-than-expected deaths: respiratory diseases (10% lower than expected) and external causes (4% lower than expected). In addition to the global analysis of the country, we identified significant heterogeneity among the federative units. States with the highest SMR are concentrated in the northern region, and those with the lowest SMR are concentrated in the southern and southeastern regions. Excess mortality occurs during the COVID-19 pandemic. This excess results not only from COVID-19 itself, but also from the social response and the management of the health system in responding to a myriad of causes that already had a trend pattern before it.


Molecular characterization and spatial distribution of SAP97, a novel presynaptic protein homologous to SAP90 and the Drosophila discs-large tumor suppressor protein.
Synapses are highly specialized sites of cell-cell contact involved in signal transfer. The molecular mechanisms modulating the assembly and stability of synapses are unknown. We previously reported the identification of a 90 kDa synapse-associated protein, SAP90, that is localized at the presynaptic termini of inhibitory GABAergic synapses. SAP90 is a mosaic protein composed of three 90 amino acid residue repeats, an SH3 domain and a region homologous to guanylate kinases. SAP90 shares domain specific homology with a family of proteins involved in the assembly and possibly stability of sites of cell contact. These include the product of the lethal(1) discs-large-1 (dlgA) tumor suppressor gene and the zonula occludens proteins ZO-1, ZO-2. The further characterization of cDNA clones encoding components of synaptic junctions has lead to the identification of a 97 kDa protein, called SAP97, that exhibits a strong overall sequence similarity to SAP90. The present study was undertaken to determine the spatial distribution of SAP97, and to reveal further clues to the possible roles of these proteins in synapses. Light and immunoelectron microscopic analysis of the rat hippocampal formation revealed that SAP97 is localized in the presynaptic nerve termini of excitatory synapses. In other brain regions, SAP97 is found in and along bundles of unmyelinated axons. SAP97 is not restricted to the CNS, but is also present at the basal lateral membrane between a variety of epithelial cells. In cultured T84 cells, it is restricted to the cytoplasmic surface of the plasma membranes between adjacent cells, but not at the edges of cells lacking cell-cell contact suggesting a role for SAP97 in cell adhesion. These data suggest that members of the SAP90/SAP97 subfamily may be involved in the site specific assembly, stability or functions of membrane specialization at sites of cell-cell contact.


Selection and Characterization of Tau Binding ᴅ-Enantiomeric Peptides with Potential for Therapy of Alzheimer Disease.
A variety of neurodegenerative disorders, including Alzheimer disease (AD), are associated with neurofibrillary tangles composed of the tau protein, as well as toxic tau oligomers. Inhibitors of pathological tau aggregation, interrupting tau self-assembly, might be useful for the development of therapeutics. Employing mirror image phage display with a large peptide library (over 109 different peptides), we have identified tau fibril binding peptides consisting of d-enantiomeric amino acids. d-enantiomeric peptides are extremely protease stable and not or less immunogenic than l-peptides, and the suitability of d-peptides for in vivo applications have already been demonstrated. Phage display selections were performed using fibrils of the d-enantiomeric hexapeptide VQIVYK, representing residues 306 to 311 of the tau protein, as a target. VQIVYK has been demonstrated to be important for fibril formation of the full lengths protein and forms fibrils by itself. Here, we report on d-enantiomeric peptides, which bind to VQIVYK, tau isoforms like tau3RD (K19) as well as to full lengths tau fibrils, and modulate the aggregation of the respective tau form. The peptides are able to penetrate cells and might be interesting for therapeutic and diagnostic applications in AD research.


The use of deficiencies to determine essential gene content in the let-56-unc-22 region of Caenorhabditis elegans.
We have investigated the possibility of using the polymerase chain reaction to detect deletions of coding elements in the unc-22-let-56 interval on chromosome IV in the nematode Caenorhabditis elegans. Our analysis of approximately 13 kb of genomic sequence immediately to the left of the unc-22 gene resulted in the identification of four possible genes. Partial cDNAs have been identified for three of them. To determine whether any of these coding elements are essential for development, we required a method for the induction and selection of mutations in these elements. Our approach was to identify a set of formaldehyde and gamma radiation induced unc-22 mutations that mapped to the unc-22-let-56 region, and then employ polymerase chain reaction methodology to identify deficiencies that affected one or more of the four identified coding elements. Two small deficiencies were identified in this manner. Characterization of these deficiencies shows that there are no coding elements between unc-22 and let-56 (the nearest mutationally identified gene to the left of unc-22), which are required in development under laboratory conditions. We conclude that the polymerase chain reaction is a practical tool for the detection of deletions of coding elements identified in this region, and that characterization of such deficiencies provides a method for assessing whether or not these elements are required for development.


Surgery Does Not Improve Survival in Patients With Isolated Severe Tricuspid Regurgitation.
Patients with isolated tricuspid regurgitation (TR) in the absence of left-sided valvular dysfunction are often managed nonoperatively. The purpose of this study was to assess the impact of surgery for isolated TR, comparing survival for isolated severe TR patients who underwent surgery with those who did not. A longitudinal echocardiography database was used to perform a retrospective analysis of 3,276 adult patients with isolated severe TR from November 2001 to March 2016. All-cause mortality for patients who underwent surgery versus those who did not was analyzed in the entire cohort and in a propensity-matched sample. To assess the possibility of immortal time bias, the analysis was performed considering time from diagnosis to surgery as a time-dependent covariate. Of 3,276 patients with isolated severe TR, 171 (5%) underwent tricuspid valve surgery, including 143 (84%) repairs and 28 (16%) replacements. The remaining 3,105 (95%) patients were medically managed. When considering surgery as a time-dependent covariate in a propensity-matched sample, there was no difference in overall survival between patients who received medical versus surgical therapy (hazard ratio: 1.34; 95% confidence interval: 0.78 to 2.30; p = 0.288). In the subgroup that underwent surgery, there was no difference in survival between tricuspid repair versus replacement (hazard ratio: 1.53; 95% confidence interval: 0.74 to 3.17; p = 0.254). In patients with isolated severe TR, surgery is not associated with improved long-term survival compared to medical management alone after accounting for immortal time bias.


Qualitative Research in Correctional Settings: Researcher Bias, Western Ideological Influences, and Social Justice.
Within correctional settings, justice, health, and academic systems overlap for forensic nurse researchers. Within an environment that stresses social control, a researcher's implicit views, perspectives, and biases can lead to altering the authentic (re)presentation of a participant's experience. Researcher bias may be influenced by predominately western ideologies and societal discourses. Qualitative methods to mitigate and raise awareness around researcher biases include bracketing, unstructured interviews, diverse peer review, thinking inductively, investigator responsiveness, and critical reflexivity. In addition to these methods, a social justice perspective should be included within the ethical foundation, guiding theories, and worldview in the research design to mitigate western ideological influences on researcher bias. Finally, a forensic nurse researcher should consider how possible western influences on researcher bias impact their ethical and moral obligation to their participants, the research community, and their clinical practice.


In SYNC: the ins and outs of circadian oscillations in calcium.
Many stimuli induce short-term increases in the cytosolic concentration of free calcium ions ([Ca(2+)](i)) that encode signaling information about diverse physiological and developmental events. Slow cytosolic Ca(2+) oscillations that span an entire day have also been discovered in both plants and animals; it is thought that these daily Ca(2+) oscillations may encode circadian clock signaling information. A recent study focusing on the characterization of the extracellular Ca(2+)-sensing receptor (CAS) has provided insight into the molecular mechanisms by which the daily Ca(2+) oscillation in plants is generated. We summarize the major findings regarding daily oscillations of cytosolic Ca(2+) concentrations in plants and animals, and discuss hypothetical biological roles for the circadian clock-regulated physiology in plants.


Sociodemographic characteristics of cigarette smoking initiation in the United States. Implications for smoking prevention policy.
Cigarette smoking initiation greatly influences smoking prevalence in the United States. To understand better the initiation of cigarette smoking, we estimated the age-specific incidence of cigarette smoking initiation in relation to race/ethnicity, sex, and educational attainment, using the reported age at smoking onset for 18- to 35-year-old respondents in the 1987 National Health Interview Survey (N = 14764) and the Hispanic Health and Nutrition Examination Survey (N = 3123) conducted during 1982 to 1984. Among white, black, and Hispanic respondents the incidence of smoking initiation increased rapidly after 11 years of age, reaching a peak in groups 17 to 19 years of age, rapidly declining in groups through age 25 years, and gradually declining thereafter. Age-specific smoking initiation rates were generally lower among black than white respondents, similar between white and Hispanic respondents, and appreciably higher among black and Hispanic men than women. Compared with persons who graduated from high school, persons with less than high school education were consistently more likely to start smoking cigarettes during childhood and adolescence. These data indicate that age and educational attainment are the factors most consistently associated with cigarette smoking initiation among all race/ethnic groups in the United States. These data also emphasize the need for smoking-prevention education beginning at an early age, particularly among persons of low socioeconomic status.


[p53, bcl-2 and Ki-67 in the diagnosis of insular thyroid gland cancer. Case report with a review of literature].
The report covers the first case of insular thyroid cancer recorded in Croatian medical literature. A 71-year old female patient presented to our hospital with symptoms of inspiratory stridor. Clinical examination disclosed an expansive tumor mass. US guided FNA indicated anaplastic cancer and total thyroidectomy was accordingly indicated. Pathohistological analysis of H/E biopsies disclosed a tumor mass with a characteristic insular growth pattern of monomorphic tumor cells. Immunohistochemical analysis confirmed diagnosis by a diffuse positive reaction to thyreoglobulin, focally to TTF-1, and scant to cytokeratin, while calcitonin, FVIII, CD34 and LCA were clearly negative. P53 and bcl-2 were expressed in 35.9% and 85% of tumor cells, respectively. The proliferation index for Ki-67 was 4.19. According to our survey we suggest a panel of immunohistochemistry for diagnosing insular cancer. Even if partly present, insular cancer should be mentioned in the pathohistological description because of its prognostic meaning.


Reducing two-unit red cell transfusions on the oncology ward: a choosing wisely initiative.
Despite Choosing Wisely recommendations for single unit red blood cell transfusion orders, ~50% of orders on the oncology ward at London Health Sciences Centre (LHSC) were for two units. The oncology ward at LHSC is a 60 bed tertiary care unit. In mid 2016, LHSC was 18 months into its implementation of computerised provider order entry (CPOE). By December 2017, increase the proportion of one-unit red cell transfusion orders on the oncology ward from 50% to 80. Outcome: % one-unit red cell transfusion orders (aggregated monthly). Our initial theory was that unawareness of the guidelines (established in 2014) and subscription to the obsolete doctrine of two-unit transfusions were the primary behavioural drivers. Initial change ideas included an educational/awareness blitz including rounds presentations, memos and posters. Failure led us to revisit our hypothesis and carry out a real-time audit, where our team was notified on each two-unit transfusion. This revealed the true root cause: the overwhelming majority of two-unit transfusions could be traced back to standing orders that were entered on an admission order set. After provider engagement, we proceeded to remove all admission order sets containing two-unit transfusions. After order set removal, our one-unit transfusion rate rose to 86% and was sustained for 17 months. We learnt two primary lessons. First that CPOE and poor order set design combined to perpetuate poor ordering practices. Second that revisiting our hypothesis and engaging in thoughtful root cause analysis that included direct observation ultimately led to an effective, sustainable solution. Our study underscores the importance of executing root cause analysis on a microsystem level. We would expect the factors driving poor performance to be completely different on a service such as general internal medicine. Our study also highlights the potential pitfalls of CPOE and the importance of regular order set review to ensure adherence to current evidence.