Lipid profile components and subclinical cerebrovascular disease in the northern Manhattan study.
Subclinical cerebrovascular disease has been associated with multiple adverse events related to aging, including stroke and dementia. The modifiable risk factors for subclinical cerebrovascular disease beyond hypertension have not been well characterized. Our objective was to examine the association between baseline, and changes over time, in lipid profile components and subclinical cerebrovascular disease on magnetic resonance imaging (MRI). Fasting plasma lipids were collected on participants in the Northern Manhattan Study, a prospective cohort study examining risk factors for cardiovascular disease in a multiethnic elderly urban-dwelling population. A subsample of the cohort underwent brain MRI between 2003 and 2008 (a median of 6.2 years, range = 0-14, after enrollment), when repeat fasting lipids were obtained. We used lipid profile components at the time of initial enrollment (n = 1,256 with lipids available) as categorical variables, as well as change in clinical categories over the two measures (n = 1,029). The main outcome measures were (1) total white matter hyperintensity volume (WMHV) using linear regression and (2) silent brain infarcts (SBI) using logistic regression. None of the plasma lipid profile components at the time of enrollment were associated with WMHV. The association between baseline lipids and WMHV was, however, modified by apolipoprotein E (apoE) status (χ(2) with 2 degrees of freedom, p = 0.03), such that among apoE4 carriers those with total cholesterol (TC) ≥200 mg/dl had a trend towards smaller WMHV than those with TC <200 mg/dl (difference in logWMHV -0.19, p = 0.07), while there was no difference among apoE3 carriers. When examining the association between WMHV and change in lipid profile components we noted an association with change in high-density lipoprotein cholesterol (HDL-C, >50 mg/dl for women, >40 mg/dl for men) and TC. A transition from low-risk HDL-C (>50 mg/dl for women, >40 mg/dl for men) at baseline to high-risk HDL-C at the time of MRI (vs. starting and remaining low risk) was associated with greater WMHV (difference in logWMHV 0.34, p value 0.03). We noted a similar association with transitioning to a TC ≥200 mg/dl at the time of MRI (difference in logWMHV 0.25, p value 0.006). There were no associations with baseline or change in lipid profile components with SBI. The association of plasma lipid profile components with greater WMHV may depend on apoE genotype and worsening HDL and TC risk levels over time.


Uptake of newly introduced universal BCG vaccination in newborns.
Universal neonatal BCG vaccination was discontinued in Cork in 1972. Following an outbreak of TB in 2 creches in the HSE South, a universal BCG vaccination program was re-introduced in October 2008. The aim of this study was to determine the vaccination process (in-hospital and community) and the in-hospital uptake of the vaccine. Following informed parental consent, babies of birth weight > 2.5 Kg were eligible for in-hospital vaccination if they were not: febrile, jaundiced on phototherapy, on antibiotics and if not born to HIV- positive mothers. Parents of babies not vaccinated in-hospital were asked to book an appointment in either of the 2 Cork community clinics. The immunisation nurse collected data on BCG vaccination, prospectively. This study examined vaccination uptakes in-hospital and community over a 6 month period (October 2008 to March 2009). There were 4018 deliveries during the study period. In-hospital consent was declined in only 16 babies (<1%) while the in-hospital vaccination uptake was 80% of total liv births. Although 635 newborns were admitted to the NICU, only 46 (8%) were vaccinated while in the NICU. At least 48% of planned community vaccination has been achieved to date. In conclusion, in-hospital consent was almost universal and vaccination uptake was satisfactory. NICU exclusion criteria accounted for a significant proportion of non-vaccination in-hospital. These criteria need to be readdressed considering that all premature babies are given other routine newborn vaccines at 2 months of age, regardless of weight.


Expression Changes Confirm Genomic Variants Predicted to Result in Allele-Specific, Alternative mRNA Splicing.
Splice isoform structure and abundance can be affected by either noncoding or masquerading coding variants that alter the structure or abundance of transcripts. When these variants are common in the population, these nonconstitutive transcripts are sufficiently frequent so as to resemble naturally occurring, alternative mRNA splicing. Prediction of the effects of such variants has been shown to be accurate using information theory-based methods. Single nucleotide polymorphisms (SNPs) predicted to significantly alter natural and/or cryptic splice site strength were shown to affect gene expression. Splicing changes for known SNP genotypes were confirmed in HapMap lymphoblastoid cell lines with gene expression microarrays and custom designed q-RT-PCR or TaqMan assays. The majority of these SNPs (15 of 22) as well as an independent set of 24 variants were then subjected to RNAseq analysis using the ValidSpliceMut web beacon (http://validsplicemut.cytognomix.com), which is based on data from the Cancer Genome Atlas and International Cancer Genome Consortium. SNPs from different genes analyzed with gene expression microarray and q-RT-PCR exhibited significant changes in affected splice site use. Thirteen SNPs directly affected exon inclusion and 10 altered cryptic site use. Homozygous SNP genotypes resulting in stronger splice sites exhibited higher levels of processed mRNA than alleles associated with weaker sites. Four SNPs exhibited variable expression among individuals with the same genotypes, masking statistically significant expression differences between alleles. Genome-wide information theory and expression analyses (RNAseq) in tumor exomes and genomes confirmed splicing effects for 7 of the HapMap SNP and 14 SNPs identified from tumor genomes. q-RT-PCR resolved rare splice isoforms with read abundance too low for statistical significance in ValidSpliceMut. Nevertheless, the web-beacon provides evidence of unanticipated splicing outcomes, for example, intron retention due to compromised recognition of constitutive splice sites. Thus, ValidSpliceMut and q-RT-PCR represent complementary resources for identification of allele-specific, alternative splicing.


Enhancement of field electron emission in topological insulator Bi2Se3 by Ni doping.
Nanostructures of bismuth selenide (Bi2Se3), a 3D topological insulator material, and nickel (Ni) doped Bi2Se3 samples were prepared by a hydrothermal method to explore the field emission properties. An enrichment in the field electron emission (FE) properties in terms of the threshold and turn-on field values of Bi2Se3 and Ni doped Bi2Se3 nanostructures was measured at a base pressure of ∼1 × 10-8 mbar. Using the background of the Fowler-Nordheim (FN) theory a field enhancement factor (β) of 5.7 × 103 and a threshold field value of 2.5 V μm-1 for 7.5% Ni doped Bi2Se3 were determined by investigating the J-E plot of the FE data. The value of β is three times higher than that of pure Bi2Se3 confirming the superior FE properties. The emission current was found to be very stable with the property of long standing durability as a negligible amount of variation was observed when measured at a constant value of 5 mA for 3 hours. The experimental results signify many opportunities for potential applications of Ni doped Bi2Se3 as a source of electrons in scanning as well as transmission electron microscopy, flat panel displays and as an X-ray generator, etc.


Restoration of R117H CFTR folding and function in human airway cells through combination treatment with VX-809 and VX-770.
Cystic fibrosis (CF) is a lethal recessive genetic disease caused primarily by the F508del mutation in the CF transmembrane conductance regulator (CFTR). The potentiator VX-770 was the first CFTR modulator approved by the FDA for treatment of CF patients with the gating mutation G551D. Orkambi is a drug containing VX-770 and corrector VX809 and is approved for treatment of CF patients homozygous for F508del, which has folding and gating defects. At least 30% of CF patients are heterozygous for the F508del mutation with the other allele encoding for one of many different rare CFTR mutations. Treatment of heterozygous F508del patients with VX-809 and VX-770 has had limited success, so it is important to identify heterozygous patients that respond to CFTR modulator therapy. R117H is a more prevalent rare mutation found in over 2,000 CF patients. In this study we investigated the effectiveness of VX-809/VX-770 therapy on restoring CFTR function in human bronchial epithelial (HBE) cells from R117H/F508del CF patients. We found that VX-809 stimulated more CFTR activity in R117H/F508del HBEs than in F508del/F508del HBEs. R117H expressed exclusively in immortalized HBEs exhibited a folding defect, was retained in the ER, and degraded prematurely. VX-809 corrected the R117H folding defect and restored channel function. Because R117 is involved in ion conductance, VX-770 acted additively with VX-809 to restore CFTR function in chronically treated R117H/F508del cells. Although treatment of R117H patients with VX-770 has been approved, our studies indicate that Orkambi may be more beneficial for rescue of CFTR function in these patients.


Genetic variants are not associated with outcome in patients with coronary artery disease and left ventricular dysfunction: results of the Genetic Substudy of the Surgical Treatment for Ischemic Heart Failure (STICH) trials.
We evaluated the ability of 23 genetic variants to provide prognostic information in patients enrolled in the Genetic Substudy of the Surgical Treatment for Ischemic Heart Failure (STICH) trials. Patients assigned to STICH Hypothesis 1 were randomized to medical therapy with or without coronary artery bypass grafting (CABG). Those assigned to STICH Hypothesis 2 were randomized to CABG or CABG with left ventricular reconstruction. In patients assigned to STICH Hypothesis 2 (n = 714), no genetic variant met the prespecified Bonferroni-adjusted threshold for statistical significance (p < 0.002); however, several variants met nominal prognostic significance: variants in the β2-adrenergic receptor gene (β2-AR Gln27Glu) and in the A1-adenosine receptor gene (A1-717 T/G) were associated with an increased risk of a subject dying or being hospitalized for a cardiac problem (p = 0.027 and 0.031, respectively). These relationships remained nominally significant even after multivariable adjustment for prognostic clinical variables. However, none of the 23 genetic variants influenced all-cause mortality or the combination of death or cardiovascular hospitalization in the STICH Hypothesis 1 population (n = 532) by either univariate or multivariable analysis. We were unable to identify the predictive genotypes in optimally treated patients in these two ischemic heart failure populations.


Experiences of patients with hypertension at primary health care in facilitating own lifestyle change of regular physical exercise.
Regular physical exercise is one of the lifestyle modification general measures to control the blood pressure (BP) of patients with hypertension. Globally, hypertension is considered a non-communicable disease (NCD), as well as a chronic condition of lifestyle, that contributes to the mortality rate caused by complications of cardiovascular burden of diseases. In South Africa, NCDs account for nearly 40% of adult deaths, with a high prevalence among black people in urban areas such as Soweto.The first step in treating hypertension is lifestyle modification, referred to in this study as health-promoting lifestyle change measures. Despite the positive benefits of regular physical exercise in controlling hypertension, in 2014, only 10% of men and 18% of women with hypertension had their BP controlled to a level that would eliminate the risk of cardiovascular disease (CVD) complications. The aim of this article is to present the experiences of patients with hypertension regarding the facilitation of their own health-promoting lifestyle change measure of regular physical exercise. A qualitative, exploratory, descriptive and contextual research design was used. The accessible population of patients with hypertension at three primary health care (PHC) clinics in Soweto was targeted and purposefully sampled. Focus group and individual interviews were conducted to collect data till data saturation occurred. Tesch's open-coding method of data analysis was used. Findings show that participants experienced poor self-care due to poor self-efficacy, demonstrated by not engaging in regular physical exercise, which in turn, resulted in uncontrolled BP and cardiovascular complications from hypertension. More should be done to educate, motivate and empower patients with the necessary knowledge, skills and the values in facilitating their own regular physical exercise in order to improve their own quality of health.


Coming out of the Hasidic closet: Jiří Mordechai Langer (1894–1943) and the fashioning of homosexual-Jewish identity.
This essay inaugurates the historical study of the modern homosexual Jewish experience before Stonewall. I begin with a historiographic introduction to the emerging subfield of gay Jewish history. I then turn to reintroduce Jiri Langer, a homosexual and Hasidic writer affiliated with the interwar "Prague circle" (and friend of Franz Kafka and Max Brod) into the purview of modern Jewish Studies. I take up two questions: first, how Langer reconciled his homosexual and Orthodox religious identity; and second, why Langer"s homosexuality became exigent as a Jewish question at this particular historical moment. In his key text, Die Erotik der Kabbala, Langer engages with the dominant interwar debates on homosexuality, but most directly with the work of Hans Blüher, the major theoretician of the German Wandervogelbewegung. In the course of correcting Blüher's antisemitic claims about Jews and homosexuality, Langer managed to delineate a specifically homosexual Jewish identity by renegotiating the relationship between homosexuality and Judaism and by adumbrating a history of "gay" Jews. I contextualize this long-neglected text within Langer's fascinating biography; the debates in the early homosexual rights movement; the particular cultural features of the "Prague circle" in which Langer wrote; and the dislocation and devastation of Langer's beloved eastern-European Hasidic communities caused by World War I—communities that Langer experienced as deeply homoerotic.


Bioisosteric replacement of central 1,2,4-oxadiazole ring of high affinity CB2 ligands by regioisomeric 1,3,4-oxadiazole ring.
It has been reported that bioisosteric replacement of an 1,2,4-oxadiazole ring by an 1,3,4-oxadiazole ring leads to higher polarity, reduced metabolic degradation by human liver microsomes and reduced interaction with hERG channels. In a seven to eight step synthesis 1,3,4-oxadiazles 9a-c were synthesized as bioisosteric analogs of high-affinity but rather lipophilic CB2 ligands 1a-c containing an 1,2,4-oxadiazole ring. The 1,3,4-oxadiazole derivatives 9a and 9b show 10- and 50-fold reduced CB2 affinity compared to the 1,2,4-oxadiazole derivatives 1a and 1b, respectively. However, the 1,3,4-oxadiazole 9a has high CB2 affinity (Ki = 25 nM) and high selectivity over the CB1 receptor.


History of preterm birth and subsequent cardiovascular disease: a systematic review.
A history of preterm birth (PTB) may be an important lifetime risk factor for cardiovascular disease (CVD) in women. We identified all peer-reviewed journal articles that met study criteria (English language, human studies, female, and adults ≥19 years old), that were found in the PubMed/MEDLINE databases, and that were published between Jan. 1, 1995, and Sept. 17, 2012. We summarized 10 studies that assessed the association between having a history of PTB and subsequent CVD morbidity or death. Compared with women who had term deliveries, women with any history of PTB had increased risk of CVD morbidity (variously defined; adjusted hazard ratio [aHR] ranged from 1.2-2.9; 2 studies), ischemic heart disease (aHR, 1.3-2.1; 3 studies), stroke (aHR, 1.7; 1 study), and atherosclerosis (aHR, 4.1; 1 study). Four of 5 studies that examined death showed that women with a history of PTB have twice the risk of CVD death compared with women who had term births. Two studies reported statistically significant higher risk of CVD-related morbidity and death outcomes (variously defined) among women with ≥2 pregnancies that ended in PTBs compared with women who had at least 2 births but which ended in only 1 PTB. Future research is needed to understand the potential impact of enhanced monitoring of CVD risk factors in women with a history of PTB on risk of future CVD risk.


Erythropoietin improves mood and modulates the cognitive and neural processing of emotion 3 days post administration.
Erythropoietin (Epo) has neuroprotective and neurotrophic effects and is a promising candidate for treatment of neurodegenerative and psychiatric disorder. Recently, we demonstrated that Epo modulates memory-relevant hippocampal response and fear processing in human models of antidepressant drug action 1 week post-administration, and improves self-reported mood for 3 days immediately following administration. The present study explored the effects of Epo (40 000 IU) vs saline on self-reported mood and on neural and cognitive function in healthy volunteers 3 days post-administration to test the reliability of the rapid mood improvement and its neuropsychological basis. Neuronal responses during the processing of happy and fearful faces were investigated using functional magnetic resonance imaging (fMRI); facial expression recognition performance was assessed after the fMRI scan. Daily ratings of mood were obtained for 3 days after Epo/saline administration. During faces processing Epo enhanced activation in the left amygdala and right precuneus to happy and fearful expressions. This was paired with improved recognition of all facial expressions, in particular of low intensity happiness and fear. This is similar to behavioral effects observed with acute administration of serotonergic antidepressants. Consistent with our previous finding, Epo improved self-reported mood for all 3 days post-administration. Together, these results suggest that characterization of the effects of Epo in a clinically depressed group is warranted.


Shock-like haemodynamic responses induced in the primary visual cortex by moving visual stimuli.
It is shown that recently discovered haemodynamic waves can form shock-like fronts when driven by stimuli that excite the cortex in a patch that moves faster than the haemodynamic wave velocity. If stimuli are chosen in order to induce shock-like behaviour, the resulting blood oxygen level-dependent (BOLD) response is enhanced, thereby improving the signal to noise ratio of measurements made with functional magnetic resonance imaging. A spatio-temporal haemodynamic model is extended to calculate the BOLD response and determine the main properties of waves induced by moving stimuli. From this, the optimal conditions for stimulating shock-like responses are determined, and ways of inducing these responses in experiments are demonstrated in a pilot study.


Within-subject comparison between connected and nonconnected tooth-to-implant fixed partial prostheses: up to 14-year follow-up study.
This long-term follow-up study aimed to compare the outcome of fixed prostheses supported by teeth and implants and by freestanding implants only. From prosthesis insertion up to 14 years (mean 6.5 y), 18 patients were followed. Implant-supported prostheses with and without tooth connection were compared within the same jaw. The tooth-implant prostheses were supported by 30 implants and 30 teeth, and the freestanding prostheses were supported by 48 implants. Implant outcome, marginal bone stability, and mechanical complications were recorded. Neither implant mobility nor fractures of any component of the implants were observed. No prosthesis complications were observed, and the same applied for crown cement failure and intrusion of teeth. Only one periapical lesion was detected at the first follow up. The annual change of the marginal bone level around connected and freestanding implants did not differ significantly. The mean marginal bone loss (over the 2 groups) for the first 6 months amounted to 1.08 mm. After the first 6 months, an annual marginal bone loss of 0.015 mm was observed. There was no difference between the 3 connection types (single implant connected to single tooth, multiple implants and/or multiple teeth connected with single connector, and multiple connectors) for the first 6 months or thereafter. The marginal bone loss (over the 3 groups) for the first 6 months was 1.15 mm. After the first 6 months, the annual bone loss (over the 3 groups) amounted to 0.015 mm. Based on the results of this study, splinting teeth with implants for implant-supported fixed prostheses did not affect the long-term outcome in comparison to freestanding implants.


Long-range in situ picometer measurement of the period of an interference field.
A scanning reference grating (SRG) method is proposed for high-precision in situ measuring and controlling the period of a long-range interference field. The reference grating is produced with the in situ interference field; then it is used to obtain phase shift signal when scanning in the interference field. With the phase shift signal collected by the SRG system, before the exposure process of the holographic grating fabrication, the period and the period uniformity of the holographic grating can be evaluated directly from the interference field; then optical adjustment can be applied until the grating period is tuned to any certain desired value. Experiments of measurement and adjustment are conducted, and an interference field with period value of 833.335 nm±10 pm in 60 mm range is reached. The proposed method gives an efficient way to fabricate large gratings of an accurate period; furthermore, it provides a reliable tool that may lead us to picometer-level optical metrology and fabrication for the most advanced lithographic equipment and in other scientific fields.


Estrogenic activity of o,p'-DDT in the mammalian uterus and avian oviduct.
When rats and birds were treated with o, p-DDT, their reproductive tissues exhibited the same response as when they were treated with estrogen. Weight, water content, glycogen, and RNA increased in uteri and oviducts of rats, chickens, and quail receiving o, p-DDT; p, p-DDT produced little if any response. The o, p-DDT did not accumulate in the reproductive or adipose tissues to a greater extent than p, p-DDT.


A family of helminth molecules that modulate innate cell responses via molecular mimicry of host antimicrobial peptides.
Over the last decade a significant number of studies have highlighted the central role of host antimicrobial (or defence) peptides in modulating the response of innate immune cells to pathogen-associated ligands. In humans, the most widely studied antimicrobial peptide is LL-37, a 37-residue peptide containing an amphipathic helix that is released via proteolytic cleavage of the precursor protein CAP18. Owing to its ability to protect against lethal endotoxaemia and clinically-relevant bacterial infections, LL-37 and its derivatives are seen as attractive candidates for anti-sepsis therapies. We have identified a novel family of molecules secreted by parasitic helminths (helminth defence molecules; HDMs) that exhibit similar biochemical and functional characteristics to human defence peptides, particularly CAP18. The HDM secreted by Fasciola hepatica (FhHDM-1) adopts a predominantly α-helical structure in solution. Processing of FhHDM-1 by F. hepatica cathepsin L1 releases a 34-residue C-terminal fragment containing a conserved amphipathic helix. This is analogous to the proteolytic processing of CAP18 to release LL-37, which modulates innate cell activation by classical toll-like receptor (TLR) ligands such as lipopolysaccharide (LPS). We show that full-length recombinant FhHDM-1 and a peptide analogue of the amphipathic C-terminus bind directly to LPS in a concentration-dependent manner, reducing its interaction with both LPS-binding protein (LBP) and the surface of macrophages. Furthermore, FhHDM-1 and the amphipathic C-terminal peptide protect mice against LPS-induced inflammation by significantly reducing the release of inflammatory mediators from macrophages. We propose that HDMs, by mimicking the function of host defence peptides, represent a novel family of innate cell modulators with therapeutic potential in anti-sepsis treatments and prevention of inflammation.


Dual HIV risk and vulnerabilities among women who use or inject drugs: no single prevention strategy is the answer.
This article examines the dual HIV and sexually transmitted infection (STI) risk behaviors engaged in by women who use or inject drugs; the individual, social, and structural drivers of HIV and STI risk; prevention strategies; and the implications for multilevel, combined, sex-specific HIV prevention strategies. Women who use or inject drugs, especially female sex workers, are at dual risk for HIV, the hepatitic C virus (HCV), and other STIs. In countries with HIV prevalence higher than 20% among injecting drug users (IDUs), female IDUs have slightly higher HIV prevalence than male IDUs. Women who use or inject drugs face multilevel drivers that increase their vulnerabilities to HIV, HCV, and STIs. Despite advances in behavioral HIV prevention strategies for this population, most prevention studies have not sufficiently targeted dyadic, social, and structural levels. Few recent advances in biomedical HIV prevention have focused on women who use drugs and their unique needs. HIV prevention strategies and services need to address the unique and multilevel drivers that increase the vulnerabilities to HIV, HCV, and STIs among women who use drugs including those who engage in sex work. Scaling-up and improving access to multilevel and combined HIV prevention strategies for these women is central to combating the HIV epidemic.


Design and analysis of single mode Fabry-Perot lasers with high speed modulation capability.
The single mode Fabry-Perot (FP) semiconductor lasers are investigated systematically by a rigorous time-domain theoretical model based on the transfer matrix method. Static and high-speed dynamic performances under direct modulation and strong external optical feedbacks are simulated for both symmetric and asymmetric longitudinal structures of the lasers. Comparisons with the DFB and conventional FP lasers are made to confirm its effectiveness in achieving single-mode lasing with high spectrum purity under modulation and feedback conditions. Structural optimization is also carried out with respect to the key design parameters.


Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration.
The role of microglial cells in the development and progression of Alzheimer's disease (AD) has not been elucidated. Here, we demonstrated the existence of a weak microglial response in human AD hippocampus which is in contrast to the massive microglial activation observed in APP-based models. Most importantly, microglial cells displayed a prominent degenerative profile (dentate gyrus > CA3 > CA1 > parahippocampal gyrus), including fragmented and dystrophic processes with spheroids, a reduced numerical density, and a significant decrease in the area of surveillance ("microglial domain"). Consequently, there was a substantial decline in the area covered by microglia which may compromise immune protection and, therefore, neuronal survival. In vitro experiments demonstrated that soluble fractions (extracellular/cytosolic) from AD hippocampi were toxic for microglial cells. This toxicity was abolished by AT8 and/or AT100 immunodepletion, validating that soluble phospho-tau was the toxic agent. These results were reproduced using soluble fractions from phospho-tau-positive Thy-tau22 hippocampi. Cultured microglial cells were not viable following phagocytosis of SH-SY5Y cells expressing soluble intracellular phospho-tau. Because the phagocytic capacity of microglial cells is highly induced by apoptotic signals in the affected neurons, we postulate that accumulation of intraneuronal soluble phospho-tau might trigger microglial degeneration in the AD hippocampus. This microglial vulnerability in AD pathology provides new insights into the immunological mechanisms underlying the disease progression and highlights the need to improve or develop new animal models, as the current models do not mimic the microglial pathology observed in the hippocampus of AD patients.


Adaptive Anchoring Model: How Static and Dynamic Presentations of Time Series Influence Judgments and Predictions.
When attempting to predict future events, people commonly rely on historical data. One psychological characteristic of judgmental forecasting of time series, established by research, is that when people make forecasts from series, they tend to underestimate future values for upward trends and overestimate them for downward ones, so-called trend-damping (modeled by anchoring on, and insufficient adjustment from, the average of recent time series values). Events in a time series can be experienced sequentially (dynamic mode), or they can also be retrospectively viewed simultaneously (static mode), not experienced individually in real time. In one experiment, we studied the influence of presentation mode (dynamic and static) on two sorts of judgment: (a) predictions of the next event (forecast) and (b) estimation of the average value of all the events in the presented series (average estimation). Participants' responses in dynamic mode were anchored on more recent events than in static mode for all types of judgment but with different consequences; hence, dynamic presentation improved prediction accuracy, but not estimation. These results are not anticipated by existing theoretical accounts; we develop and present an agent-based model-the adaptive anchoring model (ADAM)-to account for the difference between processing sequences of dynamically and statically presented stimuli (visually presented data). ADAM captures how variation in presentation mode produces variation in responses (and the accuracy of these responses) in both forecasting and judgment tasks. ADAM's model predictions for the forecasting and judgment tasks fit better with the response data than a linear-regression time series model. Moreover, ADAM outperformed autoregressive-integrated-moving-average (ARIMA) and exponential-smoothing models, while neither of these models accounts for people's responses on the average estimation task.


Prospective multicenter study of primary EUS-guided choledochoduodenostomy using a covered metal stent.
EUS-guided biliary drainage (EUS-BD) is increasingly reported as a salvage technique after failed endoscopic retrograde cholangiopancreatography, but it is still controversial whether EUS-BD can replace transpapillary biliary stenting. Therefore, we conducted this multicenter, prospective study of EUS-guided choledochoduodenostomy (EUS-CDS) using a covered metallic stent (CMS) as primary biliary drainage for unresectable distal malignant biliary obstruction (MBO). Patients with unresectable distal MBO without any prior drainage are enrolled. Primary endpoint is a technical success and secondary endpoints are adverse events, functional success, and recurrent biliary obstruction (RBO) of EUS-CDS. Clinical outcomes were compared between EUS-CDS and transpapillary stenting as a control. A total of 34 patients were enrolled in 10 Japanese institutions. The cause of MBO was pancreatic cancer in 28 patients. Median tumor size and common bile duct diameter were 31 and 13 mm, respectively. Technical success rate was 97% with a median procedure time of 25 min and functional success rate was 100%. The rate of RBO was 29% and the causes of RBO were nontumor related: Migration in 18%, sludge/food impaction in 9%, and stent impaction to the duodenal wall in 3%. Other adverse events were abdominal pain in 6% and cholecystitis in 9%. A median cumulative time to RBO was 11.3 months. The rate of RBO and cumulative time to RBO of EUS-CDS were comparable to those of transpapillary stenting (36% and 9.1 months, respectively). EUS-CDS using a CMS as primary biliary drainage was technically feasible and its safety appeared comparable to transpapillary stenting.


Unusual features of vaccinia virus extracellular virion form neutralization resistance revealed in human antibody responses to the smallpox vaccine.
The extracellular virion form (EV) of vaccinia virus (VACV) is essential for viral pathogenesis and is difficult to neutralize with antibodies. Why this is the case and how the smallpox vaccine overcomes this challenge remain incompletely understood. We previously showed that high concentrations of anti-B5 antibodies are insufficient to directly neutralize EV (M. R. Benhnia, et al., J. Virol. 83:1201-1215, 2009). This allowed for at least two possible interpretations: covering the EV surface is insufficient for neutralization, or there are insufficient copies of B5 to allow anti-B5 IgG to cover the whole surface of EV and another viral receptor protein remains active. We endeavored to test these possibilities, focusing on the antibody responses elicited by immunization against smallpox. We tested whether human monoclonal antibodies (MAbs) against the three major EV antigens, B5, A33, and A56, could individually or together neutralize EV. While anti-B5 or anti-A33 (but not anti-A56) MAbs of appropriate isotypes were capable of neutralizing EV in the presence of complement, a mixture of anti-B5, anti-A33, and anti-A56 MAbs was incapable of directly neutralizing EV, even at high concentrations. This remained true when neutralizing the IHD-J strain, which lacks a functional version of the fourth and final known EV surface protein, A34. These immunological data are consistent with the possibility that viral proteins may not be the active component of the EV surface for target cell binding and infectivity. We conclude that the protection afforded by the smallpox vaccine anti-EV response is predominantly mediated not by direct neutralization but by isotype-dependent effector functions, such as complement recruitment for antibodies targeting B5 and A33.


Psychiatric disorders and violence: a study of delinquent youth after detention.
To examine the relationship between psychiatric disorders and violence in delinquent youth after detention. The Northwestern Juvenile Project is a longitudinal study of youth from the Cook County Juvenile Temporary Detention Center (Chicago, Illinois). Violence and psychiatric disorders were assessed via self-report in 1,659 youth (56% African American, 28% Hispanic, 36% female, aged 13-25 years) interviewed up to 4 times between 3 and 5 years after detention. Using generalized estimating equations and logistic regression, we examined the following: the prevalence of violence 3 and 5 years after detention; the contemporaneous relationships between psychiatric disorders and violence as youth age; and whether the presence of a psychiatric disorder predicts subsequent violence. Rates of any violence decreased between 3 and 5 years after detention, from 35% to 21% (males), and from 20% to 17% (females). There was a contemporaneous relationship between disorder and violence. Compared to the group with no disorder, males and females with any disorder had greater odds of any violence (adjusted odds ratio [AOR] = 3.0, 95% CI = 1.9-4.7, and AOR = 4.4, 95% CI = 3.0-6.3, respectively). All specific disorders were associated contemporaneously with violence, except for major depressive disorder/dysthymia among males. Substance use disorders predicted subsequent violence. Males with other drug use disorder and females with marijuana use disorder 3 years after detention had greater odds of any violence 2 years later (AOR = 3.4, 95% CI = 1.4-8.2, and AOR = 2.0, 95% CI = 1.1-3.8, respectively). Aside from substance use disorders, the psychiatric disorders studied may not be useful markers of subsequent violence. Violence assessment and reduction must be key components of ongoing psychiatric services for high-risk youth.


Stochastic resonance in MoS2 photodetector.
In this article, we adopt a radical approach for next generation ultra-low-power sensor design by embracing the evolutionary success of animals with extraordinary sensory information processing capabilities that allow them to survive in extreme and resource constrained environments. Stochastic resonance (SR) is one of those astounding phenomena, where noise, which is considered detrimental for electronic circuits and communication systems, plays a constructive role in the detection of weak signals. Here, we show SR in a photodetector based on monolayer MoS2 for detecting ultra-low-intensity subthreshold optical signals from a distant light emitting diode (LED). We demonstrate that weak periodic LED signals, which are otherwise undetectable, can be detected by a MoS2 photodetector in the presence of a finite and optimum amount of white Gaussian noise at a frugal energy expenditure of few tens of nano-Joules. The concept of SR is generic in nature and can be extended beyond photodetector to any other sensors.


Rapamycin Rescues Endoplasmic Reticulum Stress-Induced Dry Eye Syndrome in Mice.
To investigate whether rapamycin protects tear production and the ocular surface during endoplasmic reticulum (ER) stress-induced dry eye syndrome in mice. Tunicamycin was injected intraperitoneally in BALB/c mice without or with rapamycin (TM or RM5 group). Peritoneal injection of PBS performed in vehicle group. Group without injection served as control. Blinking rate, fluorescein staining score (FSS), and phenol red thread tear production test were measured at 4 days, 1 week, and 2 weeks after treatment. Levels of inflammatory and angiogenic cytokines were measured by ELISA. Blinking rate and FSS were elevated, and tear production was decreased in TM group compared with controls (P < 0.05 for all), which was ameliorated by rapamycin at 1 and 2 weeks. Levels of inflammatory and angiogenic cytokines in the cornea and lacrimal glands were higher in the TM group than controls, and lower in the RM5 group than the TM group at 1 and 2 weeks (P < 0.05 for all). Rapamycin protected tear production and the ocular surface against this dry eye syndrome by ameliorating ER stress-induced vascular damage and inflammation of lacrimal glands and the ocular surface.


Chemoprevention of colon and small intestinal tumorigenesis in APC(min/+) mice by SHetA2 (NSC721689) without toxicity.
The occurrence of intestinal polyps in people at high risk for developing colorectal cancer provides an opportunity to test the efficacy of chemoprevention agents. In this situation of treating otherwise healthy people, the potential for toxicity must be minimal. The small-molecule flexible heteroarotinoid (Flex-Het), called SHetA2, has chemoprevention activity in organotypic cultures in vitro and lack of toxicity at doses capable of inhibiting xenograft tumor growth in vivo. The objective of this study was to evaluate SHetA2 chemoprevention activity and toxicity in the APC(min/+) murine model. Oral administration of SHetA2 at 30 and 60 mg/kg five days per week for 12 weeks significantly reduced development of intestinal polyps by 40% to 60% depending on the dose and sex of the treatment group. Immunohistochemical and Western blot analysis of polyps showed reduced levels of cyclin D1 and proliferating cell nuclear antigen in both SHetA2 treatment groups. Western blot analysis also showed SHetA2 induction of E-cadherin, Bax, and caspase-3 cleavage along with reduction in Bcl-2, COX-2, and VEGF, consistent with SHetA2 regulation of apoptosis, inflammation, and angiogenesis. Neither dose caused weight loss nor gross toxicity in APC(min/+) or wild-type littermates. Magnetic resonance imaging (MRI) of cardiac function showed no evidence of SHetA2 toxicity. SHetA2 did not alter left ventricular wall thickness. In summary, SHetA2 exerts chemoprevention activity without overt or cardiac toxicity in the APC(min/+) model. SHetA2 modulation of biomarkers in colon polyps identifies potential pharmacodynamic endpoints for SHetA2 clinical trials.


Flow replacement bypass for aneurysms: decision-making using intraoperative blood flow measurements.
There is much debate regarding the optimal strategy for extracranial-intracranial (EC-IC) bypass for complex aneurysms. We introduce the concept of a flow replacement bypass which aims to compensate for loss of flow in the efferent vessels of the aneurysm. The strategy to achieve this utilizes direct intraoperative flow measurements to guide optimal revascularization by matching graft flow to demand. We reviewed all EC-IC bypass cases performed over a 6-year period. We identified cases in which intraoperative flow measurements using an ultrasonic flow probe were utilized to determine the revascularization strategy and analyzed the decision-making paradigm. Twenty-three cases were analyzed. For terminal aneurysms, flow measurement in the affected vessel at baseline predicted the flow required for full replacement: middle cerebral artery (MCA), 50 +/- 25 cc/min (n = 9); posterior inferior cerebellar artery (PICA), 13 +/- 7 cc/min (n = 4); posterior cerebral artery (PCA), 33 cc/min (n = 1); and superior cerebellar artery (SCA), 10 cc/min (n = 1). For proximal internal carotid artery (ICA) aneurysms (n = 8), the flow deficit from baseline during carotid temporary occlusion was measured (26 +/- 18 cc/min, an average of 44% drop from baseline). The adequacy of flow from the superficial temporal artery (STA) or occipital artery (OA), when available, was assessed prior to bypass, and STA, OA, or vein interposition grafts were used accordingly. Measurement of bypass flow following anastomosis confirmed not only patency but sufficient flow in all cases: MCA 50 +/- 25 cc/min, PICA 18 +/- 9 cc/min, PCA 64 cc/min, SCA 12 cc/min, ICA 36 +/- 25 cc/min (STA), and >200 cc/min (vein). Direct intraoperative measurement of flow deficit in aneurysm surgery requiring parent vessel sacrifice can guide the choice of flow replacement graft and confirm the subsequent adequacy of bypass flow.


Effect of short-term, high-dose retinol on dark adaptation in aging and early age-related maculopathy.
To examine the effect of a short course of high-dose retinol (preformed vitamin A) on dark adaptation in older adults with normal retinal health or early age-related maculopathy (ARM). The study design was a randomized, double-masked, placebo-controlled experiment. Adults > or = 50 years of age whose fundus photographs for the eye to be tested psychophysically fell within steps 1 to 9 of the Age-Related Eye Disease Study (AREDS) Grading System were randomly assigned to a 30-day course of 50,000 IU oral retinol or a placebo. At baseline and 30-day follow-up, dark adaptation was tested and the Low Luminance Questionnaire (LLQ), an instrument for assessing difficulty with vision in reduced lighting, was administered. Primary outcomes of interest were rod- and cone-mediated parameters of dark adaptation, with scores on the LLQ's six subscales as secondary outcomes. The sample consisted of 104 participants with 52 each in the intervention and placebo groups. There were no group differences in baseline variables. At 30-days, the dark-adaptation parameters of cone time-constant, cone threshold, rod-cone break, and rod threshold did not differ. The retinol intervention group had significantly larger (i.e., steeper) rod slopes, indicating faster sensitivity recovery, than did the placebo group (P = 0.0419). There were no group differences in scores on the LLQ subscales driving, extreme lighting, emotional distress, general lighting, or peripheral vision. The retinol group had a higher score by five points on the mobility subscale compared with the placebo group (P = 0.0141). Those who had the most self-reported change on the mobility subscale at day 30 were more likely to have greater change in the speed of dark adaptation, as indicated by the rod slope parameter (r = 0.24, P = 0.0141). A short-term, high-dose course of retinol increased the rate of rod-mediated dark adaptation in older adults who were in the early phases of ARM or were exhibiting normal retinal aging. These results are consistent with the hypothesis that depositions and other structural changes in the retinal pigment epithelium and Bruch's membrane in aging and early ARM cause a localized retinoid deficiency.


Microvascular and endothelial function for risk prediction in dengue: an observational study.
Dengue infection can result in a wide spectrum of disease. The defining feature of severe disease is increased capillary permeability, which can lead to hypovolaemic shock. Microvascular and endothelial dysfunction might underlie hypovolaemic shock, but they have not been assessed clinically. We aimed to investigate the use of microvascular assessment as a prognostic method in dengue. This is an ongoing prospective observational study that aims to recruit 300 participants: children over the age of 3 years and adults presenting to two outpatient departments in Vietnam with fever of less than 72 h duration and suspected dengue, and patients admitted to hospital with warning signs or severe disease. Participants are being clinically assessed daily for 6 days, and 2 weeks later. Microvascular imaging using sublingual sidestream darkfield imaging (SDF) and endothelial function testing using peripheral artery tonometry are being performed at enrolment, defervescence, and follow-up To date, 167 patients have been recruited (92 outpatient arm, 75 inpatient arm, median age 27 years [IQR 21-33], 78 male [47%]). Dengue has been confirmed in 67 individuals in the outpatient arm, of whom 29 (43%) developed warning signs, three (4%) developed severe disease, and 35 had uncomplicated dengue; the other 25 outpatients (27%) were diagnosed as other febrile illness. At enrolment, the reactive hyperaemic index, a marker of endothelial function, was lowest in the patients who went on to develop severe dengue (median 1·54, IQR 1·36-1·77) followed by those who developed warning signs (1·78, 1·43-2·36) and then uncomplicated dengue (2·18, 1·65-2·24). Initial SDF results showed a lower proportion of perfused vessels and mean flow index during the febrile phase of dengue compared with follow-up, and were worst in the severe group at defervescence. This study of vascular function at serial timepoints in dengue is, to our knowledge, the first and most comprehensive. Our preliminary results suggest that microvascular and endothelial dysfunction are associated with severity of dengue, and occur before the appearance of severe clinical manifestations. These techniques might be useful in risk prediction in dengue. A limitation is that a formal sample size could not be calculated because no previous microvascular data in dengue exist. Wellcome Trust.


Submerged and transmucosal healing yield the same clinical outcomes with two-piece implants in the anterior maxilla and mandible: interim 1-year results of a randomized, controlled clinical trial.
To test whether or not transmucosal healing at two-piece implants is as successful as submerged placement regarding crestal bone levels and patient satisfaction. Adults requiring implants in the anterior maxilla or mandible in regions 21-25, 11-15, 31-35 or 41-45 (WHO) were recruited for this randomized, controlled multi-center clinical trial of a 5-year duration. Randomization was performed at implantation allowing for either submerged or transmucosal healing. Final reconstructions were seated 6 months after implantation. Radiographic interproximal crestal bone levels and peri-implant soft tissue parameters were measured at implant placement (IP) (baseline), 6 and 12 months. Patient satisfaction was assessed by a questionnaire. A two-sided t-test (80% power, significance level α=0.05) was performed on bone-level changes at 6 and 12 months. One hundred and twenty-seven subjects were included in the 12-month analysis (submerged [S]: 52.5%, transmucosal [TM]: 47.2%). From IP to 6 months, the change in the crestal bone level was -0.32 mm (P<0.001) for the S group and -0.29 mm (P<0.001) for the TM group. From IP to 12 months, bone-level changes were statistically significant in both groups (S -0.47 mm, P<0.001; TM -0.48 mm, P<0.001). The mean differences of change in the bone levels between the two groups were not statistically significant at either time point, indicating the equivalence of both procedures. For both groups, very good results were obtained for soft tissue parameters and for patient satisfaction. Transmucosal healing of two-piece implants is as successful as the submerged healing mode with respect to tissue integration and patient satisfaction within the first 12 months after IP.


How many replicates of arrays are required to detect gene expression changes in microarray experiments? A mixture model approach.
It has been recognized that replicates of arrays (or spots) may be necessary for reliably detecting differentially expressed genes in microarray experiments. However, the often-asked question of how many replicates are required has barely been addressed in the literature. In general, the answer depends on several factors: a given magnitude of expression change, a desired statistical power (that is, probability) to detect it, a specified Type I error rate, and the statistical method being used to detect the change. Here, we discuss how to calculate the number of replicates in the context of applying a nonparametric statistical method, the normal mixture model approach, to detect changes in gene expression. The methodology is applied to a data set containing expression levels of 1,176 genes in rats with and without pneumococcal middle-ear infection. We illustrate how to calculate the power functions for 2, 4, 6 and 8 replicates. The proposed method is potentially useful in designing microarray experiments to discover differentially expressed genes. The same idea can be applied to other statistical methods.


Coinfection with hepatitis C virus, oxidative stress and antioxidant status in HIV-positive drug users in Miami.
The pathogenesis of HIV/hepatitis C virus (HCV) coinfection is poorly understood. We examined markers of oxidative stress, plasma antioxidants and liver disease in HIV/HCV-coinfected and HIV-monoinfected adults. Demographics, medical history, and proof of infection with HIV, hepatitis A virus (HAV), hepatitis B virus (HBV) and HCV were obtained. HIV viral load, CD4 cell count, complete blood count (CBC), complete metabolic panel, lipid profile, and plasma concentrations of zinc, selenium, and vitamins A and E were determined. Malondialdehyde (MDA) and glutathione peroxidase concentrations were obtained as measures of oxidative stress. Aminotransferase to platelet ratio index (APRI) and fibrosis index (FIB-4) markers were calculated. Significant differences were found between HIV/HCV-coinfected and HIV-monoinfected participants in levels of alanine aminotransferase (ALT) (mean±standard deviation: 51.4±50.6 vs. 31.9±43.1 U/L, respectively; P=0.014), aspartate aminotransferase (AST) (56.2±40.9 vs. 34.4±30.2 U/L; P<0.001), APRI (0.52±0.37 vs. 0.255±0.145; P=0.0001), FIB-4 (1.64±.0.91 vs. 1.03±0.11; P=0.0015) and plasma albumin (3.74±0.65 vs. 3.94±0.52 g/dL; P=0.038). There were no significant differences in CD4 cell count, HIV viral load or antiretroviral therapy (ART) between groups. Mean MDA was significantly higher (1.897±0.835 vs. 1.344± 0.223 nmol/mL, respectively; P=0.006) and plasma antioxidant concentrations were significantly lower [vitamin A, 39.5 ± 14.1 vs. 52.4±16.2 μg/dL, respectively (P=0.0004); vitamin E, 8.29±2.1 vs. 9.89±4.5 μg/mL (P=0.043); zinc, 0.61±0.14 vs. 0.67±0.15 mg/L (P=0.016)] in the HIV/HCV-coinfected participants than in the HIV-monoinfected participants, and these differences remained significant after adjusting for age, gender, CD4 cell count, HIV viral load, injecting drug use and race. There were no significant differences in glutathione peroxidase concentration, selenium concentration, body mass index (BMI), alcohol use or tobacco use between groups. Glutathione peroxidase concentration significantly increased as liver disease advanced, as measured by APRI (β=0.00118; P=0.0082) and FIB-4 (β=0.0029; P=0.0177). Vitamin A concentration significantly decreased (β=-0.00581; P=0.0417) as APRI increased. HIV/HCV coinfection is associated with increased oxidative stress and decreased plasma antioxidant concentrations compared with HIV monoinfection. Research is needed to determine whether antioxidant supplementation delays liver disease in HIV/HCV coinfection.


Phenoptosis: programmed death of an organism.
Programmed cell death (apoptosis) is well-established in many multicellular organisms. Apoptosis purifies a tissue from cells that became useless or even harmful for the organism. Similar phenomena are already described also at subcellular level (suicide of mitochondria, i.e., mitoptosis) as well as at supracellular level (degradation of some organs temporarily appearing in the course of ontogenesis and then disappearing by means of apoptosis of the organ-composing cells). Following the same logic, one may put a question about programmed death of an organism as a mechanism of purification of a kin, community of organisms, or population from individuals who became unwanted for this kin, etc. A putative mechanism of such kind is proposed to be coined "phenoptosis" by analogy with apoptosis and mitoptosis. In a unicellular organism (the bacterium Escherichia coli), three different biochemical mechanisms of programmed death are identified. All of them are actuated by the appearance of phages inside the bacterial cell. This may be regarded as a precedent of phenoptosis which prevents expansion of the phage infection among E. coli cells. Purification of a population from infected individuals looks like an evolutionary invention useful for a species. Such an invention has high chances to be also employed by multicellular organisms. Most probably, septic shock in animals and humans serves as an analog of the phage-induced bacterial phenoptosis. It is hypothesized that the stress-induced ischemic diseases of brain and heart as well as carcinogenesis if they are induced by repeated stresses also represent phenoptoses that, in contrast to sepsis, are age-dependent. There are interrelations of programmed death phenomena at various levels of complexity of the living systems. Thus, extensive mitoptosis in a cell leads to apoptotic death of this cell and extensive apoptosis in an organ of vital importance results in phenoptotic death of an individual. In line with this logic, some cases are already described when inhibition of apoptosis strongly improves the postischemic state of the organism.


Perceptions of discriminatory treatment by staff as predictors of drug treatment completion: utility of a mixed methods approach.
Staff interactions with their clients are an important factor in the quality of care that is provided to people in drug treatment. Yet there is very little research that addresses staff attitudes or clients' perceptions of discrimination and prejudice by staff with regard to treatment outcomes. This research aimed to assess whether perceptions of discrimination by staff predict drug treatment completion. The study used a mixed methods approach. Ninety-two clients in residential rehabilitation facilities in Sydney were administered a series of quantitative measures assessing drug history, severity of drug use, treatment history, perceptions of staff discrimination and treatment motivation. Clients were followed up regularly until an outcome (dropout or completion) was obtained for the full sample. Perceptions of discrimination were a significant predictor of treatment completion, with greater perceived discrimination associated with increased dropout. Qualitative interviews with 13 clients and eight health-care workers from these treatment services were then conducted to gain insight into how perceived discrimination may impact on treatment experiences. Clients and staff discussed how they would address the issue of perceived discrimination during the current treatment experience. Adopting a mixed methods approach facilitated exploration of the impact of perceived discrimination on treatment from both clients' and health-care workers' perspectives. This methodology may also enhance interpretation and utilisation of these findings in drug treatment.


Inorganic Nitrate in Angina Study: A Randomized Double-Blind Placebo-Controlled Trial.
In this double-blind randomized placebo-controlled crossover trial, we investigated whether oral sodium nitrate, when added to existing background medication, reduces exertional ischemia in patients with angina. Seventy patients with stable angina, positive electrocardiogram treadmill test, and either angiographic or functional test evidence of significant ischemic heart disease were randomized to receive oral treatment with either placebo or sodium nitrate (600 mg; 7 mmol) for 7 to 10 days, followed by a 2-week washout period before crossing over to the other treatment (n=34 placebo-nitrate, n=36 nitrate-placebo). At baseline and at the end of each treatment, patients underwent modified Bruce electrocardiogram treadmill test, modified Seattle Questionnaire, and subgroups were investigated with dobutamine stress, echocardiogram, and blood tests. The primary outcome was time to 1 mm ST depression on electrocardiogram treadmill test. Compared with placebo, inorganic nitrate treatment tended to increase the primary outcome exercise time to 1 mm ST segment depression (645.6 [603.1, 688.0] seconds versus 661.2 [6183, 704.0] seconds, P=0.10) and significantly increased total exercise time (744.4 [702.4, 786.4] seconds versus 760.9 [719.5, 802.2] seconds, P=0.04; mean [95% confidence interval]). Nitrate treatment robustly increased plasma nitrate (18.3 [15.2, 21.5] versus 297.6 [218.4, 376.8] μmol/L, P<0.0001) and almost doubled circulating nitrite concentrations (346 [285, 405] versus 552 [398, 706] nmol/L, P=0.003; placebo versus nitrate treatment). Other secondary outcomes were not significantly altered by the intervention. Patients on antacid medication appeared to benefit less from nitrate supplementation. Sodium nitrate treatment may confer a modest exercise capacity benefit in patients with chronic angina who are taking other background medication. URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02078921. EudraCT number: 2012-000196-17.


Comparison of the toxicity of fluoridation compounds in the nematode Caenorhabditis elegans.
Fluorides are commonly added to drinking water in the United States to decrease the incidence of dental caries. Silicofluorides, such as sodium hexafluorosilicate (Na2 SiF6 ) and fluorosilicic acid (H2 SiF6 ), are mainly used for fluoridation, although fluoride salts such as sodium fluoride (NaF) are also used. Interestingly, only the toxicity of NaF has been examined and not that of the more often used silicofluorides. In the present study, the toxicities of NaF, Na2 SiF6 , and H2 SiF6 were compared. The toxicity of these fluorides on the growth, feeding, and reproduction in the alternative toxicological testing organism Caenorhabditis elegans was examined. Exposure to these compounds produced classic concentration-response toxicity profiles. Although the effects of the fluoride compounds varied among the 3 biological endpoints, no differences were found between the 3 compounds, relative to the fluoride ion concentration, in any of the assays. This suggests that silicofluorides have similar toxicity to NaF.


Tobacco and nicotine use.
Tobacco smoking is a major determinant of preventable morbidity and mortality worldwide. More than a billion people smoke, and without major increases in cessation, at least half will die prematurely from tobacco-related complications. In addition, people who smoke have a significant reduction in their quality of life. Neurobiological findings have identified the mechanisms by which nicotine in tobacco affects the brain reward system and causes addiction. These brain changes contribute to the maintenance of nicotine or tobacco use despite knowledge of its negative consequences, a hallmark of addiction. Effective approaches to screen, prevent and treat tobacco use can be widely implemented to limit tobacco's effect on individuals and society. The effectiveness of psychosocial and pharmacological interventions in helping people quit smoking has been demonstrated. As the majority of people who smoke ultimately relapse, it is important to enhance the reach of available interventions and to continue to develop novel interventions. These efforts associated with innovative policy regulations (aimed at reducing nicotine content or eliminating tobacco products) have the potential to reduce the prevalence of tobacco and nicotine use and their enormous adverse impact on population health.


Sexual structures and recombination of the wheat rust fungus Puccinia striiformis on Berberis vulgaris.
An isolate of the basidiomycete Puccinia striiformis, which causes yellow (stripe) rust on wheat, was selfed on the newly discovered alternate host, Berberis vulgaris. This allowed a study of the segregation of molecular markers and virulence in the progeny isolates, and of the development of fungal sexual structures and spore forms. Pycnia and aecia were obtained after inoculation of B. vulgaris with basidiospores resulting from germinating teliospores from infected wheat leaves. Subsequent inoculation of wheat with aeciospores from bulked aecia resulted in 16 progeny isolates of the S1 generation. Genotyping with 42 simple sequence repeat (SSR) markers confirmed a parental origin of progeny isolates. Of the 42 analyzed loci, 15 were heterozygous in the parental isolate and 14 revealed segregation in the progenies. This resulted in 11 new multilocus genotypes (MLGs), which confirmed segregation following sexual reproduction. Additionally, parental and progeny isolates were phenotyped using a genetic stock of wheat genotypes representing 21 resistance genes. All S1 progeny isolates had virulence for 14 out of 15 loci where the parental isolate was virulent. This was consistent with the hypothesis that virulence in plant pathogens is often recessive to avirulence, i.e., only expressed in a homozygous state. Furthermore, no segregation was observed for five out of six loci, for which the parental isolate had an avirulent phenotype. The results for one of the two segregating virulence/avirulence loci suggested that the parental isolate was heterozygous with Avr alleles resulting in different but clearly avirulent phenotypes. The other locus indicated that additional genes modifying the phenotypic expression of avirulence were involved.


High-pressure behaviour of Prussian blue analogues: interplay of hydration, Jahn-Teller distortions and vacancies.
We report a high-pressure crystallographic study of four hydrated Prussian blue analogues: M[Pt(CN)6] and M[Co(CN)6]0.67 (M = Mn2+, Cu2+) in the range 0-3 GPa. Mn[Co(CN)6]0.67 was studied by single-crystal X-ray diffraction, whereas the other systems were only available in polycrystalline form. The Mn-containing compounds undergo pressure-induced phase transitions from Fm3[combining macron]m to R3[combining macron] at ∼1.0-1.5 GPa driven by cooperative tilting of the octahedral units. No phase transition was found for the orbitally disordered Cu[Co(CN)6]0.67 up to 3 GPa. Mn[Co(CN)6]0.67 is significantly softer than the other samples, with a bulk modulus of ∼14 GPa compared to ∼35 GPa of the powdered samples. The discrepant pressure responses are discussed in terms of the presence of structural defects, Jahn-Teller distortions, and hydration. The implications for the development of polar systems are reviewed based upon our high-pressure study.


Information Extraction as Link Prediction: Using Curated Citation Networks to Improve Gene Detection.
In this paper we explore the usefulness of various types of publication-related metadata, such as citation networks and curated databases, for the task of identifying genes in academic biomedical publications. Specifically, we examine whether knowing something about which genes an author has previously written about, combined with information about previous coauthors and citations, can help us predict which new genes the author is likely to write about in the future. Framed in this way, the problem becomes one of predicting links between authors and genes in the publication network. We show that this solely social-network based link prediction technique outperforms various baselines, including those relying only on non-social biological information.


Home support workers perceptions of family members of their older clients: a qualitative study.
Health care discourse is replete with references to building partnerships between formal and informal care systems of support, particularly in community and home based health care. Little work has been done to examine the relationship between home health care workers and family caregivers of older clients. The purpose of this study is to examine home support workers' (HSWs) perceptions of their interactions with their clients' family members. The goal of this research is to improve client care and better connect formal and informal care systems. A qualitative study, using in-depth interviews was conducted with 118 home support workers in British Columbia, Canada. Framework analysis was used and a number of strategies were employed to ensure rigor including: memo writing and analysis meetings. Interviews were transcribed verbatim and sent to a professional transcription agency. Nvivo 10 software was used to manage the data. Interactions between HSWs and family members are characterized in terms both of complementary labour (family members providing informational and instrumental support to HSWs), and disrupted labour (family members creating emotion work and additional instrumental work for HSWs). Two factors, the care plan and empathic awareness, further impact the relationship between HSWs and family caregivers. HSWs and family members work to support one another instrumentally and emotionally through interdependent interactions and empathic awareness. Organizational Care Plans that are too rigid or limited in their scope are key factors constraining interactions.


Comprehensive characterization of 536 patient-derived xenograft models prioritizes candidatesfor targeted treatment.
Development of candidate cancer treatments is a resource-intensive process, with the research community continuing to investigate options beyond static genomic characterization. Toward this goal, we have established the genomic landscapes of 536 patient-derived xenograft (PDX) models across 25 cancer types, together with mutation, copy number, fusion, transcriptomic profiles, and NCI-MATCH arms. Compared with human tumors, PDXs typically have higher purity and fit to investigate dynamic driver events and molecular properties via multiple time points from same case PDXs. Here, we report on dynamic genomic landscapes and pharmacogenomic associations, including associations between activating oncogenic events and drugs, correlations between whole-genome duplications and subclone events, and the potential PDX models for NCI-MATCH trials. Lastly, we provide a web portal having comprehensive pan-cancer PDX genomic profiles and source code to facilitate identification of more druggable events and further insights into PDXs' recapitulation of human tumors.


JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin.
Activation of Janus kinase 2 (JAK2) by chromosomal translocations or point mutations is a frequent event in haematological malignancies. JAK2 is a non-receptor tyrosine kinase that regulates several cellular processes by inducing cytoplasmic signalling cascades. Here we show that human JAK2 is present in the nucleus of haematopoietic cells and directly phosphorylates Tyr 41 (Y41) on histone H3. Heterochromatin protein 1alpha (HP1alpha), but not HP1beta, specifically binds to this region of H3 through its chromo-shadow domain. Phosphorylation of H3Y41 by JAK2 prevents this binding. Inhibition of JAK2 activity in human leukaemic cells decreases both the expression of the haematopoietic oncogene lmo2 and the phosphorylation of H3Y41 at its promoter, while simultaneously increasing the binding of HP1alpha at the same site. Tauhese results identify a previously unrecognized nuclear role for JAK2 in the phosphorylation of H3Y41 and reveal a direct mechanistic link between two genes, jak2 and lmo2, involved in normal haematopoiesis and leukaemia.


Preparation of graphene by electrical explosion of graphite sticks.
Graphene nanosheets were produced by electrical explosion of high-purity graphite sticks in distilled water at room temperature. The as-prepared samples were characterized by various techniques to find different forms of carbon phases, including graphite nanosheets, few-layer graphene, and especially, mono-layer graphene with good crystallinity. Delicate control of energy injection is critical for graphene nanosheet formation, whereas mono-layer graphene was produced under the charging voltage of 22.5-23.5 kV. On the basis of electrical wire explosion and our experimental results, the underlying mechanism that governs the graphene generation was carefully illustrated. This work provides a simple but innovative route for producing graphene nanosheets.


Multiorgan Immune-Related Adverse Events During Treatment With Atezolizumab.
Immune-related adverse events (irAEs) are known to occur in patients with cancer who are treated with immune checkpoint inhibitors. However, limited literature exists on the incidence, time of onset, and risk factors for irAEs, particularly those affecting multiple organs, associated with anti-PD-L1 inhibitors. A post hoc pooled analysis was conducted using individual patient data from atezolizumab monotherapy arms of 4 non-small cell lung cancer clinical trials. Incidence, clinical patterns, outcomes, and risk factors were investigated of selected organ-specific and multiorgan irAEs during treatment using the anti-PD-L1 inhibitor atezolizumab. From a total of 1,548 patients, 730 irAE episodes were reported in 424 patients (27%). Skin irAEs were the most common (42%), followed by laboratory abnormalities (27%) and endocrine (11.6%), neurologic (7.6%), and pulmonary (6.2%) irAEs. A total of 84 patients (5.4%) had multiorgan irAEs, 70 had 2, 13 had 3, and 1 had 4 different organs affected. "Skin plus" or "laboratory plus" were the most common irAE multiorgan clusters. Patients with multiorgan irAEs were more likely to be white and have a good performance status, a lower baseline neutrophil-lymphocyte ratio, and a good or intermediate lung immune prognostic index score. Multiorgan irAEs were also associated with improved overall survival (hazard ratio, 0.47; 95% CI, 0.28-0.78; P<.0001) but not with progression-free survival (hazard ratio, 0.92; 95% CI, 0.62-1.35; P=.74) compared with the cohort with no irAEs. Multiorgan irAEs occurred in 5.4% of patients treated with atezolizumab in non-small cell lung cancer trials. Future trials should consider routine reporting of data on multiorgan toxicities in addition to organ-specific toxicities.


Toxoplasma gondii virulence: changing pattern under different maintenance conditions.
Toxoplasma gondii parasites were isolated in vitro and in vivo from a hare that had died of disseminated toxoplasmosis. Intraperitoneal inoculation of either homogenate of hare organs or parasites isolated on culture produced chronic infection in mice. However, a progressive increase of virulence following subsequent mouse-to-mouse transfections was observed. These findings suggest that host-parasite interaction plays a major role in determining the degree of pathogenicity, and that in vitro and in vivo isolation, if not followed by subsequent passages, may fail to reveal major differences in virulence between isolates.


Generalized systemic and mucosal immunity in mice after mucosal stimulation with cholera toxin.
Cholera toxin (CT) has been found to be an extremely potent immunogen for mucosal IgA responses when administered via the intestine. This study has examined both mucosal and systemic immune responses after feeding CT and compared these responses with those obtained after feeding keyhole limpet hemocyanin (KLH), another protein that is strongly immunogenic in mice. Feeding CT to mice resulted not only in IgA antibody in intestinal secretions but also resulted in substantial plasma IgG and IgA antibody levels. Feeding KLH in much larger quantity resulted in little or no antibody response in intestinal secretions or plasma. Lymphoid cells from various tissues of mice fed CT were cultured in vitro for 10 days and the supernatant was tested for antibody to CT. Spontaneous antibody synthesis (no antigen added to cultures) was present in cultures of each cell type, but IgG anti-CT was found mainly in cultures of spleen and mesenteric lymph node cells and IgA anti-CT mainly in cultures of Peyer's patch and lamina propria cells. Peyer's patch cells cultured with CT as antigen synthesized both IgG and IgA anti-CT, suggesting that the antibody response to both isotypes originated in this site. Helper T cell activity for both IgA and IgG anti-CT was detected in spleens, mesenteric lymph nodes, and Peyer's patches. Lastly, when KLH and CT were fed to mice at the same time, an intestinal IgA anti-KLH and plasma IgG anti-KLH response was stimulated, a response pattern similar to that occurring to CT after CT was fed alone. We conclude that mucosal stimulation by CT generates both a systemic IgG and mucosal IgA response to this antigen, and that CT can cause a similar pattern of response to an unrelated protein antigen when both are administered into the intestine at the same time. The data favor the idea that both the IgG and IgA responses originate in GALT and then disseminate to other tissues. We propose that CT accomplishes these effects by altering the regulatory environment within GALT.


Targeting Iron Dyshomeostasis for Treatment of Neurodegenerative Disorders.
While iron has an important role in the normal functioning of the brain owing to its involvement in several physiological processes, dyshomeostasis has been found in many neurodegenerative disorders, as evidenced by both histopathological and imaging studies. Although the exact causes have remained elusive, the fact that altered iron levels have been found in disparate diseases suggests that iron may contribute to their development and/or progression. As such, the processes involved in iron dyshomeostasis may represent novel therapeutic targets. There are, however, many questions about the exact interplay between neurodegeneration and altered iron homeostasis. Some insight can be gained by considering the parallels with respect to what occurs in healthy aging, which is also characterized by increased iron throughout many regions in the brain along with progressive neurodegeneration. Nevertheless, the exact mechanisms of iron-mediated damage are likely disease specific to a certain degree, given that iron plays a crucial role in many disparate biological processes, which are not always affected in the same way across different neurodegenerative disorders. Moreover, it is not even entirely clear yet whether iron actually has a causative role in all of the diseases where altered iron levels have been noted. For example, there is strong evidence of iron dyshomeostasis leading to neurodegeneration in Parkinson's disease, but there is still some question as to whether changes in iron levels are merely an epiphenomenon in multiple sclerosis. Recent advances in neuroimaging now offer the possibility to detect and monitor iron levels in vivo, which allows for an improved understanding of both the temporal and spatial dynamics of iron changes and associated neurodegeneration compared to post-mortem studies. In this regard, iron-based imaging will likely play an important role in the development of therapeutic approaches aimed at addressing altered iron dynamics in neurodegenerative diseases. Currently, the bulk of such therapies have focused on chelating excess iron. Although there is some evidence that these treatment options may yield some benefit, they are not without their own limitations. They are generally effective at reducing brain iron levels, as assessed by imaging, but clinical benefits are more modest. New drugs that specifically target iron-related pathological processes may offer the possibility to prevent, or at the least, slow down irreversible neurodegeneration, which represents an unmet therapeutic target.


[Epilepsy and Turner's syndrome: report of a case and review of the literature].
Fifty years ago Henry Turner identified the association of sexual infantilism, webbed neck and cubitus valgus to be a separate entity and subsequently gonadal dysgenesis was appended to the definition. Twenty years after the original report it was demonstrated that in typical patients with Turner's syndrome the chromosomal composition was 45.XO and in addition cases of mosaicism were described. Although much general information is now available about Turner's syndrome the neurological complications are largely neglected. In this paper we review the case of a patient with Turner's syndrome who at age of 16 years developed severe epilepsy. In addition, a survey of the literature concerning neurological abnormalities associated with this syndrome is presented. It seems clear that neurological symptoms in patients with Turner's syndrome deserves consideration for many reasons; may be the most significant is the evidence that patients with this syndrome have a high incidence of vascular abnormalities, which may also affect the CNS. Empirically patients with Turner's syndrome are at risk of developing cerebral vascular diseases. Also the relatively high frequency of cognitive abnormalities in these patients seems to justify the hypothesis that in a certain percentage of cases a CNS dysfunction or malformation, not necessarily of a vascular nature, may be a component of the syndrome still nor described.


Architecture of a Host-Parasite Interface: Complex Targeting Mechanisms Revealed Through Proteomics.
Surface membrane organization and composition is key to cellular function, and membrane proteins serve many essential roles in endocytosis, secretion, and cell recognition. The surface of parasitic organisms, however, is a double-edged sword; this is the primary interface between parasites and their hosts, and those crucial cellular processes must be carried out while avoiding elimination by the host immune defenses. For extracellular African trypanosomes, the surface is partitioned such that all endo- and exocytosis is directed through a specific membrane region, the flagellar pocket, in which it is thought the majority of invariant surface proteins reside. However, very few of these proteins have been identified, severely limiting functional studies, and hampering the development of potential treatments. Here we used an integrated biochemical, proteomic and bioinformatic strategy to identify surface components of the human parasite Trypanosoma brucei. This surface proteome contains previously known flagellar pocket proteins as well as multiple novel components, and is significantly enriched in proteins that are essential for parasite survival. Molecules with receptor-like properties are almost exclusively parasite-specific, whereas transporter-like proteins are conserved in model organisms. Validation shows that the majority of surface proteome constituents are bona fide surface-associated proteins and, as expected, most present at the flagellar pocket. Moreover, the largest systematic analysis of trypanosome surface molecules to date provides evidence that the cell surface is compartmentalized into three distinct domains with free diffusion of molecules in each, but selective, asymmetric traffic between. This work provides a paradigm for the compartmentalization of a cell surface and a resource for its analysis.


Atlantic Bluefin Tuna (Thunnus thynnus) Biometrics and Condition.
The compiled data for this study represents the first Atlantic and Mediterranean-wide effort to pool all available biometric data for Atlantic bluefin tuna (Thunnus thynnus) with the collaboration of many countries and scientific groups. Biometric relationships were based on an extensive sampling (over 140,000 fish sampled), covering most of the fishing areas for this species in the North Atlantic Ocean and Mediterranean Sea. Sensitivity analyses were carried out to evaluate the representativeness of sampling and explore the most adequate procedure to fit the weight-length relationship (WLR). The selected model for the WLRs by stock included standardized data series (common measurement types) weighted by the inverse variability. There was little difference between annual stock-specific round weight-straight fork length relationships, with an overall difference of 6% in weight. The predicted weight by month was estimated as an additional component in the exponent of the weight-length function. The analyses of monthly variations of fish condition by stock, maturity state and geographic area reflect annual cycles of spawning and feeding behavior. We update and improve upon the biometric relationships for bluefin currently used by the International Commission for the Conservation of Atlantic Tunas, by incorporating substantially larger datasets than ever previously compiled, providing complete documentation of sources and employing robust statistical fitting. WLRs and other conversion factors estimated in this study differ from the ones used in previous bluefin stock assessments.


Factors Affecting the Suppression of Heterodera glycines by N-Viro Soil.
Previous laboratory research demonstrated that N-Viro Soil (NVS), an alkaline-stabilized municipal biosolid, suppressed plant-parasitic nematodes. This study continued to explore the use of NVS as a nematode management tool specifically addressing factors that could influence its use. N-Viro Soil from different locations, the components of NVS (de-watered biosolids and fly ash admixtures), and sterilized NVS were applied to sand microcosms to determine effects on nematode survival sand solution pH and ammonia concentrations. This study confirmed the previous finding that an important mechanism of Heterodera glycines suppression by NVS was the generation of alkaline soil conditions. Only the fly ash admixture that resulted in an increase in pH to 10.0 suppressed H. glycines to the same level as NVS. Alkaline-stabilization of biosolids was necessary to achieve nematode suppression. Biosolids applied at rates <3% dry w/w did not suppress H. glycines to the same level as equivalent amounts of NVS. Sand solution pH levels after biosolid application, regardless of rate, were approximately 8.5 whereas 1% and 4% w/w NVS amendment resulted in pH levels of 10.3 and 11.6, respectively. NVS from different processing facilities were all effective in suppressing H. glycines. The NVS source that produced the highest concentration of ammonia did not reduce H. glycines survival to the same level as those sources generating pH levels above 10.1. Microbes associated with NVS appeared not to be responsible for the nematode suppressiveness of the amendment; there was no difference in nematode suppression between autoclaved and nonautoclaved NVS. The role that ammonia plays in the suppression of H. glycines by NVS is still unclear.


Implementation and adoption of a health insurance support tool in the electronic health record: a mixed methods analysis within a randomized trial.
In addition to delivering vital health care to millions of patients in the United States, community health centers (CHCs) provide needed health insurance outreach and enrollment support to their communities. We developed a health insurance enrollment tracking tool integrated within the electronic health record (EHR) and conducted a hybrid implementation-effectiveness trial in a CHC-based research network to assess tool adoption using two implementation strategies. CHCs were recruited from the OCHIN practice-based research network. Seven health center systems (23 CHC clinic sites) were recruited and randomized to receive basic educational materials alone (Arm 1), or these materials plus facilitation (Arm 2) during the 18-month study period, September 2016-April 2018. Facilitation consisted of monthly contacts with clinic staff and utilized audit and feedback and guided improvement cycles. We measured total and monthly tool utilization from the EHR. We conducted structured interviews of CHC staff to assess factors associated with tool utilization. Qualitative data were analyzed using an immersion-crystallization approach with barriers and facilitators identified using the Consolidated Framework for Implementation Research. The majority of CHCs in both study arms adopted the enrollment tool. The rate of tool utilization was, on average, higher in Arm 2 compared to Arm 1 (20.0% versus 4.7%, p < 0.01). However, by the end of the study period, the rate of tool utilization was similar in both arms; and observed between-arm differences in tool utilization were largely driven by a single, large health center in Arm 2. Perceived relative advantage of the tool was the key factor identified by clinic staff as driving tool utilization. Implementation climate and leadership engagement were also associated with tool utilization. Using basic education materials and low-intensity facilitation, CHCs quickly adopted an EHR-based tool to support critical outreach and enrollment activities aimed at improving access to health insurance in their communities. Though facilitation carried some benefit, a CHC's perceived relative advantage of the tool was the primary driver of decisions to implement the tool. ClinicalTrials.gov: NCT02355262, Posted February 4, 2015.


Rapid cloning of genes in hexaploid wheat using cultivar-specific long-range chromosome assembly.
Cereal crops such as wheat and maize have large repeat-rich genomes that make cloning of individual genes challenging. Moreover, gene order and gene sequences often differ substantially between cultivars of the same crop species. A major bottleneck for gene cloning in cereals is the generation of high-quality sequence information from a cultivar of interest. In order to accelerate gene cloning from any cropping line, we report 'targeted chromosome-based cloning via long-range assembly' (TACCA). TACCA combines lossless genome-complexity reduction via chromosome flow sorting with Chicago long-range linkage to assemble complex genomes. We applied TACCA to produce a high-quality (N50 of 9.76 Mb) de novo chromosome assembly of the wheat line CH Campala Lr22a in only 4 months. Using this assembly we cloned the broad-spectrum Lr22a leaf-rust resistance gene, using molecular marker information and ethyl methanesulfonate (EMS) mutants, and found that Lr22a encodes an intracellular immune receptor homologous to the Arabidopsis thaliana RPM1 protein.


Patient and provider barriers to colorectal cancer screening in the primary care safety-net.
This study examines patient and provider barriers to screening for colorectal cancer among low-income uninsured African-Americans aged 50 years or older in an urban safety-net primary care clinic, with the goal of informing a future intervention. Four focus groups were conducted among 40 patients from, or living in the immediate neighborhood of, a primary care clinic for uninsured residents of Washington, DC. An additional focus group was conducted among primary care providers from the same clinic. Using semistructured open-ended questions, moderators elicited perceptions of barriers and promoters of colorectal cancer screening and suggestions to improve adherence to screening guidelines. The focus groups were audio-taped and transcribed verbatim. The transcripts were independently coded by two reviewers using established qualitative methodology. Patient and provider comments from the five focus groups fell into one of eight content areas: primary care characteristics (36% of comments), procedural issues related to screening (16% of comments), knowledge (14% of comments), cost/insurance coverage (13%), ordering of priorities (12%), attitudes (5%), information sources (2%), and perceptions of discrimination (2%). Involving various members of the primary care team in colorectal cancer screening processes, and using reminders with feedback, were identified as promising avenues for future interventions in the safety-net setting. Patients and providers cited the lack of referral sources for colonoscopy for follow-up of abnormal fecal occult blood tests (FOBT), and lack of treatment sources as major barriers to the initiation of colorectal cancer screening in uninsured populations. Organizational level interventions, such as a team approach to colorectal cancer screening, are important areas identified for future colorectal cancer screening interventions in the safety-net primary care setting. Larger policy efforts to provide coverage for screening, diagnosis, and treatment among the uninsured are critical to implementing adequate colorectal cancer screening for this population.


Assessing Ultrasonography as a Diagnostic Tool for Porcine Cysticercosis.
Taenia solium inflicts substantial neurologic disease and economic losses on rural communities in many developing nations. "Ring-strategy" is a control intervention that targets treatment of humans and pigs among clusters of households (rings) that surround pigs heavily infected with cysticerci. These pigs are typically identified by examining the animal's tongue for cysts. However, as prevalence decreases in intervened communities, more sensitive methods may be needed to identify these animals and to maintain control pressure. The purpose of this study was to evaluate ultrasonography as an alternative method to detect pigs heavily infected with T. solium cysts. We purchased 152 pigs representing all seropositive animals villagers were willing to sell from eight communities (pop. 2085) in Piura, Peru, where T. solium is endemic. Tongue and ultrasound examinations of the fore and hind-limbs were performed in these animals, followed by necropsy with fine dissection as gold standard to determine cyst burden. We compared the sensitivity and specificity of ultrasonography with tongue examination for their ability to detect heavy infection (≥ 100 viable cysts) in pigs. Compared to tongue examination, ultrasonography was more sensitive (100% vs. 91%) but less specific (90% vs. 98%), although these differences were not statistically significant. The greater sensitivity of ultrasound resulted in detection of one additional heavily infected pig compared to tongue examination (11/11 vs. 10/11), but resulted in more false positives (14/141 vs. 3/141) due to poor specificity. Ultrasonography was highly sensitive in detecting heavily infected pigs and may identify more rings for screening or treatment compared to tongue examination. However, the high false positive rate using ultrasound would result in substantial unnecessary treatment. If specificity can be improved with greater operator experience, ultrasonography may benefit ring interventions where control efforts have stalled due to inadequate sensitivity of tongue examination.


CD8 memory precursor cell generation is a continuous process.
In this work, we studied the generation of memory precursor cells following an acute infection by analyzing single-cell RNA-seq data that contained CD8 T cells collected during the postinfection expansion phase. We used different tools to reconstruct the developmental trajectory that CD8 T cells followed after activation. Cells that exhibited a memory precursor signature were identified and positioned on this trajectory. We found that these memory precursors are generated continuously with increasing numbers arising over time. Similarly, expression of genes associated with effector functions was also found to be raised in memory precursors at later time points. The ability of cells to enter quiescence and differentiate into memory cells was confirmed by BrdU pulse-chase experiment in vivo. Analysis of cell counts indicates that the vast majority of memory cells are generated at later time points from cells that have extensively divided.


Studying bacteria in respiratory specimens by using conventional and molecular microbiological approaches.
Drawing from previous studies, the traditional routine diagnostic microbiology evaluation of samples from chronic respiratory conditions may provide an incomplete picture of the bacteria present in airways disease. Here, the aim was to determine the extent to which routine diagnostic microbiology gave a different assessment of the species present in sputa when analysed by using culture-independent assessment. Six different media used in routine diagnostic microbiology were inoculated with sputum from twelve patients. Bacterial growth on these plates was harvested and both RNA and DNA extracted. DNA and RNA were also extracted directly from the same sample of sputum. All nucleic acids served as templates for PCR and reverse transcriptase-PCR amplification of "broad range" bacterial 16S rRNA gene regions. The regions amplified were separated by Terminal Restriction Fragment Length Polymorphism (T-RFLP) profiling and compared to assess the degree of overlap between approaches. A mean of 16.3 (SD 10.0) separate T-RF band lengths in the profiles from each sputum sample by Direct Molecular Analysis, with a mean of 8.8 (SD 5.8) resolved by DNA profiling and 13.3 (SD 8.0) resolved by RNA profiling. In comparison, 8.8 (SD 4.4) T-RF bands were resolved in profiles generated by Culture-derived Molecular Analysis. There were a total of 184 instances of T-RF bands detected in the direct sputum profiles but not in the corresponding culture-derived profiles, representing 83 different T-RF band lengths. Amongst these were fifteen instances where the T-RF band represented more than 10% of the total band volume (with a mean value of 23.6%). Eight different T-RF band lengths were resolved as the dominant band in profiles generated directly from sputum. Of these, only three were detected in profiles generated from the corresponding set of cultures. Due to their focus on isolation of a small group of recognised pathogens, the use of culture-dependent methods to analyse samples from chronic respiratory infections can provide a restricted understanding of the bacterial species present. The use of a culture-independent molecular approach here identifies that there are many bacterial species in samples from CF and COPD patients that may be clinically relevant.


Prevention of the musculoskeletal complications of hemophilia.
Hemophilia is an inherited disorder of clotting factor deficiencies resulting in musculoskeletal bleeding, including hemarthroses, leading to musculoskeletal complications. The articular problems of hemophiliac patients begin in infancy. These include: recurrent hemarthroses, chronic synovitis, flexion deformities, hypertrophy of the growth epiphyses, damage to the articular cartilage, and hemophilic arthropathy. The most commonly affected joints are the ankle, the knee, and the elbow. Hematologic prophylactic treatment from ages 2 to 18 years could avoid the development of hemophilic arthropathy if the concentration of the patient's deficient factor is prevented from falling below 1% of normal. Hemarthroses can be prevented by the administration of clotting factor concentrates (prophylaxis). However, high costs and the need for venous access devices in younger children continue to complicate recommendations for universal prophylaxis. Prevention of joint arthropathy needs to focus on prevention of hemarthroses through prophylaxis, identifying early joint disease through the optimal use of cost-effective imaging modalities and the validation of serological markers of joint arthropathy. Screening for effects on bone health and optimal management of pain to improve quality of life are, likewise, important issues. Major hemarthrosis and chronic hemophilic synovitis should be treated aggressively to prevent hemophilic arthropathy.


A cost analysis of a community-based support centre for cancer patients and their families in Ireland: the EVeCANs study.
Cancer patients and their families experience a range of physical, psychological and financial adverse effects. Community-based cancer centres offer a range of services and interventions, free of charge, to support those affected by cancer. While shown to be effective, there is a lack of information on the costs of these services. Our aim was to estimate the resource impact of a community-based cancer support centre. Over a 7-month period, there were 2032 contacts with 238 clients whose average age was 60 years. The most frequently used services were transport to treatment (20%), complementary therapies (48%), exercise classes (10%) and counselling (9%). This cost analysis estimated total annual cost to provide all services was €313,744. Average annual cost per person was €1138. Current uptake at the centre represents 8% of all cancer incidences in seven counties surrounding the centre. If uptake increases by 10%, scenario analyses predict an increase in total costs increase to €429,043 and a decrease in costs per patient to €915. As cancer incidences increase, the need for supportive care is growing. Community-based services have been established to meet these needs and fill this gap in national health services. Long-term sustainability of these centres is uncertain as they are entirely reliant on donations and volunteers. This analysis estimates the costs of one such community-based cancer support centre, for the first time in Ireland. Findings can be used to inform future planning of cancer supportive care services, including establishing links between tertiary and community-based centres, and cost effectiveness analyses, nationally and internationally.