Poly (ADP) ribose polymerase inhibition: A potential treatment of malignant peripheral nerve sheath tumor.
Poly (ADP) ribose polymerase (PARP) inhibitors, first evaluated nearly a decade ago, are primarily used in malignancies with known defects in DNA repair genes, such as alterations in breast cancer, early onset 1/2 (BRCA1/2). While no specific mutations in BRCA1/2 have been reported in malignant peripheral nerve sheath tumors (MPNSTs), MPNST cells could be effectively targeted with a PARP inhibitor to drive cells to synthetic lethality due to their complex karyotype and high level of inherent genomic instability. In this study, we assessed the expression levels of PARP1 and PARP2 in MPNST patient tumor samples and correlated these findings with overall survival. We also determined the level of PARP activity in MPNST cell lines. In addition, we evaluated the efficacy of the PARP inhibitor AZD2281 (Olaparib) in MPNST cell lines. We observed decreased MPNST cell proliferation and enhanced apoptosis in vitro at doses similar to, or less than, the doses used in cell lines with established defective DNA repair genes. Furthermore, AZD2281 significantly reduced local growth of MPNST xenografts, decreased the development of macroscopic lung metastases, and increased survival of mice with metastatic disease. Our results suggest that AZD2281 could be an effective therapeutic option in MPNST and should be further investigated for its potential clinical use in this malignancy.


Freeze-induced expression of a novel gene, fr47, in the liver of the freeze-tolerant wood frog, Rana sylvatica.
The ability to endure the freezing of body fluids is well developed as an adaptation for winter survival in several species of woodland frogs. Recently, the mechanisms supporting natural freeze tolerance have been shown to include the expression of novel genes. One such novel gene, fr47, codes for a 390-amino acid protein present in the livers of freeze-tolerant anurans (Rana sylvatica, Pseudacris crucifer, Hyla versicolor) but not in freeze-intolerant species (Rana pipiens, Scaphiopus couchii). Regulatory influences on gene and protein expression were investigated using R. sylvatica. Northern blot analysis showed that transcript levels were increased following 24 h of freezing (5.1-fold), 24 h of anoxia exposure (6.4-fold), or the loss of 20% of total body water (2.7-fold). Immunoblotting with anti-FR47 antibody indicated that protein levels increased during freezing and thawing, but decreased somewhat during anoxia or dehydration exposure, although rebounding during recovery. These results suggest that (i) FR47 function is important for freeze survival, and (ii) that control at the protein level may be exerted posttranscriptionally. Finally, assessment of putative signal transduction pathways regulating fr47 gene expression, via in vitro incubations of liver slices, indicated the involvement of a protein kinase C-mediated pathway.


Evolution of ultraviolet vision in shorebirds (Charadriiformes).
Diurnal birds belong to one of two classes of colour vision. These are distinguished by the maximum absorbance wavelengths of the SWS1 visual pigment sensitive to violet (VS) and ultraviolet (UVS). Shifts between the classes have been rare events during avian evolution. Gulls (Laridae) are the only shorebirds (Charadriiformes) previously reported to have the UVS type of opsin, but too few species have been sampled to infer that gulls are unique among shorebirds or that Laridae is monomorphic for this trait. We have sequenced the SWS1 opsin gene in a broader sample of species. We confirm that cysteine in the key amino acid position 90, characteristic of the UVS class, has been conserved throughout gull evolution but also that the terns Anous minutus, A. tenuirostris and Gygis alba, and the skimmer Rynchops niger carry this trait. Terns, excluding Anous and Gygis, share the VS conferring serine in position 90 with other shorebirds but it is translated from a codon more similar to that found in UVS shorebirds. The most parsimonious interpretation of these findings, based on a molecular gene tree, is a single VS to UVS shift and a subsequent reversal in one lineage.


Endometrial fluid associated with Essure implants placed before in vitro fertilization: Considerations for patient counseling and surgical management.
Essure (Bayer) received approval from the U.S. Food and Drugs Administration as a permanent non-hormonal contraceptive implant in November 2002. While the use of Essure in the management of hydrosalpinx prior to in vitro fertilization (IVF) remains off-label, it has been used specifically for this purpose since at least 2007. Although most published reports on Essure placement before IVF have been reassuring, clinical experience remains limited, and no randomized studies have demonstrated the safety or efficacy of Essure in this context. In fact, no published guidelines deal with patient selection or counseling regarding the Essure procedure specifically in the context of IVF. Although Essure is an irreversible birth control option, some patients request the surgical removal of the implants for various reasons. While these patients could eventually undergo hysterectomy, at present no standardized technique exists for simple Essure removal with conservation of the uterus. This article emphasizes new aspects of the Essure procedure, as we describe the first known association between the placement of Essure implants and the subsequent development of fluid within the uterine cavity, which resolved after the surgical removal of both devices.


Endothelium under stress: local and systemic messages.
Endothelial responses to stressors are nonuniform and follow the rules of stress-induced hormesis. Responses to the same stressor, depending on its intensity, can range from pro-regenerative to pro-lethal. Exposure to sublethal stressors induces a programmed response that results in stress resistance, whereas a lethal level of a stressor accelerates cell demise. Diverse stressors turn on several default programs within the cells; such programs tend to induce anti-oxidative defenses and anti-inflammatory and pro-survival systems, whereas others tend to switch on pro-apoptotic systems. The response of the kidney endothelium to various forms of acute kidney injury follows these general principles. It is characterized by a proinflammatory pattern that includes up-regulation of different adhesion molecules promoting endothelial-leukocyte interactions, generation of reactive oxygen species, with formation of oxidative and nitrosative stress and mitochondrial damage. Simultaneously, a series of adaptive mechanisms, both local and systemic, are ignited. Stressed endothelial cells broadcast distress signals systemically; these signals can be directed toward the restoration of homeostasis or aggravation of the original insult.


Control of arterial blood pressure and renal sodium excretion by nitric oxide synthase in the renal medulla.
Work in our laboratory has focused on the role of nitric oxide synthase (NOS) in the regulation of renal medullary function. Biochemical studies demonstrated that the renal medulla is enriched in immunoreactive NOS protein and NOS enzymatic activity when compared with the renal cortex. Further experiments showed large amounts of NOS activity in the inner medullary collecting ducts, while moderate NOS activity was found in glomeruli and vasa recta and minimal NOS activity was detected in other nephron segments examined. In subsequent functional studies, selective renal medullary infusion of NOS stimulators (bradykinin or acetylcholine) or inhibitors (L-NAME) preferentially altered medullary blood flow. The alterations in medullary flow were associated with parallel changes in sodium and water excretion. Similar to the effects observed in anaesthetized rats, chronic infusion of L-NAME directly into the renal medullary interstitial space of conscious, uninephrectomized SD rats selectively decreased renal medullary blood flow throughout a 5-day L-NAME infusion period. The decrease in medullary blood flow was associated with retention of sodium and the development of hypertension, and the effects were reversible. In contrast to the effects of chronic NOS inhibition, renal medullary infusion of NOS substrate L-arginine prevented the development of sodium-sensitive hypertension in the Dahl salt-sensitive rat placed on a high sodium diet. The data reviewed in this paper indicate that NOS isoforms expressed in the renal medulla have a potent influence on renal medullary tubular and vascular function with consequential effects on fluid and electrolyte homeostasis and arterial blood pressure.


Gastrointestinal motor effects of erythromycin.
We studied the small intestinal motor effects of oral and intravenous (iv) erythromycin in 10 conscious dogs. After control recordings with placebo, oral or iv erythromycin was given at 40% of the migrating motor complex (MMC) cycle. Recordings were made after administration until normal contractile activity had returned or 12 h postdrug administration. Low doses initiated a premature MMC. High doses, however, prolonged the MMC cycle length. Erythromycin reduced the MMC propagation velocity at all doses. Both oral and iv erythromycin induced amyogenesia. During this pattern, electrical control activity was obliterated in the proximal and destabilized in the distal small intestine. Erythromycin also increased the incidence of retrograde giant contractions (RGCs) and vomiting. These effects occurred within the first 2 h after oral and within the first 30 min after iv administration. The incidence of giant migrating contractions (GMCs) increased significantly from 5 to 12 h but not from 0 to 5 h after administration. The distance of origination of GMCs from the ileocolonic junction was significantly increased from 5 to 12 h. The amplitude ratio, duration, and velocity of migration of GMCs induced after erythromycin were similar to control values. Clusters of coordinated antral and duodenal contractions also occurred early after administration. Our findings suggest that erythromycin has multiple motor effects on the stomach and small intestine. Diarrhea, abdominal cramping, and vomiting associated with erythromycin may be related to increased incidence of GMCs and RGCs. Erythromycin has a biphasic effect on MMC cycle length, initiating premature MMCs at low doses and prolonging their cycle length at higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)


Looking for change in response to the AIDS epidemic: trends in AIDS knowledge and sexual behavior in Zambia, 1990 through 1998.
This study investigates trends in AIDS knowledge and sexual behavior among men and women in urban Lusaka 1990 to 1998, and in all of Zambia, 1992 to 1998. Using data from representative surveys of urban Lusaka and of the country as a whole, population proportions were estimated to examine trends in knowledge and sexual risk behaviors. Differences in the estimated proportions between 1990 and 1998 were tested in Lusaka. In all Zambia, tests of difference were conducted between the earliest and latest years for which data were available for each indicator. A decline in premarital sexual activity was observed in urban Lusaka. In 1990, 50% of never married women reported no sexual experience, compared with 60% in 1998 (p =. 003); among men, the figures were 38% and 53%, respectively (p <. 001). Fewer women (1990, 8%; 1998, 2%; p <.001) and men (1990, 31%; 1998, 19%; p =.07) had extramarital partners. The bulk of change observed in urban Lusaka took place from 1990 to 1996; the changes in men's behavior observed between 1996 and 1998 were also observed in the national estimates for those years. National figures for other indicators from 1992 to 1998 were less encouraging. Apart from an increase in having ever used condoms, no change in women's sexual behavior was observed. Fewer men had premarital sex from 1996 to 1998 (1996, 64%; 1998, 46%; p <.001), but condom use with nonregular partners decreased among men (1996, 38%; 1998, 29%; p =.02). Prevention campaigns focused on education about AIDS and promoting safer sexual behavior appear to have made a difference in the early 1990s in Zambia. Findings from more recent years indicate that further change has stagnated. Renewed efforts are needed, particularly targeting condom use with nonregular partners.


Development of a polymerase chain reaction assay for quantification of Lawsonia intracellularis.
The objective of the present study was to develop a quantitative polymerase chain reaction (qPCR) assay using SYBR Green for quantification of Lawsonia intracellularis in cell culture and pig fecal samples. Specific primers were designed and tested using the aspartate ammonia-lyase (aspA) gene as a target. Serial 10-fold dilutions of cell culture samples and several sets of spiked feces were used for qPCR optimization. The lower limit of the linear range of the assay in cell culture was 5.1 x 10(2) L. intracellularis/ml. A concentration of between 2.55 x 10(4) and 2.55 x 10(3) L. intracellularis/g was the lower limit of the linear range when testing community DNA from spiked fecal samples. From both cell culture and fecal samples, L. intracellularis could be detected but not accurately quantified at levels approximately 1 log below the linear range. No cross-reactivity of qPCR was found when the assay was tested using the DNA extracted from 16 species of enteric bacteria commonly found in pig feces or closely related to L. intracellularis. The new qPCR assay might prove to be a sensitive, specific, precise, and accurate method for the detection and quantification of L. intracellularis in field samples.


Threshold dynamics in soil carbon storage for bioenergy crops.
Because of increasing demands for bioenergy, a considerable amount of land in the midwestern United States could be devoted to the cultivation of second-generation bioenergy crops, such as switchgrass and miscanthus. The foliar carbon/nitrogen ratio (C/N) in these bioenergy crops at harvest is significantly higher than the ratios in replaced crops, such as corn or soybean. We show that there is a critical soil organic matter C/N ratio, where microbial biomass can be impaired as microorganisms become dependent upon net immobilization. The simulation results show that there is a threshold effect in the amount of aboveground litter input in the soil after harvest that will reach a critical organic matter C/N ratio in the soil, triggering a reduction of the soil microbial population, with significant consequences in other microbe-related processes, such as decomposition and mineralization. These thresholds are approximately 25 and 15% of aboveground biomass for switchgrass and miscanthus, respectively. These results suggest that values above these thresholds could result in a significant reduction of decomposition and mineralization, which, in turn, would enhance the sequestration of atmospheric carbon dioxide in the topsoil and reduce inorganic nitrogen losses when compared to a corn-corn-soybean rotation.


Identification of agents that induce apoptosis of multicellular tumour spheroids: enrichment for mitotic inhibitors with hydrophobic properties.
Cell-based anticancer drug screening generally utilizes rapidly proliferating tumour cells grown as monolayer cultures. Hit compounds from such screens are not necessarily effective on hypoxic and slowly proliferating cells in 3-D tumour tissue. The aim of this study was to examine the potential usefulness of 3-D cultured tumour cells for anticancer drug screening. We used colon carcinoma multicellular spheroids containing hypoxic and quiescent cells in core areas for this purpose. Three libraries (∼11 000 compounds) were screened using antiproliferative activity and/or apoptosis as end-points. Screening of monolayer and spheroid cultures was found to identify different sets of hit compounds. Spheroid screening enriched for hydrophobic compounds: median XLogP values of 4.3 and 4.4 were observed for the hits in two independent screening campaigns. Mechanistic analysis revealed that the majority of spheroid screening hits were microtubuli inhibitors. One of these inhibitors was examined in detail and found to be effective against non-dividing cells in the hypoxic centres of spheroids. Spheroid screening represents a conceptually new strategy for anticancer drug discovery. Our findings have implications for drug library design and hit selection in projects aimed to develop drugs for the treatment of solid tumours.


Evaluation of the Tsima community mobilization intervention to improve engagement in HIV testing and care in South Africa: study protocol for a cluster randomized trial.
HIV transmission can be decreased substantially by reducing the burden of undiagnosed HIV infection and expanding early and consistent use of antiretroviral therapy (ART). Treatment as prevention (TasP) has been proposed as key to ending the HIV epidemic. To activate TasP in high prevalence countries, like South Africa, communities must be motivated to know their status, engage in care, and remain in care. Community mobilization (CM) has the potential to significantly increase uptake testing, linkage to and retention in care by addressing the primary social barriers to engagement with HIV care-including poor understanding of HIV care; fear and stigma associated with infection, clinic attendance and disclosure; lack of social support; and gender norms that deter men from accessing care. Using a cluster randomized trial design, we are implementing a 3-year-theory-based CM intervention and comparing gains in HIV testing, linkage, and retention in care among individuals residing in 8 intervention communities to that of individuals residing in 7 control communities. Eligible communities include 15 villages within a health and demographic surveillance site (HDSS) in rural Mpumalanga, South Africa, that were not exposed to previous CM efforts. CM activities conducted in the 8 intervention villages map onto six mobilization domains that comprise the key components for community mobilization around HIV prevention. To evaluate the intervention, we will link a clinic-based electronic clinical tracking system in all area clinics to the HDSS longitudinal census data, thus creating an open, population-based cohort with over 30,000 18-49-year-old residents. We will estimate the marginal effect of the intervention on individual outcomes using generalized estimating equations. In addition, we will evaluate CM processes by conducting baseline and endline surveys among a random sample of 1200 community residents at each time point to monitor intervention exposure and community level change using validated measures of CM. Given the known importance of community social factors with regard to uptake of testing and HIV care, and the lack of rigorously evaluated community-level interventions effective in improving testing uptake, linkage and retention, the proposed study will yield much needed data to understand the potential of CM to improve the prevention and care cascade. Further, our work in developing a CM framework and domain measures will permit validation of a CM conceptual framework and process, which should prove valuable for community programming in Africa. NCT02197793 Registered July 21, 2014.


A 20-year experience in unilateral cleft lip repair: From Millard to the triple unilimb Z-plasty technique.
This study describes a 20-year experience of treating patients with unilateral cleft lip. During this time, various techniques were used including Millard's technique and its modification and two types of geometrically designed procedures. The study objective was to compare surgical outcomes of different surgical techniques for unilateral cleft lip repair. This is a retrospective audit of outcomes after unilateral cleft lip repair performed by a single surgeon since 1995. Of the 827 patients who underwent surgery, 277 met the criterion of having anthropometric measurements performed ≥1 year postoperatively. The patients were stratified into three groups according to cleft severity: incomplete, complete with less deficiency (3-6 mm difference between cleft and non-cleft lip height) and complete with more deficiency (>6 mm difference between cleft and non-cleft lip height). Anthropometric measurements, scar assessment and complications were recorded. There were no differences in outcomes between Millard and Reichert-Millard techniques for incomplete unilateral cleft lip. For complete unilateral cleft lip and less tissue deficiency, lip symmetry was better using upper rotation advancement plus double unilimb Z-plasty than the Reichert-Millard technique. For complete unilateral cleft lip and more tissue deficiency, lip symmetry was better after triple unilimb Z-plasty than after upper rotation advancement plus double unilimb Z-plasty. We presented a 20-year experience performing unilateral cleft lip repair. An individualised classification system with corresponding surgical techniques was successfully used during this period. The individualised surgical protocol used in this study allowed us to achieve improved surgical outcomes.


Could revenue recycling make effective carbon taxation politically feasible?
Carbon taxes are widely regarded as a potentially effective and economically efficient policy instrument for decarbonizing the global energy supply and thus limiting global warming. The main obstacle is political feasibility because of opposition from citizens and industry. Earmarking revenues from carbon taxation for spending that benefits citizens (i.e., revenue recycling) might help policy makers escape this political impasse. On the basis of choice experiments with representative samples of citizens in Germany and the United States, we examine whether revenue recycling could mitigate two key obstacles to achieving sufficient public support for carbon taxes: (i) declines in support as taxation levels increase and (ii) concerns over the international economic level playing field. For both countries, we find that revenue recycling could help achieve majority support for carbon tax levels of up to $50 to $70 per metric ton of carbon, but only if industrialized countries join forces and adopt similar carbon taxes.


Impact of the prostaglandin synthase-2 inhibitor celecoxib on ovulation and luteal events in women.
Ovarian prostaglandins are critical in normal ovulation processes; thus, their inhibition may provide contraceptive benefits. This study was performed to determine the effect of the cyclooxygenase-2 (COX2) inhibitor celecoxib on ovulation and luteal events in women. The study had a randomized, double-blind, crossover design. Ovulatory, reproductive-aged women underwent ovarian ultrasound and serum hormone monitoring during four menstrual cycles (control cycle, treatment cycle 1, washout cycle, treatment cycle 2). Subjects received study drug (oral celecoxib 400 mg or placebo) either (a) once daily starting on cycle day 8 and continuing until follicle rupture or the onset of next menses if follicle rupture did not occur [pre-luteinizing hormone (LH) surge dosing] or (b) once daily beginning with the LH surge and continuing for 6 days (post-LH surge dosing). Subjects were randomly assigned to one of the above treatment schemes and received the other in the subsequent treatment cycle. The main outcomes were evidence of ovulatory and luteal dysfunction as determined by inhibited/delayed follicle rupture and reduced luteal progesterone synthesis or lifespan, respectively. A total of 20 women enrolled and completed the study (Group 1=10, Group 2=10), with similar demographics between groups. Nineteen subjects exhibited normal ovulation in the control cycle (one had a blunted LH peak). In comparison to control cycles, treatment cycles resulted in a significant increase in ovulatory dysfunction [pre-LH treatment: 30% (6/20), p=.04; post-LH treatment: 25% (5/20), p=.04]. Mean peak progesterone, estradiol, and LH levels and luteal phase length did not differ significantly between control and either treatment cycle. Although treatment with celecoxib before or after the LH surge increases the rate of ovulatory dysfunction, most women ovulate normally. Thus, this selective COX2 inhibitor appears to be of limited usefulness as a potential emergency contraceptive.


The case of national health promotion policy in Australia: where to now?
Issue addressed Over the last three decades there has been an incremental investment in health promotion and prevention across Australia; yet, the Commonwealth Government and some state/territory governments have more recently instigated funding cuts in health promotion and prevention. This paper argues that the role of health promotion is critical in contemporary Australia and discusses strategies needed to move forward within the context of recent disinvestments. Discussion Key areas of concern relating to recent health promotion and prevention disinvestment in Australia include the abolishment of the Australian National Preventive Health Agency, the cessation of the National Partnership Agreement on Preventive Health and significant cuts to Indigenous programs. These changes pose a significant threat to the health, economic and social well being of Australians and the region, particularly those that are most vulnerable. Conclusions Future health promotion and prevention efforts will require strategic leadership and action to enhance the promotion of health equity in Australia over the coming decades. We call on governments to (re)invest in health promotion and prevention both in and outside the health sector so that health promotion professionals can continue their advocacy efforts aimed at articulating their professional place in improving population health. So what? Recent changes to national health promotion and prevention policy are detrimental to the health and well being of the Australian population, particularly those most vulnerable. Sound planning to revitalise and refocus health promotion action in Australia is urgently required.


A novel silent posttranslational mechanism converts methionine to aspartate in hemoglobin Bristol (beta 67[E11] Val-Met->Asp).
The first reported case of congenital Heinz body hemolytic anemia was subsequently shown to be caused by an unstable hemoglobin, Hb Bristol [beta 67(E11) Val-Asp]. This has become one of the classic models of an unstable hemoglobin, the hydrophilic aspartate disrupting the hydrophobic heme pocket. We have restudied this original case, who remains clinically well after nearly 50 years of severe hemolysis with a hemoglobin level of about 7 g/dL and two unrelated Japanese cases. Surprisingly, all three cases show the same DNA changes, predicting a valine to methionine change at beta 67, rather than the expected aspartate. Further analysis with electrospray ionization mass spectrometry and globin chain biosynthesis strongly suggests that this anomaly is because of a novel posttranslational mechanism, with slow conversion of the translated methionine into an aspartate residue. The proximity of the heme and oxygen may be important in facilitating the reaction. These findings show the importance of complete characterization of variant hemoglobins using protein, DNA, and biosynthetic analyses.


"They're homeless in a home": Retaining homeless-experienced consumers in supported housing.
Permanent, community-based housing with supportive services ("supported housing") has numerous favorable outcomes for homeless-experienced consumers. Little is known, however, about consumers who attain but subsequently lose their supported housing. Using mixed methods, we compared persons who retained their supported housing for at least 1 year ("stayers") with those who lost their supported housing within 1 year of move-in ("exiters"). Among persons housed through the VA Supported Housing (VASH) program at the VA Greater Los Angeles between 2011 and 2012, we queried VA homeless registry data to identify stayers (n = 1,558) and exiters (n = 85). We reviewed the medical records of 85 randomly selected stayers and all 85 exiters to compare demographics, homelessness chronicity, era of service, income, presence or absence of a serious mental illness, and health service utilization. From this subsample, we purposively selected 20 stayers and 20 exiters for semistructured, qualitative interviews, and more detailed medical record review. We also performed qualitative interviews and focus groups with VASH staff/leadership (n = 15). Recursive partitioning identified quantitative variables that best-differentiated stayers from exiters. Thematic analyses were performed on qualitative data. Interrelated factors were associated with exiting supported housing: chronic homelessness; low intrinsic motivation; unmet needs for mental health care, substance abuse treatment, and independent living skills; poor primary care engagement; frequent emergency department use; and recent mental health hospitalizations. These findings suggest the value of clinical interventions that address these factors-for example, motivational interviewing or social skills training-adapted to the setting and context of supported housing. (PsycINFO Database Record


Ocular-Component-Specific miRNA Expression in a Murine Model of Lens-Induced Myopia.
To identify tissues and molecules involved in refractive myopic shift and axial length elongation in a murine lens-induced myopia model, we performed a comprehensive analysis of microRNA (miRNA) expression. Three weeks after negative 30 diopter lens fixation on three-week-old C57BL/6J mice, total RNA was extracted from individual ocular components including cornea, iris, lens, retina, retinal pigment epithelium (RPE)/choroid, and sclera tissue. The miRNA expression analysis was pooled from three samples and carried out using Agilent Mouse miRNA Microarray (8 × 60 K) miRBase21.0. The expression ratio was calculated, and differentially expressed miRNAs were extracted, using GeneSpring GX 14.5. Myopic induction showed a significant myopic refractive change, axial elongation, and choroidal thinning. Through the comprehensive miRNA analysis, several upregulated miRNAs (56 in cornea tissue, 13 in iris tissue, 6 in lens tissue, 0 in retina tissue, 29 in RPE/choroid tissue, and 30 in sclera tissue) and downregulated miRNAs (7 in cornea tissue, 28 in iris tissue, 17 in lens tissue, 9 in retina tissue, 7 in RPE/choroid tissue, and 40 in sclera tissue) were observed. Overlapping expression changes in miRNAs were also found in different ocular components. Some of this miRNA dysregulation may be functionally involved in refractive myopia shift and axial length elongation.


In vitro analysis of a hepatic device with intrinsic microvascular-based channels.
A novel microfluidics-based bilayer device with a discrete parenchymal chamber modeled upon hepatic organ architecture is described. The microfluidics network was designed using computational models to provide appropriate flow behavior based on physiological data from human microvasculature. Patterned silicon wafer molds were used to generate films with the vascular-based microfluidics network design and parenchymal chamber by soft lithography. The assembled device harbors hepatocytes behind a nanoporous membrane that permits transport of metabolites and small proteins while protecting them from the effects of shear stress. The device can sustain both human hepatoma cells and primary rat hepatocytes by continuous in vitro perfusion of medium, allowing proliferation and maintaining hepatic functions such as serum protein synthesis and metabolism. The design and fabrication processes are scalable, enabling the device concept to serve as both a platform technology for drug discovery and toxicity, and for the continuing development of an improved liver-assist device.


Improved conditions for the generation of beta oscillations in the subthalamic nucleus--globus pallidus network.
A key pathology in the development of Parkinson's disease is the occurrence of persistent beta oscillations, which are correlated with difficulty in movement initiation. We investigated the network model composed of the subthalamic nucleus (STN) and globus pallidus (GP) developed by A. Nevado Holgado et al. [(2010) Journal of Neuroscience, 30, 12340-12352], who identified the conditions under which this circuit could generate beta oscillations. Our work extended their analysis by deriving improved analytic stability conditions for realistic values of the synaptic transmission delay between STN and GP neurons. The improved conditions were significantly closer to the results of simulations for the range of synaptic transmission delays measured experimentally. Furthermore, our analysis explained how changes in cortical and striatal input to the STN-GP network influenced oscillations generated by the circuit. As we have identified when a system of mutually connected populations of excitatory and inhibitory neurons can generate oscillations, our results may also find applications in the study of neural oscillations produced by assemblies of excitatory and inhibitory neurons in other brain regions.


Community Cultural Norms, Stigma and Disclosure to Sexual Partners among Women Living with HIV in Thailand, Brazil and Zambia (HPTN 063).
Serostatus disclosure may facilitate decreased HIV transmission between serodiscordant partners by raising risk awareness and heightening the need for prevention. For women living with HIV (WLWH), the decision to disclose may be influenced by culturally determined, community-level stigma and norms. Understanding the impact of community HIV stigma and gender norms on disclosure among WLWH in different countries may inform intervention development. HPTN063 was a longitudinal, observational study of sexually active HIV-infected individuals, including heterosexual women, in care in Zambia, Thailand and Brazil. At baseline, a questionnaire measuring community HIV stigma and gender norms, anticipated stigma, demographic, partner/relationship characteristics, and intimate partner violence was administered. Longitudinal HIV disclosure to sexual partners was determined via audio-computer assisted self-interview (ACASI) at the baseline and quarterly during the one year following up. Logistic regression was conducted to identify the predictors of disclosure. Almost half (45%) of women living with HIV acknowledged perceived community HIV stigma (the belief that in their community HIV infection among women is associated with sex work and multiple sexual partners). Many women (42.9%) also acknowledged perceived community gender norms (the belief that traditional gender norms such as submissiveness to husbands/male sexual partners is necessary and that social status is lost if one does not procreate). HIV disclosure to current sex partners was reported by 67% of women. In multivariate analysis, among all women, those who were older [OR 0.16, 95%CI(0.06,0.48)], reported symptoms of severe depression [OR 0.53, 95%CI(0.31, 0.90)], endorsed anticipated stigma [OR 0.30, 95%CI(0.18, 0.50)], and were unmarried [OR 0.43, 95%CI(0.26,0.71)] were less likely to disclose to current partners. In an analysis stratified by marital status and cohabitation, unmarried [OR 0.41, 95%CI(0.20,0.82)] and non-cohabiting women [OR 0.31, 95%CI(0.13,0.73)] who perceived community HIV stigma were less likely to disclose to their sex partners. Perceived community level HIV stigma, along with individual level factors such as anticipated stigma, depressive symptoms, and older age, predict non-disclosure of HIV status to sexual partners among WLWH in diverse geographic settings. Interventions to promote disclosure among women in serodiscordant relationships should incorporate community-level interventions to reduce stigma and promote gender equality.


Botulinum toxin and the treatment of headache: A clinical review.
Since its discovery, Onabotulinum toxins have been tried for the treatment of various head, neck and face pain syndromes. The end result of controlled clinical trials was that there was not clear evidence for use in many of the common primary and secondary headaches. In chronic migraine, affecting 1-2% of the population, a fixed site and fixed dose treatment approach was shown to be superior to placebo and was approved for use. In this review, evidence for that use and the history leading to it is described.


Tuning a racetrack ring resonator by an integrated dielectric MEMS cantilever.
The principle, fabrication and characterization of a dielectric MEMS cantilever located a few 100 nm above a racetrack ring resonator are presented. After fabrication of the resonators on silicon-on-insulator (SOI) wafers in a foundry process, the cantilevers were integrated by surface micromachining techniques. Off-state deflections of the cantilevers have been optimized to appropriately position them near the evanescent field of the resonator. Using electrostatic actuation, moving the cantilevers into this evanescent field, the propagation properties of the ring waveguide are modulated. We demonstrate 122 pm tuning of the resonance wavelength of the optical ring resonator (in the optical C-band) without change of the optical quality factor, on application of 9 V to a 40 µm long cantilever. This compact integrated device can be used for tuning/switching a specific wavelength, with very little energy for operation and negligible cross talk with surrounding devices.


The acceptability and impact of a randomised controlled trial of welfare rights advice accessed via primary health care: qualitative study.
Qualitative research is increasingly used alongside randomised controlled trials (RCTs) to study a range of factors including participants' experiences of a trial. The need for a sound evidence base within public health will increase the need for RCTs of non-clinical interventions. Welfare rights advice has been proposed as an intervention with potential to reduce health inequalities. This qualitative study, nested within an RCT of the impact of welfare rights advice, examined the acceptability of the intervention, the acceptability of the research process and the perceived impact of the intervention. 25 men and women aged 60 years or over were recruited from four general practices in Newcastle upon Tyne (UK), a sub-sample of those who consented to be contacted (n = 96) during the RCT baseline interview. Semi-structured interviews were undertaken and analysed using the Framework Method. Participants viewed the trial positively although, despite agreeing that the information leaflet was clear, some had agreed to participate without being fully aware of what was involved. Some participants were unaware of the implications of randomisation. Most thought it fair, but a few concerns were raised about the control condition. The intervention was acceptable and made participants feel confident about applying for benefit entitlements. 14 out of 25 participants received some financial award; median weekly income gain was pounds 57 (Euro 84, dollar 101). The perceived impact of additional finances was considerable and included: increased affordability of necessities and occasional expenses; increased capacity to deal with emergencies; and a reduction in stress related to financial worries. Overall, perceived independence and ability to participate in society increased. Most participants perceived benefits to their mental well-being, but no-one reported an improvement in physical health. The RCT showed little or no effect on a wide range of outcome measures. Participation in the trial and the intervention was acceptable to participants. Welfare rights advice targeted at people aged 60 years or over and accessed via primary care had a positive impact on quality of life and resulted in increased social participation. The divergence of qualitative and quantitative findings suggests that both methods make important contributions to the evaluation of complex social interventions.


Trust and compactness in social network groups.
Understanding the dynamics behind group formation and evolution in social networks is considered an instrumental milestone to better describe how individuals gather and form communities, how they enjoy and share the platform contents, how they are driven by their preferences/tastes, and how their behaviors are influenced by peers. In this context, the notion of compactness of a social group is particularly relevant. While the literature usually refers to compactness as a measure to merely determine how much members of a group are similar among each other, we argue that the mutual trustworthiness between the members should be considered as an important factor in defining such a term. In fact, trust has profound effects on the dynamics of group formation and their evolution: individuals are more likely to join with and stay in a group if they can trust other group members. In this paper, we propose a quantitative measure of group compactness that takes into account both the similarity and the trustworthiness among users, and we present an algorithm to optimize such a measure. We provide empirical results, obtained from the real social networks EPINIONS and CIAO, that compare our notion of compactness versus the traditional notion of user similarity, clearly proving the advantages of our approach.


Surfactant enhanced lipase containing films characterized by confocal laser scanning microscopy.
Confocal laser scanning microscopy (CLSM) in combination with a fluorescently labeling enzyme dye, LavaPurple™, was demonstrated as a technique for the visualization of Thermomyces (Humicola) lanuginosa lipase (LIP(HLL)) and Candida antarctica lipase A (LIP(CA)) within a transparent latex coating. Addition of Teric Surfactants (C(16) non-ionic Teric 475, 1.8% (w/w) or C(10) non-ionic Teric 460, 2.0% (w/w)) significantly increased the accumulation of both LIP(HLL) and LIP(CA) to the surface of a latex coating. An α-naphthyl acetate substrate assay was used to quantify the accumulated lipase. The results derived from the acetate assay correlated with the enzyme accumulation (at the surface) observed in the CLSM images of the latex coating. This correlation demonstrated that the increased enzyme accumulation within the top 2μm of the latex film was responsible for the increase in surface enzymatic activity. The combination of CLSM imagery and quantifiable image analysis provided a valuable tool for the optimization of surfactant concentrations for maximizing the activity of an enzyme (and potentially other additives) within a latex coating.


The Role of Immunohistochemistry and Molecular Analysis of Succinate Dehydrogenase in the Diagnosis of Endocrine and Non-Endocrine Tumors and Related Syndromes.
Succinate dehydrogenase (SDH) is an enzyme complex, composed of four protein subunits, that plays a role in both the citric acid cycle and the electron transport chain. The genes for SDHA, SDHB, SDHC, and SDHD are located in the nuclear DNA, and mutations in these genes have initially been described in paragangliomas (PGL) and pheochromocytomas (PCC), which are relatively rare tumors derived from the autonomic nervous system and the adrenal medulla, respectively. Patients with SDH mutations, that are almost exclusively in the germline, are frequently affected by multiple PGL and/or PCC. In addition, other tumors have been associated with SDH mutations as well, including gastrointestinal stromal tumors, SDH-deficient renal cell carcinoma, and pituitary adenomas. Immunohistochemistry for SDHB and SDHA has been shown to be a valuable additional tool in the histopathological analysis of these tumors, and can be considered as a surrogate marker for molecular analysis. In addition, SDHB immunohistochemistry is relevant in the decision-making whether a genetic sequence variant represents a pathogenic mutation or not. In this review, we highlight the current knowledge of the physiologic and pathologic role of the SDH enzyme complex and its involvement in endocrine and non-endocrine tumors, with an emphasis on the applicability of immunohistochemistry.


Risk Factors for Major Amputation on Hindfoot Ulcers in Hospitalized Diabetic Patients.
Objective: The purpose of this study was to investigate the risk factors for major amputation in patients hospitalized with diabetic foot ulcers involving the hindfoot. Approach: Between January 2003 and October 2017, a total of 1,657 diabetic patients were admitted to the diabetic wound center of Korea University Guro Hospital, for the management of foot ulcers. Among the admitted patients, 117 diabetic patients with hindfoot ulcers were included in this study. One hundred and four patients (89%) healed without major amputation, while 13 patients (11%) healed with major amputation. Data related to 88 potential risk factors, including demographics, ulcer condition, vascularity, bioburden, neurology, and serology, were collected from patients in these two groups for comparison. Results: Among the 88 potential risk factors, 15 showed statistically significant differences between the two groups. In univariate analysis of 88 potential risk factors, nine showed statistically significant differences. In stepwise multiple logistic regression analysis, three of the nine risk factors remained statistically significant. Multivariate-adjusted odds ratios for pulmonary disorders, erythrocyte sedimentation rate (ESR) levels, and total iron-binding capacity (TIBC) levels were 38.525, 1.047, and 0.976, respectively. Innovation: Compared with forefoot and midfoot ulcers, diabetic foot ulcers involving the hindfoot are at increased risk of major amputation because infection may spread proximal to the ankle. However, large-scale cohort studies that specifically discuss the outcomes and characteristics of diabetic hindfoot ulcers are not widely available. Conclusion: Risk factors for major amputation in patients hospitalized with diabetic hindfoot ulcers include pulmonary disorders, high levels of ESR, and decreased TIBC levels.


Five-Year Outcomes of Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial.
Ranibizumab is a viable treatment option for eyes with proliferative diabetic retinopathy (PDR) through 2 years. However, longer-term results are needed. To evaluate efficacy and safety of 0.5-mg intravitreous ranibizumab vs panretinal photocoagulation (PRP) over 5 years for PDR. Diabetic Retinopathy Clinical Research Network multicenter randomized clinical trial evaluated 394 study eyes with PDR enrolled February through December 2012. Analysis began in January 2018. Eyes were randomly assigned to receive intravitreous ranibizumab (n = 191) or PRP (n = 203). Frequency of ranibizumab was based on a protocol-specified retreatment algorithm. Diabetic macular edema could be managed with ranibizumab in either group. Mean change in visual acuity (intention-to-treat analysis) was the main outcome. Secondary outcomes included peripheral visual field loss, development of vision-impairing diabetic macular edema, and ocular and systemic safety. The 5-year visit was completed by 184 of 277 participants (66% excluding deaths). Of 305 enrolled participants, the mean (SD) age was 52 (12) years, 135 (44%) were women, and 160 (52%) were white. For the ranibizumab and PRP groups, the mean (SD) number of injections over 5 years was 19.2 (10.9) and 5.4 (7.9), respectively; the mean (SD) change in visual acuity letter score was 3.1 (14.3) and 3.0 (10.5) letters, respectively (adjusted difference, 0.6; 95% CI, -2.3 to 3.5; P = .68); the mean visual acuity was 20/25 (approximate Snellen equivalent) in both groups at 5 years. The mean (SD) change in cumulative visual field total point score was -330 (645) vs -527 (635) dB in the ranibizumab (n = 41) and PRP (n = 38) groups, respectively (adjusted difference, 208 dB; 95% CI, 9-408). Vision-impairing diabetic macular edema developed in 27 and 53 eyes in the ranibizumab and PRP groups, respectively (cumulative probabilities: 22% vs 38%; hazard ratio, 0.4; 95% CI, 0.3-0.7). No statistically significant differences between groups in major systemic adverse event rates were identified. Although loss to follow-up was relatively high, visual acuity in most study eyes that completed follow-up was very good at 5 years and was similar in both groups. Severe vision loss or serious PDR complications were uncommon with PRP or ranibizumab; however, the ranibizumab group had lower rates of developing vision-impairing diabetic macular edema and less visual field loss. Patient-specific factors, including anticipated visit compliance, cost, and frequency of visits, should be considered when choosing treatment for patients with PDR. These findings support either anti-vascular endothelial growth factor therapy or PRP as viable treatments for patients with PDR. ClinicalTrials.gov Identifier: NCT01489189.


Spatial dynamics of human-origin H1 influenza A virus in North American swine.
The emergence and rapid global spread of the swine-origin H1N1/09 pandemic influenza A virus in humans underscores the importance of swine populations as reservoirs for genetically diverse influenza viruses with the potential to infect humans. However, despite their significance for animal and human health, relatively little is known about the phylogeography of swine influenza viruses in the United States. This study utilizes an expansive data set of hemagglutinin (HA1) sequences (n = 1516) from swine influenza viruses collected in North America during the period 2003-2010. With these data we investigate the spatial dissemination of a novel influenza virus of the H1 subtype that was introduced into the North American swine population via two separate human-to-swine transmission events around 2003. Bayesian phylogeographic analysis reveals that the spatial dissemination of this influenza virus in the US swine population follows long-distance swine movements from the Southern US to the Midwest, a corn-rich commercial center that imports millions of swine annually. Hence, multiple genetically diverse influenza viruses are introduced and co-circulate in the Midwest, providing the opportunity for genomic reassortment. Overall, the Midwest serves primarily as an ecological sink for swine influenza in the US, with sources of virus genetic diversity instead located in the Southeast (mainly North Carolina) and South-central (mainly Oklahoma) regions. Understanding the importance of long-distance pig transportation in the evolution and spatial dissemination of the influenza virus in swine may inform future strategies for the surveillance and control of influenza, and perhaps other swine pathogens.


What are the perspectives for blood donations and blood component transfusion worldwide? A systematic review of time series studies.
Analysis of the literature suggests that changes relating to blood donations and blood component transfusion are occurring due to the aging of the population. To gain better understanding of the demand and supply of these inputs over time, and to identify the main associated demographic characteristics. Systematic review conducted on time series relating to blood donations and blood component transfusions worldwide. A systematic review of the literature was conducted based on articles that presented time series relating to blood donation or blood component transfusion. We found 1,814 articles. After the deletion process, only thirteen were read. Overall, these suggested that there is increasing demand for blood components and decreasing donation. The existence of seasonality regarding blood donation was pointed out. Men usually donated more blood and demanded more blood components than women. Approximately 50% of blood transfusions were performed in people aged ≥ 60 years. This analysis on articles that presented time series relating to blood donations and blood component transfusion showed that aging of the population was the main factor associated with the increasing demand for blood and the decreasing supply of blood.


Effect of Coenzyme Q10 on Radiation Nephropathy in Rats.
The kidney is one of the most radiosensitive organs in the abdominal cavity and is the dose-limiting structure in cancer patients receiving abdominal or total body irradiation. In the present study, the effect of coenzyme Q10 (CoQ10) on radiation nephropathy was evaluated in rats. A total of 72 rats were equally randomized into 4 groups: Control, CoQ10, irradiation with 10 Gy (RT) + placebo, or RT + CoQ10. The 2 RT groups received single 10 Gy of abdominal irradiation. The 2 CoQ10 groups were supplemented daily with 1 mL of soybean oil containing 10 mg/kg of CoQ10. The RT + placebo and control groups received same dose of soybean oil. After 24 weeks, laboratory and histopathologic findings were compared. The 2 RT groups showed significant increases in blood urea nitrogen (BUN) and creatinine levels and significant pathologic changes such as glomerulosclerosis and tubulointerstitial fibrosis. CoQ10 supplementation resulted in significant reductions of BUN and creatinine levels compared with the RT + placebo group (P < 0.001 and P = 0.038, respectively). CoQ10 treatment significantly attenuated glomerular and tubular changes of irradiated kidney in semiquantitative analysis (P < 0.001 for both). Administration of CoQ10 can alleviate the radiation-induced nephropathy.


Final results of Australasian Gastrointestinal Trials Group ARCTIC study: an audit of raltitrexed for patients with cardiac toxicity induced by fluoropyrimidines.
Cardiac toxicity an uncommon but serious side-effect of some fluoropyrimides. Cardiac toxicity from raltitrexed is rarely reported. With this background, we initiated this study to investigate the incidence of cardiac events in patients who had switched to raltitrexed following cardiac toxicity from fluoropyrimidines (5-fluorouracil or capecitabine). Pharmacy records were used to identify patients receiving raltitrexed from January 2004 till March 2012. Medical records were then reviewed to confirm the use of raltitrexed after cardiac toxicity from 5-fluorouracil or capecitabine. The primary end point was the rate of further cardiac events after commencing raltitrexed. Forty-two patients were identified and the majority had colorectal cancer. Prior regimens included 5-fluorouracil ± leucovorin, capecitabine alone, FOLFOX, FOLFIRI, epirubicin/cisplatin/5-fluorouracil, and capecitabine/oxaliplatin. Seven patients (17%) had bolus 5-fluorouracil regimens, 26 patients (62%) had infusion 5-fluorouracil regimens, and 9 patients (21%) had capecitabine alone or in combination. Angina was the most common cardiac toxicity from 5-fluorouracil or capecitabine and usually occurred in the first or the second cycle. Four patients after their first cardiac event continued with the same 5-fluorouracil or capecitabine regimen with the addition of nitrates and calcium antagonists but still had further cardiac events. After changing to raltitrexed, either as a single agent or a continuing combination regimen, no patients experienced further cardiac toxicity. Raltitrexed is associated with no significant cardiac toxicity in patients who have experienced prior cardiac toxicity from 5-fluorouracil or capecitabine. Raltitrexed, alone or in combination with oxaliplatin or irinotecan, provides a safe option in terms of cardiac toxicity for such patients.


Intelligent analysis of EMG data for improving lifestyle.
In the tragic situation when a person loses his or her hand, they are usually faced with only one option if they wish to regain a good level of mobility; learn to control an artificial hand. It has been suggested that our brain stores a "body map" of the different parts in our body. Thus, if a person loses a hand, their "body map" remains intact and produces phantom sensations that permit the person to feel like they still have their hand. Some discomfort is felt during these sensations; nevertheless, there is a positive side to them as they enable patients to control prosthetic replacements. Sensations experienced can be measured using a method known as Electromyography (EMG) and can be acquired and processed to control an artificial hand. This research involved the acquisition, analysis and classification of EMG signals through construction of a recording device and the development of classification models based on heuristic approaches and Artificial Intelligence classifiers based on Neural Networks to control artificial hands.


Phosphate uptake in an obligately marine fungus: a specific requirement for sodium.
Phosphate uptake in the obligately marine fungus Thraustochytrium roseum is maximally stimulated by sodium chloride in a range of concentrations (0.2 to 0.4 molar) similar to those commonly encountered in littoral habitats. The effectiveness of sodium chloride for phosphate transport extends beyond its osmotic function and can be attributed specifically to sodium. Increases in respiration in the presence of the salt can be ascribed primarily to an osmotic effect.


Strategy to discover full-length amyloid-beta peptide ligands using high-efficiency microarray technology.
Although the formation of β-amyloid (Aβ) fibrils in neuronal tissues is a hallmark of Alzheimer disease (AD), small-sized Aβ oligomers rather than mature fibrils have been identified as the most neurotoxic species. Therefore, the design of new inhibitors, able to prevent the aggregation of Aβ, is believed to be a promising therapeutic approach to AD. Unfortunately, the short-lived intermediate structures that occur in a solution along the Aβ aggregation pathway escape conventional experimental investigations and there is urgent need of new tools aimed at the discovery of agents targeting monomeric Aβ and blocking the early steps of amyloid aggregation. Here, we show the combination of high-efficiency slides (HESs) with peptide microarrays as a promising tool for identifying small peptides that bind Aβ monomers. To this aim, HESs with two immobilized reference peptides, (i.e., KLVFF and Semax) with opposite behavior, were investigated for binding to fluorescently labeled Aβ peptide. Transmission electron microscopy was used to demonstrate Aβ fibrillar aggregates missing. The use of HESs was critical to ensure convenient output of the fluorescent microarrays. The resulting sensitivity, as well as the low sample consumption and the high potential for miniaturization, suggests that the proposed combination of peptide microarrays and highly efficient slides would be a very effective technology for molecule profiling in AD drug discovery.


Regulation of transcriptome, translation, and proteome in response to environmental stress in fission yeast.
Gene expression is controlled globally and at multiple levels in response to environmental stress, but the relationships among these dynamic regulatory changes are not clear. Here we analyzed global regulation during different stress conditions in fission yeast, Schizosaccharomyces pombe, combining dynamic genome-wide data on mRNA, translation, and protein profiles. We observed a strong overall concordance between changes in mRNAs and co-directional changes in translation, for both induced and repressed genes, in response to three conditions: oxidative stress, heat shock, and DNA damage. However, approximately 200 genes each under oxidative and heat stress conditions showed discordant regulation with respect to mRNA and translation profiles, with genes and patterns of regulation being stress-specific. For oxidative stress, we also measured dynamic profiles for 2,147 proteins, comprising 43% of the proteome. The mRNAs induced during oxidative stress strongly correlated with increased protein expression, while repressed mRNAs did not relate to the corresponding protein profiles. Overall changes in relative protein expression correlated better with changes in mRNA expression than with changes in translational efficiency. These data highlight a global coordination and fine-tuning of gene regulation during stress that mostly acts in the same direction at the levels of transcription and translation. In the oxidative stress condition analyzed, transcription dominates translation to control protein abundance. The concordant regulation of transcription and translation leads to the expected adjustment in protein expression only for up-regulated mRNAs. These patterns of control might reflect the need to balance protein production for stress survival given a limited translational capacity.


Reflection spectra and near-field images of a liquid crystalline half-Skyrmion lattice.
We investigate numerically the optical properties of a hexagonal half-Skyrmion lattice exhibited by a highly chiral liquid crystal confined between two parallel plates. Our study focuses on the near and far-field reflection for normally incident light with different polarizations. We show that, when the wavelength of the incident light is longer than a threshold value, the reflectivity is almost insensitive to the polarization of the incident light, although the intensity profiles of the reflected light, in particular in the near-field regime, depend significantly on the polarization. The former property is attributable to the quasi two-dimensional nature of the half-Skyrmion lattice, that is, almost uniform orientational order along the direction normal to the confining plates. Our results for the intensity of reflected light generated by evanescent as well as propagating contributions suggest that direct evidence of the formation and structure of half-Skyrmions could be provided by near-field optics with resolutions higher than that of conventional optical microscopy.


Folinic Acid Increases Protein Arginine Methylation in Human Endothelial Cells.
Elevated plasma total homocysteine (tHcy) is associated with increased risk of cardiovascular disease, but the mechanisms underlying this association are not completely understood. Cellular hypomethylation has been suggested to be a key pathophysiologic mechanism, since S-adenosylhomocysteine (AdoHcy), the Hcy metabolic precursor and a potent inhibitor of methyltransferase activity, accumulates in the setting of hyperhomocysteinemia. In this study, the impact of folate and methionine on intracellular AdoHcy levels and protein arginine methylation status was studied. Human endothelial cells were incubated with increasing concentrations of folinic acid (FnA), a stable precursor of folate, with or without methionine restriction. The levels of intracellular AdoHcy and AdoMet, tHcy in the cell culture medium, and protein-incorporated methylarginines were evaluated by suitable liquid chromatography techniques. FnA supplementation, with or without methionine restriction, reduced the level of tHcy and did not affect intracellular AdoMet levels. Interestingly, FnA supplementation reduced intracellular AdoHcy levels only in cells grown under methionine restriction. Furthermore, these cells also displayed increased protein arginine methylation status. These observations suggest that folic acid supplementation may enhance cellular methylation capacity under a low methionine status. Our results lead us to hypothesize that the putative benefits of folic acid supplementation in restoring endothelial homeostasis, thus preventing atherothrombotic events, should be reevaluated in subjects under a methionine restriction diet.


Effective testing of personal protective equipment in blast loading conditions in shock tube: Comparison of three different testing locations.
We exposed a headform instrumented with 10 pressure sensors mounted flush with the surface to a shock wave with three nominal intensities: 70, 140 and 210 kPa. The headform was mounted on a Hybrid III neck, in a rigid configuration to eliminate motion and associated pressure variations. We evaluated the effect of the test location by placing the headform inside, at the end and outside of the shock tube. The shock wave intensity gradually decreases the further it travels in the shock tube and the end effect degrades shock wave characteristics, which makes comparison of the results obtained at three locations a difficult task. To resolve these issues, we developed a simple strategy of data reduction: the respective pressure parameters recorded by headform sensors were divided by their equivalents associated with the incident shock wave. As a result, we obtained a comprehensive set of non-dimensional parameters. These non-dimensional parameters (or amplification factors) allow for direct comparison of pressure waveform characteristic parameters generated by a range of incident shock waves differing in intensity and for the headform located in different locations. Using this approach, we found a correlation function which allows prediction of the peak pressure on the headform that depends only on the peak pressure of the incident shock wave (for specific sensor location on the headform), and itis independent on the headform location. We also found a similar relationship for the rise time. However, for the duration and impulse, comparable correlation functions do not exist. These findings using a headform with simplified geometry are baseline values and address a need for the development of standardized parameters for the evaluation of personal protective equipment (PPE) under shock wave loading.


Adolescent Male Couples-Based HIV Testing Intervention (We Test): Protocol for a Type 1, Hybrid Implementation-Effectiveness Trial.
Young men who have sex with men (YMSM), particularly those who are partnered, are at unique risk for HIV. YMSM are among those at highest risk for HIV. Meanwhile, despite the fact that primary partners account for many-possibly most-new HIV infections, partnered men who have sex with men perceive themselves to be at much lower risk for HIV infection and therefore test less often than single men. In response to the risk of primary partner HIV transmission, couples HIV testing and counseling (CHTC) procedures have been developed for use in adult populations. Although promising, YMSM couples may require additional support to complete CHTC given their developmental context in which sexual and romantic relationships are relatively new, and communication skills are emergent. The aim of this study was to test the additive benefit of adjunct treatment components tailored for YMSM, which enhance communication skills before the completion of CHTC. The intervention tests a continuum of prevention packages including assertive communication training videos and motivational interviewing focused on assisting with identification and development (MI-AID) before entering into the dyadic intervention components. This protocol is part of the Adolescent Medicine Trials Network (ATN) Scale It Up program described in this issue. This is a comparative effectiveness trial that will be executed in 3 phases. Phase 1 will gather qualitative data related to intervention development and implementation from partnered YMSM at 4 subject recruitment venues (SRVs). Phase 2 will compare a continuum of these interventions in a pilot randomized controlled trial (RCT) at 2 SRVs. Phase 3 will compare the most successful adapted intervention package from phase 2 to CHTC as usual in a larger RCT at 4 SRVs. This phase is focused on implementation and sustainment phases of the Exploration, Preparation, Implementation, and Sustainment framework. Phase 1 data will be drawn from qualitative interviews with partnered YMSM (n=24) and staff from ATN sites (n=20). Baseline enrollment for phase 2 is expected to begin across 2 SRVs in June 2018 (ncouples=36). In phase 2, survey data collection along with HIV and sexually transmitted infection (STI) testing will occur at baseline, and 1- and 3-month (postintervention) follow-ups. Phase 3 will begin enrollment across 4 SRVs in September 2019 (ncouples=144) and follow-ups will occur at 1, 3, 6, and 9 months postintervention. Although MI-AID, video-based assertive communication training, and CHTC have established efficacy when administered on their own, this study will be the first to evaluate the strongest adjunctive version of these interventions to address the specific developmental needs of partnered YMSM. ClinicalTrials.gov NCT03386110; http://clinicaltrials.gov/ct2/show/NCT03386110 (Archived by WebCite at http://www.webcitation.org/75mlO7GCx). DERR1-10.2196/11186.


Mismatch Negativity and P50 Sensory Gating in Abstinent Former Cannabis Users.
Prolonged heavy exposure to cannabis is associated with impaired cognition and brain functional and structural alterations. We recently reported attenuated mismatch negativity (MMN) and altered P50 sensory gating in chronic cannabis users. This study investigated the extent of brain functional recovery (indexed by MMN and P50) in chronic users after cessation of use. Eighteen ex-users (median 13.5 years prior regular use; median 3.5 years abstinence) and 18 nonusers completed (1) a multifeature oddball task with duration, frequency, and intensity deviants and (2) a P50 paired-click paradigm. Trend level smaller duration MMN amplitude and larger P50 ratios (indicative of poorer sensory gating) were observed in ex-users compared to controls. Poorer P50 gating correlated with prior duration of cannabis use. Duration of abstinence was positively correlated with duration MMN amplitude, even after controlling for age and duration of cannabis use. Impaired sensory gating and attenuated MMN amplitude tended to persist in ex-users after prolonged cessation of use, suggesting a lack of full recovery. An association with prolonged duration of prior cannabis use may indicate persistent cannabis-related alterations to P50 sensory gating. Greater reductions in MMN amplitude with increasing abstinence (positive correlation) may be related to either self-medication or an accelerated aging process.


Microneedling in the treatment of atrophic scars: A systematic review of randomised controlled trials.
To date, treatment of atrophic acne scars remains a therapeutic challenge for dermatologists, yet there is no standard option on the most effective treatment. Microneedling (MN) is a minimally invasive technology that involves repetitive skin puncture using sterile microneedles to disrupt dermal collagen that connects the scar tissue. Recent studies have demonstrated the potency of MN, such as dermaroller and fractionated microneedle radiofrequency, in the treatment of atrophic scars. The objective of this review is to evaluate systematically the current literature on MN for atrophic acne scars. A systematic search of literature was performed from PubMed, Medline, Cochrane Central, and Google Scholar databases for articles published during the last 20 years. Only randomised controlled trials (RCTs) with full-text version of the manuscript available were included in our study. Nine RCTs were included in this review. All treatment modalities demonstrated consistent results that MN was efficacious in treating atrophic acne scars as a monotherapy or in combination with other treatments. Moreover, no serious adverse effects were reported in all studies after MN treatment. MN is a well-tolerated and effective therapeutic modality in treating atrophic acne scars. Further research is required to validate the efficacy of MN with a larger sample size and lengthy follow-up.


From Group-Level Statistics to Single-Subject Prediction: Machine Learning Detection of Concussion in Retired Athletes.
There has been increased effort to understand the neurophysiological effects of concussion aimed to move diagnosis and identification beyond current subjective behavioral assessments that suffer from poor sensitivity. Recent evidence suggests that event-related potentials (ERPs) measured with electroencephalography (EEG) are persistent neurophysiological markers of past concussions. However, as such evidence is limited to group-level analyzes, the extent to which they enable concussion detection at the individual-level is unclear. One promising avenue of research is the use of machine learning to create quantitative predictive models that can detect prior concussions in individuals. In this paper, we translate the recent group-level findings from ERP studies of concussed individuals into a machine learning framework for performing single-subject prediction of past concussion. We found that a combination of statistics of single-subject ERPs and wavelet features yielded a classification accuracy of 81% with a sensitivity of 82% and a specificity of 80%, improving on current practice. Notably, the model was able to detect concussion effects in individuals who sustained their last injury as much as 30 years earlier. However, failure to detect past concussions in a subset of individuals suggests that the clear effects found in group-level analyses may not provide us with a full picture of the neurophysiological effects of concussion.


Abnormal resting-state cortical coupling in chronic tinnitus.
Subjective tinnitus is characterized by an auditory phantom perception in the absence of any physical sound source. Consequently, in a quiet environment, tinnitus patients differ from control participants because they constantly perceive a sound whereas controls do not. We hypothesized that this difference is expressed by differential activation of distributed cortical networks. The analysis was based on a sample of 41 participants: 21 patients with chronic tinnitus and 20 healthy control participants. To investigate the architecture of these networks, we used phase locking analysis in the 1-90 Hz frequency range of a minute of resting-state MEG recording. We found: 1) For tinnitus patients: A significant decrease of inter-areal coupling in the alpha (9-12 Hz) band and an increase of inter-areal coupling in the 48-54 Hz gamma frequency range relative to the control group. 2) For both groups: an inverse relationship (r = -.71) of the alpha and gamma network coupling. 3) A discrimination of 83% between the patient and the control group based on the alpha and gamma networks. 4) An effect of manifestation on the distribution of the gamma network: In patients with a tinnitus history of less than 4 years, the left temporal cortex was predominant in the gamma network whereas in patients with tinnitus duration of more than 4 years, the gamma network was more widely distributed including more frontal and parietal regions. In the here presented data set we found strong support for an alteration of long-range coupling in tinnitus. Long-range coupling in the alpha frequency band was decreased for tinnitus patients while long-range gamma coupling was increased. These changes discriminate well between tinnitus and control participants. We propose a tinnitus model that integrates this finding in the current knowledge about tinnitus. Furthermore we discuss the impact of this finding to tinnitus therapies using Transcranial Magnetic Stimulation (TMS).


A calorimetric evaluation of the interaction of amphiphilic prodrugs of idebenone with a biomembrane model.
Lipoamino acids (LAA) are useful promoieties to modify physicochemical properties of drugs, namely lipophilicity and amphiphilicity. The resulting membrane-like character of drug-LAA conjugates can increase the absorption profile of drugs through cell membranes and biological barriers. To show the role of amphiphilicity with respect to lipophilicity in the interaction of drugs with biomembranes, in the present study we evaluated the mode of such an interaction of lipophilic conjugates of LAA with the antioxidant drug idebenone (IDE). DSC analysis and transfer kinetic studies were carried out using dimyristoylphosphatidylcholine (DMPC) multilamellar liposomes (MLVs) as a model. For comparison, two esters of IDE with alkanoic acids were synthesized and included in the analysis. The experimental results indicate that based on their different structure, IDE-LAA conjugates interacted at different levels with respect to pure IDE with DMPC bilayers. In particular, a progressive penetration inside the vesicles was observed upon incubation of IDE-LAA compounds with empty liposomes. The enhanced amphiphilicity of the drug due to the LAA moieties caused more complex interactions with DMPC bilayers, compared to those registered with the native drug or IDE alkanoate esters.


A qualitative comparative analysis of well-managed school sanitation in Bangladesh.
Continued management of sanitation and hygiene services, post-intervention, is a global challenge, particularly in the school-setting. This situation threatens anticipated impacts of school sanitation and hygiene investments. To improve programming and policies, and increase the effectiveness of limited development resources, we seek to understand how and why some schools have well-managed sanitation post-intervention, while others do not. Based on in-depth qualitative data from 16 case schools in Meherpur, Bangladesh, we employ fuzzy-set qualitative comparative analysis to identify the necessary and sufficient conditions, or combinations of conditions (referred to as pathways), that lead to either well-managed or poorly managed school sanitation. We include posited sustainability determinants from the literature and factors that emerged from the cases themselves in the analysis. We identified three distinct pathways sufficient to support well-managed services, providing multiple options for how well-managed school sanitation could be encouraged. Two of these are applicable to both government and non-government schools: (1) quality construction, financial community support and a champion; and (2) quality construction, financial government support, a maintenance plan and school management committee involvement. On-going financial support for operations and maintenance was identified as a necessary condition for continued service management, which was absent from many schools with poorly managed services. However, financial support was insufficient alone and other conditions are needed in conjunction, including quality construction and incentivizing conditions, such as school management committee involvement in sanitation specifically, a sanitation champion, and/or one teacher clearly responsible for toilet maintenance. Surprisingly, the number of students per toilet (ranging from 18-95 students) and toilet age (ranging from 8-32 months) had no significant effect on sanitation conditions. Findings corroborate those from a similar study in Belize, and comparison suggests the need for financial community support and the possibly tenuous reliance on local champions in the absence of adequate government support for operations and maintenance. Sub-determinants to the necessary conditions are also discussed which have implications for school sanitation in Bangladesh and may have broader relevance for other low-income countries though further research is needed.


Interaction of the novel inotropic agent, ASL-7022, with alpha and beta adrenoceptors in the cardiovascular system of the pithed rat: comparison with dobutamine and dopamine.
Three selective inotropic agents, ASL-7022, dobutamine and dopamine, were evaluated for their effects at alpha and beta adrenoceptors in the cardiovascular system of the pithed rat. ASL-7022, dobutamine and dopamine were equipotent as pressor agents in propranolol- and reserpine-pretreated pithed rats; however, the mechanisms involved in their alpha adrenoceptor-mediated pressor effects were markedly different. The pressor response of ASL-7022 was mediated entirely by postsynaptic vascular alpha-2 adrenoceptors, whereas the pressor response of dobutamine was mediated exclusively by postsynaptic vascular alpha-1 adrenoceptors. The pressor response of dopamine was mediated by both postsynaptic vascular alpha-1 and alpha-2 adrenoceptors. All three compounds elicited beta-2 adrenoceptor-mediated vasodepressor responses in pithed rats when vascular tone was elevated by a constant infusion of angiotensin II. In contrast to the equal vasopressor potencies of these compounds, the vasodepressor activities varied by more than two orders of magnitude with ASL-7022 being the most potent and dopamine the least potent. Based on ratios of relative potencies for alpha adrenoceptor-mediated vasopressor effects and beta-2 adrenoceptor-mediated vasodepressor effects, it appears that dobutamine possesses an equal balance between its vasopressor and vasodepressor potencies, such that the net effect in the vasculature is a physiological antagonism with little or no change in blood pressure, consistent with clinical observations and experiments in animals. In contrast, the vasopressor potency of dopamine exceeds its potency as a depressor agent, such that the net effect is vasoconstriction, consistent with clinical and animal studies.(ABSTRACT TRUNCATED AT 250 WORDS)


Burden of Disease Estimates of Seven Pathogens Commonly Transmitted Through Foods in Denmark, 2017.
Burden of disease metrics are increasingly established to prioritize food safety interventions. We estimated the burden of disease caused by seven foodborne pathogens in Denmark in 2017: Campylobacter, Salmonella, Shiga toxin-producing Escherichia coli, norovirus, Yersinia enterocolitica, Listeria monocytogenes, and Toxoplasma gondii. We used public health surveillance data and scientific literature to estimate incidence, mortality, and total disability-adjusted life year (DALY) of each, and linked results with estimates of the proportion of disease burden that is attributable to foods. Our estimates showed that Campylobacter caused the highest burden of disease, leading to a total burden of 1709 DALYs (95% uncertainty interval [UI] 1665-1755), more than threefold higher than the second highest ranked pathogen (Salmonella: 492 DALYs; 95% UI 481-504). Campylobacter still led the ranking when excluding DALYs attributable to nonfoodborne routes of exposure. The total estimated incidence was highest for norovirus, but this agent ranked sixth when focusing on foodborne burden. Salmonella ranked second in terms of foodborne burden of disease, followed by Listeria and Yersinia. Foodborne congenital toxoplasmosis was estimated to cause the loss of ∼100 years of healthy life, a burden that was borne by a low number of cases in the population. The ranking of foodborne pathogens varied substantially when based on reported cases, estimated incidence, and burden of disease estimates. Our results reinforce the need to continue food safety efforts throughout the food chain in Denmark, with a particular focus on reducing the incidence of Campylobacter infections.


Sample Size Calculations for Population Size Estimation Studies Using Multiplier Methods With Respondent-Driven Sampling Surveys.
While guidance exists for obtaining population size estimates using multiplier methods with respondent-driven sampling surveys, we lack specific guidance for making sample size decisions. To guide the design of multiplier method population size estimation studies using respondent-driven sampling surveys to reduce the random error around the estimate obtained. The population size estimate is obtained by dividing the number of individuals receiving a service or the number of unique objects distributed (M) by the proportion of individuals in a representative survey who report receipt of the service or object (P). We have developed an approach to sample size calculation, interpreting methods to estimate the variance around estimates obtained using multiplier methods in conjunction with research into design effects and respondent-driven sampling. We describe an application to estimate the number of female sex workers in Harare, Zimbabwe. There is high variance in estimates. Random error around the size estimate reflects uncertainty from M and P, particularly when the estimate of P in the respondent-driven sampling survey is low. As expected, sample size requirements are higher when the design effect of the survey is assumed to be greater. We suggest a method for investigating the effects of sample size on the precision of a population size estimate obtained using multipler methods and respondent-driven sampling. Uncertainty in the size estimate is high, particularly when P is small, so balancing against other potential sources of bias, we advise researchers to consider longer service attendance reference periods and to distribute more unique objects, which is likely to result in a higher estimate of P in the respondent-driven sampling survey.


Investigation on the site occupation of rare-earth ions in CaIn2O4 with the fluorescence probe of Eu3.
Rare-earth doped CaIn2O4 phosphors have been widely investigated due to their excellent luminescent property, but the site occupation of rare-earth ions in CaIn2O4 is not very clear and needs to be clarified. Using Eu3+ as a fluorescence probe, such a clarification has been made in this work. 1% and 2% Eu3+ doped CaIn2O4 powder samples have been prepared by the sol-gel method. The X-ray diffraction results indicate that the lanthanide doping does not influence the structure of CaIn2O4. Site selective excitation at low temperature disclosed five different luminescent centers marked as A, B, C1, C2 and C3. The spectral analysis revealed that the A and B sites belong to Eu3+ embedded in In3+ sites; the other three are attributed to Eu3+ substitution on Ca2+ sites, which show slight distortion. Energy transfers from the B site to the A and C1 sites were observed in the 2% Eu3+ doped CaIn2O4 sample. The transitions of Eu3+ ions in the Ca2+ sites make the main contribution to the emission spectra excited at room temperature. These results may provide a guide for optimizing rare-earth doped CaIn2O4 phosphors for their application in the solid state lighting field.


The crystal structure of YloQ, a circularly permuted GTPase essential for Bacillus subtilis viability.
yloQ is one of 11 essential genes in Bacillus subtilis with unknown roles in the physiology of the cell. It encodes a polypeptide of 298 residues with motifs characteristic of GTPases. As a contribution to elucidating its indispensable cellular function, we have solved the crystal structure of YloQ to 1.6 A spacing, revealing a three-domain organisation. At the heart of the molecule is the putative GTPase domain, which exhibits a classical alpha/beta nucleotide-binding fold with a topology very similar to that of Ras and Era. However, as anticipated from the order in which the conserved G protein motifs appear in the sequence, the GTPase domain fold in YloQ is circularly permuted with respect to the classical GTPases. The nucleotide-binding pocket in YloQ is unoccupied, and analysis of the phosphate-binding (P) loop indicates that conformational changes in this region would be needed to accommodate GTP. The GTPase domain is flanked at its N terminus by a beta-barrel domain with an oligonucleotide/oligosaccharide-binding (OB) fold, and at its C terminus by an alpha-helical domain containing a coordinated zinc ion. This combination of protein modules is unique to YloQ and its orthologues. Sequence comparisons reveal a clustering of conserved basic and aromatic residues on one face of the OB domain, perhaps pointing to a role for YloQ in nucleic acid binding. The zinc ion in the alpha-helical domain is coordinated by three cysteine residues and a histidine residue in a novel ligand organisation. The juxtaposition of the switch I and switch II regions of the G domain and the OB and zinc-binding domains suggests that chemical events at the GTPase active site may be transduced into relative movements of these domains. The pattern of conserved residues and electrostatic surface potential calculations suggest that the OB and/or Zn-binding domains participate in nucleic acid binding consistent with a possible role for YloQ at some stage during mRNA translation.


A TCR binds to antagonist ligands with lower affinities and faster dissociation rates than to agonists.
T lymphocyte activation is mediated by the interaction of specific TCR with antigenic peptides bound to MHC molecules. Single amino acid substitutions are often capable of changing the effect of a peptide from stimulatory to antagonistic. Using surface plasmon resonance, we have analyzed the interaction between a complex consisting of variants of the MCC peptide bound to a mouse class II MHC (Ek) and a specific TCR. Using both an improved direct binding method as well as a novel inhibition assay, we show that the affinities of three different antagonist peptide-Ek complexes are approximately 10-50 times lower than that of the wildtype MCC-Ek complex for the TCR, largely due to an increased off-rate. These results suggest that the biological effects of peptide antagonists and partial agonists may be largely based on kinetic parameters.


Multiple origins of lichen symbioses in fungi suggested by SSU rDNA phylogeny.
Phylogenetic hypotheses provide a context for examining the evolution of heterotrophic lifestyles. The lichen lifestyle, which is the symbiotic association of fungi with algae, is found in various representatives of Dicaryomycotina, both Ascomycetes and Basidiomycetes. A highly resolved parsimony analysis of small subunit ribosomal DNA (SSU rDNA) sequences suggests at least five independent origins of the lichen habit in disparate groups of Ascomycetes and Basidiomycetes. Because lichen associations arose from parasitic, mycorrhizal, or free-living saprobic fungi, neither mutualism nor parasitism should be construed as endpoints in symbiont evolution.


Is it possible to agree on a value for inorganic arsenic in food? The outcome of IMEP-112.
Two of the core tasks of the European Union Reference Laboratory for Heavy Metals in Feed and Food (EU-RL-HM) are to provide advice to the Directorate General for Health and Consumers (DG SANCO) on scientific matters and to organise proficiency tests among appointed National Reference Laboratories. This article presents the results of the 12th proficiency test organised by the EU-RL-HM (IMEP-112) that focused on the determination of total and inorganic arsenic in wheat, vegetable food and algae. The test items used in this exercise were: wheat sampled in a field with a high concentration of arsenic in the soil, spinach (SRM 1570a from NIST) and an algae candidate reference material. Participation in this exercise was open to laboratories from all around the world to be able to judge the state of the art of the determination of total and, more in particular, inorganic arsenic in several food commodities. Seventy-four laboratories from 31 countries registered to the exercise; 30 of them were European National Reference Laboratories. The assigned values for IMEP-112 were provided by a group of seven laboratories expert in the field of arsenic speciation analysis in food. Laboratory results were rated with z and ζ scores (zeta scores) in accordance with ISO 13528. Around 85 % of the participants performed satisfactorily for inorganic arsenic in vegetable food and 60 % did for inorganic arsenic in wheat, but only 20 % of the laboratories taking part in the exercise were able to report satisfactory results in the algae test material.


Pre-emptive penile ring block with sucrose analgesia reduces pain response to neonatal circumcision.
To compare retrospective use of oral sucrose (SUC) vs oral sucrose plus lidocaine ring block (SUC + RB) in the management of pain during neonatal circumcision. A retrospective review of medical records of newborns circumcised using the "Neonatal Infant Pain Scale" was done. With regard to pain, the SUC group had a significantly greater percentage of those with pain than the SUC + RB group at 1 minute (77.7% vs 69.4%; P = .01) and 5 minutes (65.7% vs 55.7%; P = .004). There was no significant pain difference at 30 minutes. In the multivariate logistic regression analyses, those in the SUC group had significantly greater odds for pain at 1 minute than those in the SUC + RB group (odds ratio 1.45, 95% confidence interval 1.04-2.02; P = .03). No significant difference was noted at 5 minutes. Each of the SUC and SUC + RB groups had significant decreases in pain percentages at 5 minutes and 30 minutes (P <.001). In addition, post-term gestational age had significantly greater odds for pain at 5 minutes (odds ratio 3.67, 95% confidence interval 1.51-8.93; P = .004). We found that sucrose use alone as compared with sucrose and ring block combined had greater odds for pain at 1 minute but not at 5 minutes. In addition, those with post-term gestational age had greater odds for pain at 5 minutes as compared with those with regular gestational age. We recommend for hospital-based circumcision using clamps, the use of combined sucrose and ring block for increased analgesia. In addition, for post-term neonates, we recommend greater focus on pain levels, including considering higher dosages of pain medications.


The effects of competition on medical service provision.
We explore how competition between physicians affects medical service provision. Previous research has shown that, without competition, physicians deviate from patient-optimal treatment under payment systems like capitation and fee-for-service. Although competition might reduce these distortions, physicians usually interact with each other repeatedly over time and only a fraction of patients switches providers at all. Both patterns might prevent competition to work in the desired direction. To analyze the behavioral effects of competition, we develop a theoretical benchmark that is then tested in a controlled laboratory experiment. Experimental conditions vary physician payment and patient characteristics. Real patients benefit from provision decisions made in the experiment. Our results reveal that, in line with the theoretical prediction, introducing competition can reduce overprovision and underprovision, respectively. The observed effects depend on patient characteristics and the payment system, though. Tacit collusion is observed and particularly pronounced with fee-for-service payment, but it appears to be less frequent than in related experimental research on price competition.


Perceptual segmentation: combining image segmentation with object tagging.
Human observers understand the content of an image intuitively. Based upon image content, they perform many image-related tasks, such as creating slide shows and photo albums, and organizing their image archives. For example, to select photos for an album, people assess image quality based upon the main objects in the image. They modify colors in an image based upon the color of important objects, such as sky, grass or skin. Serious photographers might modify each object separately. Photo applications, in contrast, use low-level descriptors to guide similar tasks. Typical descriptors, such as color histograms, noise level, JPEG artifacts and overall sharpness, can guide an imaging application and safeguard against blunders. However, there is a gap between the outcome of such operations and the same task performed by a person. We believe that the gap can be bridged by automatically understanding the content of the image. This paper presents algorithms for automatic tagging of perceptual objects in images, including sky, skin, and foliage, which constitutes an important step toward this goal.


Treatment fears in anxiety disorders: development and validation of the treatment ambivalence questionnaire.
There are a number of effective psychological interventions for anxiety disorders. Anecdotal and empirical evidence indicates that clients are often highly apprehensive about commencing therapy. However, to date, there have been no empirical studies of the content of individuals' fears about beginning a psychological treatment for anxiety problems. Here we describe the development and initial validation of the Treatment Ambivalence Questionnaire (TAQ), a 30-item self-report measure of concerns about commencing psychological treatment for anxiety. Participants were a large group of individuals with a principal diagnosis of an anxiety disorder who were referred to a specialty anxiety disorders clinic. Participants completed the TAQ as well as several general self-report instruments before commencing treatment. The TAQ exhibited good internal consistency and, based on exploratory factor analyses, the items yielded three subscales: (a) fears of the personal consequences of engaging in treatment (e.g., personality change), (b) fears of negative or adverse reactions to treatment (e.g., not getting better), and (c) concerns about the inconvenience of engaging in treatment (e.g., treatment will be time-consuming). Confirmatory factor analysis supported this factor structure. Scores on the TAQ did not simply represent general symptom severity or distress. Preliminary data on the relation of TAQ scores to treatment outcome suggested either no relationship or a small relationship. The TAQ may be a useful means of normalizing treatment fears, identifying and addressing specific fears, and identifying people who may benefit from treatment readiness interventions.


Race and residential socioeconomics as predictors of CPAP adherence.
There are few established predictors of CPAP adherence; poor adherence limits its effectiveness. We investigated whether race, education level, and residential economic status predict CPAP adherence in participants enrolled in a trial with standard access to treatment. A multi-center randomized trial of home vs. lab-based evaluation and treatment of OSA assessing adherence to CPAP at 1 and 3 months. Seven AASM-accredited sleep centers in 5 U.S. cities. Subjects with moderate to severe OSA (AHI ≥ 15 and Epworth Sleepiness Scale score > 12) who completed follow-up at 1 and/or 3 months (n = 135). Subjects' demographic data were collected upon enrollment; CPAP use at 1 and 3 months was assessed at clinic follow-up. In unadjusted analyses, CPAP adherence (average minutes per night of CPAP use) at 3 months was lower in black subjects and in subjects from lower socioeconomic status ZIP codes. In adjusted analyses using multivariate linear regression, black race was predictive of CPAP adherence at one month (P = 0.03). At 3 months, black race was predictive in analyses only when ZIP code SES was not adjusted for. Black race and lower socioeconomic residential areas are associated with poorer adherence to CPAP in subjects with standardized access to care and treatment. Disparities remain despite provision of standardized care in a clinical trial setting. Future research is needed to identify barriers to adherence and to develop interventions tailored to improve CPAP adherence in at risk populations. Portable Monitoring for Diagnosis and Management of Sleep Apnea (HomePAP) CLINICAL TRIAL INFORMATION: NIH CLINICAL TRIALS REGISTRY NUMBER: NCT00642486. URL: http://clinicaltrials.gov/show/NCT00642486.