Processing of color, form and disparity information in visual areas VP and V2 of ventral extrastriate cortex in the macaque monkey.
The responses of single cells to light bars of different orientation, direction of motion, speed, binocular disparity, and wavelength were systematically analyzed in areas V2 and VP of ventral extrastriate visual cortex in the macaque monkey. Selectivity for each of these parameters was assessed quantitatively using computer-controlled procedures. In both VP and V2 (both representing the superior contralateral quadrant), more than half of the cells studied were selective for stimulus color and more than half for stimulus orientation. In contrast, only a small minority of the VP and V2 cells were selective for the direction of stimulus motion. Comparison with reports of single-unit properties in dorsal extrastriate cortex suggests there are no major differences in the incidence of orientation, direction, and color selectivity between ventral and dorsal subdivisions of V2. Between V3 and VP, though, there are marked differences: Color-selective cells are much less common in V3 than VP, whereas direction-selective cells are more common in V3. This dorsoventral difference in the distribution of neuronal response properties suggests a significant asymmetry in the way visual information is processed in upper and lower parts of the visual field. The properties of cells in VP suggest that it plays an important role in both form and color vision, similar to that attributed to area V4.


Community-based field implementation scenarios of a short message service reporting tool for lymphatic filariasis case estimates in Africa and Asia.
Lymphatic filariasis (LF) is a neglected tropical disease (NTD) targeted for global elimination by 2020. Currently there is considerable international effort to scale-up morbidity management activities in endemic countries, however there remains a need for rapid, cost-effective methods and adaptable tools for obtaining estimates of people presenting with clinical manifestations of LF, namely lymphoedema and hydrocele. The mHealth tool 'MeasureSMS-Morbidity' allows health workers in endemic areas to use their own mobile phones to send clinical information in a simple format using short message service (SMS). The experience gained through programmatic use of the tool in five endemic countries across a diversity of settings in Africa and Asia is used here to present implementation scenarios that are suitable for adapting the tool for use in a range of different programmatic, endemic, demographic and health system settings. A checklist of five key factors and sub-questions was used to determine and define specific community-based field implementation scenarios for using the MeasureSMS-Morbidity tool in a range of settings. These factors included: (I) tool feasibility (acceptability; community access and ownership); (II) LF endemicity (high; low prevalence); (III) population demography (urban; rural); (IV) health system structure (human resources; community access); and (V) integration with other diseases (co-endemicity). Based on experiences in Bangladesh, Ethiopia, Malawi, Nepal and Tanzania, four implementation scenarios were identified as suitable for using the MeasureSMS-Morbidity tool for searching and reporting LF clinical case data across a range of programmatic, endemic, demographic and health system settings. These include: (I) urban, high endemic setting with two-tier reporting; (II) rural, high endemic setting with one-tier reporting; (III) rural, high endemic setting with two-tier reporting; and (IV) low-endemic, urban and rural setting with one-tier reporting. A decision-making framework built from the key factors and questions, and the resulting four implementation scenarios is proposed as a means of using the MeasureSMS-Morbidity tool. This framework will help national LF programmes consider appropriate methods to implement a survey using this tool to improve estimates of the clinical burden of LF. Obtaining LF case estimates is a vital step towards the elimination of LF as a public health problem in endemic countries.


How Should Autonomous Cars Drive? A Preference for Defaults in Moral Judgments Under Risk and Uncertainty.
Autonomous vehicles (AVs) promise to make traffic safer, but their societal integration poses ethical challenges. What behavior of AVs is morally acceptable in critical traffic situations when consequences are only probabilistically known (a situation of risk) or even unknown (a situation of uncertainty)? How do people retrospectively evaluate the behavior of an AV in situations in which a road user has been harmed? We addressed these questions in two empirical studies (N = 1,638) that approximated the real-world conditions under which AVs operate by varying the degree of risk and uncertainty of the situation. In Experiment 1, subjects learned that an AV had to decide between staying in the lane or swerving. Each action could lead to a collision with another road user, with some known or unknown likelihood. Subjects' decision preferences and moral judgments varied considerably with specified probabilities under risk, yet less so under uncertainty. The results suggest that staying in the lane and performing an emergency stop is considered a reasonable default, even when this action does not minimize expected loss. Experiment 2 demonstrated that if an AV collided with another road user, subjects' retrospective evaluations of the default action were also more robust against unwanted outcome and hindsight effects than the alternative swerve maneuver. The findings highlight the importance of investigating moral judgments under risk and uncertainty in order to develop policies that are societally acceptable even under critical conditions.


Parathyroid hormone and calcium are independently associated with subclinical vascular disease in a community-based cohort.
Diseases with abnormal levels of parathyroid hormone (PTH) and calcium, such as primary and secondary hyperparathyroidism, are associated with an increased risk of cardiovascular morbidity and mortality. However, there is paucity on the association between calcium, PTH and abnormalities in the vascular system in the general population. In the PIVUS study (Prospective Investigation of the Vasculature in Uppsala Seniors), a community based cohort of 70-year old men and women (n = 1016), the associations between s-calcium, p-PTH and endothelial function, arterial stiffness and blood pressures were investigated, adjusting for cardiovascular risk factors and mineral metabolism. In multivariable linear regression models 1 SD increase in calcium was associated with 1.1 units decrease in the stroke volume/pulse pressure ratio and 0.06 decrease in common carotid artery distensibility (p < 0.001) indicative of increased arterial stiffness. Further, calcium was associated with increasing calculated central pulse pressure with 1.3 mmHg elevation per 1 SD increase in calcium (p < 0.05). 1 SD increase in PTH was associated with 1.9 and 1.0 mmHg increase in intra-arterially measured brachial artery systolic and diastolic blood pressures, respectively (p < 0.01), as well as 1.6 and 0.9 mmHg increase in calculated central systolic and diastolic blood pressures (p < 0.05). PTH was not associated with arterial stiffness, endothelial function or pulse pressure. In a large community-based sample of elderly, calcium was independently associated with increased arterial stiffness, and PTH independently to intra-arterial peripheral and calculated central blood pressures. The findings indicate a possible link between the vasculature and mineral metabolism.


Residual stresses in colloidal gels.
A combination of experiments and Brownian Dynamics (BD) simulations is utilized to examine internal stresses in colloidal gels brought to rest from steady shear at different shear rates. A model colloidal gel with intermediate volume fraction is chosen where attractions between particles are introduced by adding non-adsorbing linear polymer chains. After flow cessation, the gel releases the stress in two distinct patterns: at high shear rates, where shear forces dominate over attractive forces, the shear-melted gel behaves as a liquid and releases stresses to zero after flow cessation. After low shear rates, though, stresses relax only partially, similar to the response of hard sphere glasses and jammed soft particles. The balance between shear and attractive forces which determines the intensity of structural distortion controls the amplitude of the residual stresses through a universal scaling. Stress decomposition to repulsive and attractive contributions in BD simulations reveals that internal stresses mainly originate from attractive forces. Moreover, analysis of particle dynamics indicates that internal stresses are associated with sub-diffusive particle displacements on average smaller than the attraction range as such short-range displacements are not sufficient to completely erase structural anisotropy caused during the course of shear.


Direct Mapping of Heterogeneous Surface Coverage in DNA-Functionalized Gold Surfaces with Correlated Electron and Fluorescence Microscopy.
The characterization of biofunctionalized surfaces such as alkanethiol self-assembled monolayers (SAMs) on gold modified with DNA or other biomolecules is a challenging analytical problem, and access to a routine method is desirable. Despite substantial investigation from structural and mechanistic perspectives, robust and high-throughput metrology tools for SAMs remain elusive but essential for the continued development of these devices. We demonstrate that scanning electron microscopy (SEM) can provide image contrast of the molecular interface during SAM functionalization. The high-speed, large magnification range, and ease of use make this widely available technique a powerful platform for measuring the structure and composition of SAM surfaces. This increased throughput allows for a better understanding of the nonideal spatial heterogeneity characteristic of SAMs utilized in real-world conditions. SEM image contrast is characterized through the use of fluorescently labeled DNA, which enables correlative SEM and fluorescence microscopy. This allows identification of the DNA-modified regions at resolutions that approach the size of the biomolecule. The effect of electron beam irradiation dose is explored, which leads to straightforward lithographic patterning of DNA SAMs with nanometer resolution and with control over the surface coverage of specifically adsorbed DNA.


Cultural safety--what does it mean for our work practice?
Culturally safe service delivery is critical in enhancing personal empowerment and, as a result, should promote more effective and meaningful pathways to self determination for Indigenous people. Little has been said about encouraging people from Indigenous groups into the health and education discipline(s) to help provide a safe environment which includes cultural safety. This is a phrase originally coined by Maori nurses which means that there is no assault on a person's identity. The people most able or equipped to provide a culturally safe atmosphere are people from the same culture. We need to move on from the 'short term, cost effective, quick fix' approach to Indigenous issues, driven by economic imperatives, the clamouring of industry and conservative, hegemonic practices. To genuinely address the challenges of Indigenous health and education, the issue of cultural safety cannot be avoided. Critical reflection on experiential knowledge and defining or framing a debate on cultural safety is essential. This paper briefly examines some considerations for work practice.


Parathyroid hormone and hydrochlorothiazide increase calcium transport by the luminal membrane of rabbit distal nephron segments through different pathways.
The present study was designed to investigate the effect of PTH on calcium (Ca2+) transport through the luminal membrane of proximal and distal rabbit tubule segments. Proximal tubule and distal tubule segment suspensions were incubated with the hormone, and the luminal membranes were subsequently purified. Incubation with 10(-8) M human PTH(1-34) strongly increased initial Ca2+ uptake by the distal membranes. The effect of PTH was dose dependent, with an apparent ED50 of 8.2 +/- 1.0 nM. We recently reported the presence of two kinetics of Ca2+ uptake by the distal luminal membranes. PTH affected exclusively the high affinity component, increasing the maximum velocity from 0.31 +/- 0.02 to 0.76 +/- 0.07 pmol/micrograms.10 sec (P < 0.001), and leaving the Michaelis-Menten constant Ca2+ unchanged. The addition of 500 microM hydrochlorothiazide (HCTZ) to the luminal membranes of distal tubules incubated with PTH further enhanced Ca2+ uptake. The effect of HCTZ was on the low affinity system. HCTZ (100 microM) enhanced the maximum velocity from 2.5 +/- 0.3 to 3.7 +/- 0.6 pmol/micrograms protein.10 sec (P < 0.01) without affecting the Michaelis-Menten constant. Whereas 1 microM nitrendipine alone did not affect Ca2+ transport by the distal tubule luminal membranes, the Ca2+ channel inhibitor completely abolished the effect of PTH. Conversely, 1 microM Bay K 8644 increased Ca2+ uptake by membranes from PTH-treated distal tubules but was ineffective in membranes from control tubules. Neither PTH nor nitrendipine nor Bay K 8644 had any effect on the luminal membranes from proximal tubules. These results suggest that: 1) the high affinity, low velocity Ca2+ transport system in the luminal membrane from distal cortical segments is sensitive to PTH; 2) the effects of nitrendipine and Bay K 8644 on Ca2+ uptake were observed only in membranes from tubules incubated with PTH; 3) this uptake is distinct from the thiazide-sensitive Ca2+ transport system; and 4) PTH does not influence Ca2+ transport by the luminal membrane of proximal tubules.


Leptin selectively decreases visceral adiposity and enhances insulin action.
Intraabdominal adiposity and insulin resistance are risk factors for diabetes mellitus, dyslipidemia, arteriosclerosis, and mortality. Leptin, a fat-derived protein encoded by the ob gene, has been postulated to be a sensor of energy storage in adipose tissue capable of mediating a feedback signal to sites involved in the regulation of energy homeostasis. Here, we provide evidence for specific effects of leptin on fat distribution and in vivo insulin action. Leptin (LEP) or vehicle (CON) was administered by osmotic minipumps for 8 d to pair-fed adult rats. During the 8 d of the study, body weight and total fat mass decreased similarly in LEP and in CON. However, while moderate calorie restriction (CON) resulted in similar decreases in whole body (by 20%) and visceral (by 21%) fat, leptin administration led to a specific and marked decrease (by 62%) in visceral adiposity. During physiologic hyperinsulinemia (insulin clamp), leptin markedly enhanced insulin action on both inhibition of hepatic glucose production and stimulation of glucose uptake. Finally, leptin exerted complex effects on the hepatic gene expression of key metabolic enzymes and on the intrahepatic partitioning of metabolic fluxes, which are likely to represent a defense against excessive storage of energy in adipose depots. These studies demonstrate novel actions of circulating leptin in the regulation of fat distribution, insulin action, and hepatic gene expression and suggest that it may play a role in the pathophysiology of abdominal obesity and insulin resistance.


In vivo study of breast carcinoma radiosensitization by targeting eIF4E.
Eukaryotic initiation factor eIF4E, an important regulator of translation, plays a crucial role in the malignant transformation, progression and radioresistance of many human solid tumors. The overexpression of this gene has been associated with tumor formation in a wide range of human malignancies, including breast cancer. In the present study, we attempted to explore the use of eIF4E as a therapeutic target to enhance radiosensitivity for breast carcinomas in a xenograft BALB/C mice model. Ninety female BALB/C mice transfected with EMT-6 cells were randomly divided into six groups: control, irradiation (IR), pSecX-t4EBP1, pSecX-t4EBP1+irradiation, pSecX and pSecX+irradiation. At the end of the experiments, all mice were sacrificed, the xenografts were harvested to measure the tumor volume and mass, and the tumor inhibition rates were calculated. Apoptosis was detected with a flow cytometric assay. Immunohistochemistry was used to detect the expression of HIF-1α. The xenografts in pSecX-t4EBP1 mice showed a significantly delayed growth and smaller tumor volume, with a higher tumor inhibition rate compared with the control and pSecX groups. A similar result was obtained in the pSecX-t4EBP1+IR group compared with IR alone and pSecX+irradiation. The expression of HIF-1α in the tumor cells was significantly decreased, while the apoptosis index was much higher. pSecX-t4EBP1 can significantly inhibit tumor growth and enhance the radiosensitivity of breast carcinoma xenografts in BALB/C mice. This is possibly associated with the downregulation of HIF-1α expression, which suggests that pSecX-t4EBP1 may serve as an ideal molecular target for the radiosensitization of breast carcinoma.


The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity.
Parkinson's disease (PD) is the most common motor disorder affecting the elderly. PD is characterized by the formation of Lewy bodies and death of dopaminergic neurons. The mechanisms underlying PD are unknown, but the discoveries that mutations in alpha-synuclein can cause familial PD and that alpha-synuclein accumulates in Lewy bodies suggest that alpha-synuclein participates in the pathophysiology of PD. Using human BE-M17 neuroblastoma cells overexpressing wild-type, A53T, or A30P alpha-synuclein, we now show that iron and free radical generators, such as dopamine or hydrogen peroxide, stimulate the production of intracellular aggregates that contain alpha-synuclein and ubiquitin. The aggregates can be identified by immunocytochemistry, electron microscopy, or the histochemical stain thioflavine S. The amount of aggregation occurring in the cells is dependent on the amount of alpha-synuclein expressed and the type of alpha-synuclein expressed, with the amount of alpha-synuclein aggregation following a rank order of A53T > A30P > wild-type > untransfected. In addition to stimulating aggregate formation, alpha-synuclein also appears to induce toxicity. BE-M17 neuroblastoma cells overexpressing alpha-synuclein show up to a fourfold increase in vulnerability to toxicity induced by iron. The vulnerability follows the same rank order as for aggregation. These data raise the possibility that alpha-synuclein acts in concert with iron and dopamine to induce formation of Lewy body pathology in PD and cell death in PD.


"I Have Guys Call Me and Say 'I Can't Be the Victim of Domestic Abuse'": Exploring the Experiences of Telephone Support Providers for Male Victims of Domestic Violence and Abuse.
While previous studies have begun to provide evidence on the experiences of male victims of domestic violence and abuse (DVA), current understanding in this area is still limited, and subject to narrow methods of inquiry. Moreover, little is known regarding the challenges of providing support to men in abusive relationships, and how barriers to effective service engagement are experienced by both men and service practitioners. This is an important area for exploration, as the gender-specific experiences and needs of men have been historically overlooked within academic research and service provision. The present study therefore had two principal aims: first, to provide more detailed information regarding the nature and context of abuse toward, and help-seeking experiences of, male victims, and second, to explore the experiences of those supporting abused men. Semi-structured interviews were conducted with four call handlers at a U.K. domestic abuse charity supporting male victims. Transcribed interviews were subjected to thematic analysis, revealing a superordinate theme of stereotypes and expectations of men which affected all the other three overarching and eight subthemes, including those detailing the range and severity of abuse suffered, the role of family and friends, barriers to reporting for abused men, and challenges in supporting them. Implications for services working with male victims of DVA are discussed: centered around the need for recognition, increased awareness, increased resourcing, and the provision of gender-inclusive services catering for the gender-specific needs of men.


Advanced Imaging Adds Little Value in the Diagnosis of Femoroacetabular Impingement Syndrome.
Femoroacetabular impingement (FAI) syndrome is an increasingly recognized source of hip pain and disability in young active adults. In order to confirm the diagnosis, providers often supplement physical examination maneuvers and radiographs with intra-articular hip injection, magnetic resonance imaging (MRI), or magnetic resonance arthrography (MRA). Since diagnostic imaging represents the fastest rising cost segment in U.S. health care, there is a need for value-driven diagnostic algorithms. The purpose of this study was to identify cost-effective diagnostic strategies for symptomatic FAI, comparing history and physical examination (H&P) alone (utilizing only radiographic imaging) with supplementation with injection, MRI, or MRA. A simple-chain decision model run as a cost-utility analysis was constructed to assess the diagnostic value of the MRI, MRA, and injection that are added to the H&P and radiographs in diagnosing symptomatic FAI. Strategies were compared using the incremental cost-utility ratio (ICUR) with a willingness to pay (WTP) of $100,000/QALY (quality-adjusted life year). Direct costs were measured using the Humana database (PearlDiver). Diagnostic test accuracy, treatment outcome probabilities, and utilities were extracted from the literature. H&P with and without supplemental diagnostic injection was the most cost-effective. Adjunct injection was preferred in situations with a WTP of >$60,000/QALY, low examination sensitivity, and high FAI prevalence. With low disease prevalence and low examination sensitivity, as may occur in a general practitioner's office, H&P with injection was the most cost-effective strategy, whereas in the reciprocal scenario, H&P with injection was only favored at exceptionally high WTP (∼$990,000). H&P and radiographs with supplemental diagnostic injection are preferred over advanced imaging, even with reasonable deviations from published values of disease prevalence, test sensitivity, and test specificity. Providers with low examination sensitivity in situations with low disease prevalence may benefit most from including injection in their diagnostic strategy. Providers with high examination sensitivity in situations with high disease prevalence may not benefit from including injection in their diagnostic strategy. Providers should not routinely rely on advanced imaging to diagnose FAI syndrome, although advanced imaging may have a role in challenging clinical scenarios. Economic and Decision Analysis Level IV. See Instructions for Authors for a complete description of levels of evidence.


A coarsened multinomial regression model for perinatal mother to child transmission of HIV.
In trials designed to estimate rates of perinatal mother to child transmission of HIV, HIV assays are scheduled at multiple points in time. Still, infection status for some infants at some time points may be unknown, particularly when interim analyses are conducted. Logistic regression models are commonly used to estimate covariate-adjusted transmission rates, but their methods for handling missing data may be inadequate. Here we propose using coarsened multinomial regression models to estimate cumulative and conditional rates of HIV transmission. Through simulation, we compare the proposed models to standard logistic models in terms of bias, mean squared error, coverage probability, and power. We consider a range of treatment effect and visit process scenarios, while including imperfect sensitivity of the assay and contamination of the endpoint due to early breastfeeding transmission. We illustrate the approach through analysis of data from a clinical trial designed to prevent perinatal transmission. The proposed cumulative and conditional models performed well when compared to their logistic counterparts. Performance of the proposed cumulative model was particularly strong under scenarios where treatment was assumed to increase the risk of in utero transmission but decrease the risk of intrapartum and overall perinatal transmission and under scenarios designed to represent interim analyses. Power to estimate intrapartum and perinatal transmission was consistently higher for the proposed models. Coarsened multinomial regression models are preferred to standard logistic models for estimation of perinatal mother to child transmission of HIV, particularly when assays are missing or occur off-schedule for some infants.


Howler monkey foraging ecology suggests convergent evolution of routine trichromacy as an adaptation for folivory.
Primates possess remarkably variable color vision, and the ecological and social factors shaping this variation remain heavily debated. Here, we test whether central tenants of the folivory hypothesis of routine trichromacy hold for the foraging ecology of howler monkeys. Howler monkeys (genus Alouatta) and paleotropical primates (Parvorder: Catarrhini) have independently acquired routine trichromacy through fixation of distinct mid- to long-wavelength-sensitive (M/LWS) opsin genes on the X-chromosome. The presence of routine trichromacy in howlers, while other diurnal neotropical monkeys (Platyrrhini) possess polymorphic trichromacy, is poorly understood. A selective force proposed to explain the evolution of routine trichromacy in catarrhines-reliance on young, red leaves-has received scant attention in howlers, a gap we fill in this study. We recorded diet, sequenced M/LWS opsin genes in four social groups of Alouatta palliata, and conducted colorimetric analysis of leaves consumed in Sector Santa Rosa, Costa Rica. For a majority of food species, including Ficus trees, an important resource year-round, young leaves were more chromatically conspicuous from mature leaves to trichromatic than to hypothetical dichromatic phenotypes. We found that 18% of opsin genes were MWS/LWS hybrids; when combined with previous research, the incidence of hybrid M/LWS opsins in this species is 13%. In visual models of food discrimination ability, the hybrid trichromatic phenotype performed slightly poorer than normal trichromacy, but substantially better than dichromacy. Our results provide support for the folivory hypothesis of routine trichromacy. Similar ecological pressures, that is, the search for young, reddish leaves, may have driven the independent evolution of routine trichromacy in primates on separate continents. We discuss our results in the context of balancing selection acting on New World monkey opsin genes and hypothesize that howlers experience stronger selection against dichromatic phenotypes than other sympatric species, which rely more heavily on cryptic foods.


MONTE: An automated Monte Carlo based approach to nuclear magnetic resonance assignment of proteins.
A general-purpose Monte Carlo assignment program has been developed to aid in the assignment of NMR resonances from proteins. By virtue of its flexible data requirements the program is capable of obtaining assignments of both heavily deuterated and fully protonated proteins. A wide variety of source data, such as inter-residue scalar connectivity, inter-residue dipolar (NOE) connectivity, and residue specific information, can be utilized in the assignment process. The program can also use known assignments from one form of a protein to facilitate the assignment of another form of the protein. This attribute is useful for assigning protein-ligand complexes when the assignments of the unliganded protein are known. The program can be also be used as an interactive research tool to assist in the choice of additional experimental data to facilitate completion of assignments. The assignment of a deuterated 45 kDa homodimeric Glutathione-S-transferase illustrates the principal features of the program.


Initial endoscopy or empirical therapy with or without testing for Helicobacter pylori for dyspepsia: a decision analysis.
Empirical therapy has been proposed for initial management of dyspepsia. The aim of this study was to evaluate initial endoscopy, empirical therapy, and testing for Helicobacter pylori in the management of patients with a new onset of dyspepsia. Decision analysis was used to compare the direct medical charges in the first year after the onset of dyspepsia for patients managed by initial endoscopy or empirical therapy, with or without initial testing for H. pylori. Medical care charges were $2162.50 for initial endoscopy and $2122.60 for empirical therapy, a difference of 1.8%. For a 55-year-old adult, life expectancy was 23.49 years for initial endoscopy compared with 23.48 years for empirical therapy. Empirical therapy has lower charges than initial endoscopy when H2-receptor antagonists are used to prevent recurrence of dyspepsia. Initial noninvasive testing for H. pylori has lower charges than initial endoscopy if patients with dyspepsia with H. pylori receive antimicrobial therapy without endoscopy but would have higher charges if patients with H. pylori routinely have endoscopy. Surprisingly, the choice of optimal management strategy was a "toss-up." Only modest savings may result from practice guidelines that recommend empirical therapy in the management of patients with dyspepsia.


Familial correlation of dietary intakes among postmenopausal women.
A positive family history is a risk factor for many chronic diseases, including most cancers, coronary heart disease, and diabetes. Since diet is also associated with most chronic diseases, one possible explanation for non-Mendelian familial clustering is shared eating habits. Food frequency data were obtained on 3,515 sisters in the Iowa Women's Health Study, a prospective cohort of postmenopausal women. Intraclass correlations between sisters were computed on a range of energy-adjusted nutrients to determine whether dietary intakes were more similar among siblings than among unrelated individuals. Two methods were used to calculate correlations: analysis of variance modeling and weighted sibling correlations. F-tests and randomization tests were used to determine statistical significance. The intraclass correlations for all of the nutrients examined were statistically significantly greater than the hypothesized value of zero (P < 0.05). Representative correlations include dietary fiber (0.15), animal fat (0.12), vegetable fat (0.13), calcium (0.14), iron (0.04), cholesterol (0.08), sodium (0.10), vitamin D (0.16), and total energy intake (0.11). When corrected for measurement error, the magnitude of these correlations increased, on average 62%. Although modest in magnitude, these correlations may be high enough to influence familial clustering of complex diseases that are attributed, in part, to diet.


Individual and developmental differences in semantic priming: empirical and computational support for a single-mechanism account of lexical processing.
Existing accounts of single-word semantic priming phenomena incorporate multiple mechanisms, such as spreading activation, expectancy-based processes, and postlexical semantic matching. The authors provide empirical and computational support for a single-mechanism distributed network account. Previous studies have found greater semantic priming for low- than for high-frequency target words as well as inhibition following unrelated primes only at long stimulus-onset asynchronies (SOAs). A series of experiments examined the modulation of these effects by individual differences in age or perceptual ability. Third-grade, 6th-grade, and college students performed a lexical-decision task on high- and low-frequency target words preceded by related, unrelated, and nonword primes. Greater priming for low-frequency targets was exhibited only by participants with high perceptual ability. Moreover, unlike the college students, the children showed no inhibition even at the long SOA. The authors provide an account of these results in terms of the properties of distributed network models and support this account with an explicit computational simulation.


A highly sensitive and flexible pressure sensor with electrodes and elastomeric interlayer containing silver nanowires.
The next-generation application of pressure sensors is gradually being extended to include electronic artificial skin (e-skin), wearable devices, humanoid robotics and smart prosthetics. In these advanced applications, high sensing capability is an essential feature for high performance. Although surface patterning treatments and some special elastomeric interlayers have been applied to improve sensitivity, the process is complex and this inevitably raises the cost and is an obstacle to large-scale production. In the present study a simple printing process without complex patterning has been used for constructing the sensor, and an interlayer is employed comprising elastomeric composites filled with silver nanowires. By increasing the relative permittivity, εr, of the composite interlayer induced by compression at high nanowire concentration, it has been possible to achieve a maximum sensitivity of 5.54 kPa(-1). The improvement in sensitivity did not sacrifice or undermine the other features of the sensor. Thanks to the silver nanowire electrodes, the sensor is flexible and stable after 200 cycles at a bending radius of 2 mm, and exhibits outstanding reproducibility without hysteresis under similar pressure pulses. The sensor has been readily integrated onto an adhesive bandage and has been successful in detecting human movements. In addition to measuring pressure in direct contact, non-contact pressures such as air flow can also be detected.


d- chiro-Inositol Ameliorates High Fat Diet-Induced Hepatic Steatosis and Insulin Resistance via PKCε-PI3K/AKT Pathway.
d- chiro-Inositol (DCI) is a biologically active component found in tartary buckwheat, which can reduce hyperglycemia and ameliorate insulin resistance. However, the mechanism underlying the antidiabetic effects of DCI remains largely unclear. This study investigated the effects and underlying molecular mechanisms of DCI on hepatic gluconeogenesis in mice fed a high fat diet and saturated palmitic acid-treated hepatocytes. DCI attenuated free fatty acid uptake by the liver via lipid trafficking inhibition, reduced diacylglycerol deposition, and hepatic PKCε translocation. Thus, DCI could improve insulin sensitivity by suppressing hepatic gluconeogenesis. Subsequent analyses revealed that DCI decreased hepatic glucose output and the expression levels of PEPCK and G6 Pase in insulin resistant mice through PKCε-IRS/PI3K/AKT signaling pathway. Likewise, such effects of DCI were confirmed in HepG2 cells with palmitate-induced insulin resistance. These findings indicate a novel pathway by which DCI prevents hepatic gluconeogenesis, reduces lipid deposition, and ameliorates insulin resistance via regulation of PKCε-PI3K/AKT axis.


Three-Dimensional Bioprinting of Functional Skeletal Muscle Tissue Using GelatinMethacryloyl-Alginate Bioinks.
Skeletal muscle tissue engineering aims to fabricate tissue constructs to replace or restore diseased or injured skeletal muscle tissues in the body. Several biomaterials and microscale technologies have been used in muscle tissue engineering. However, it is still challenging to mimic the function and structure of the native muscle tissues. Three-dimensional (3D) bioprinting is a powerful tool to mimic the hierarchical structure of native tissues. Here, 3D bioprinting was used to fabricate tissue constructs using gelatin methacryloyl (GelMA)-alginate bioinks. Mechanical and rheological properties of GelMA-alginate hydrogels were characterized. C2C12 myoblasts at the density 8 × 106 cells/mL were used as the cell model. The effects of alginate concentration (0, 6, and 8% (w/v)) and crosslinking mechanism (UV crosslinking or ionic crosslinking with UV crosslinking) on printability, cell viability, proliferation, and differentiation of bioinks were studied. The results showed that 10% (w/v) GelMA-8% (w/v) alginate crosslinked using UV light and 0.1 M CaCl2 provided the optimum niche to induce muscle tissue formation compared to other hydrogel compositions. Furthermore, metabolic activity of cells in GelMA bioinks was improved by addition of oxygen-generating particles to the bioinks. It is hoped that such bioprinted muscle tissues may find wide applications in drug screening and tissue regeneration.


CDKN2B-AS1 genotype-glaucoma feature correlations in primary open-angle glaucoma patients from the United States.
To assess the association between single nucleotide polymorphisms (SNPs) of the gene region containing cyclin-dependent kinase inhibitor 2B antisense noncoding RNA (CDKN2B-AS1) and glaucoma features among primary open-angle glaucoma (POAG) patients. Retrospective observational case series. We studied associations between 10 CDKN2B-AS1 SNPs and glaucoma features among 976 POAG cases from the Glaucoma Genes and Environment (GLAUGEN) study and 1971 cases from the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium. For each patient, we chose the feature from the eye with the higher value. We created cohort-specific multivariable models for glaucoma features and then meta-analyzed the results. For 9 of the 10 protective CDKN2B-AS1 SNPs with minor alleles associated with reduced disease risk (eg, the G allele at rs2157719), POAG patients carrying these minor alleles had smaller cup-to-disc ratio (0.05 units smaller per G allele at diagnosis; 95% CI: -0.08, -0.03; P = 6.23E-05) despite having higher intraocular pressure (IOP) (0.70 mm Hg higher per G allele at DNA collection; 95% CI: 0.40, 1.00; P = 5.45E-06). For the 1 adverse rs3217992 SNP with minor allele A associated with increased disease risk, POAG patients with A alleles had larger cup-to-disc ratio (0.05 units larger per A allele at diagnosis; 95% CI: 0.02, 0.07; P = 4.74E-04) despite having lower IOP (-0.57 mm Hg per A allele at DNA collection; 95% CI: -0.84, -0.29; P = 6.55E-05). Alleles of CDKN2B-AS1 SNPs, which influence risk of developing POAG, also modulate optic nerve degeneration among POAG patients, underscoring the role of CDKN2B-AS1 in POAG.


A novel synthetic approach of cerium oxide nanoparticles with improved biomedical activity.
Cerium oxide nanoparticles (CNPs) are novel synthetic antioxidant agents proposed for treating oxidative stress-related diseases. The synthesis of high-quality CNPs for biomedical applications remains a challenging task. A major concern for a safe use of CNPs as pharmacological agents is their tendency to agglomerate. Herein we present a simple direct precipitation approach, exploiting ethylene glycol as synthesis co-factor, to synthesize at room temperature nanocrystalline sub-10 nm CNPs, followed by a surface silanization approach to improve nanoparticle dispersibility in biological fluids. CNPs were characterized using transmission electron microscopy (TEM) observations, X-ray diffraction (XRD) analysis, thermogravimetric analysis (TGA), Fourier-transform infrared (FT-IR) spectroscopy, proton nuclear magnetic resonance (1H-NMR) spectroscopy, dynamic light scattering (DLS) and zeta potential measurements. CNP redox activity was studied in abiotic systems using electron spin resonance (ESR) measurements, and in vitro on human cell models. In-situ silanization improved CNP colloidal stability, in comparison with non-functionalized particles, and allowed at the same time improving their original biological activity, yielding thus functionalized CNPs suitable for biomedical applications.


Simulation of scenarios of oil droplet formation from the Deepwater Horizon blowout.
Knowledge of the droplet size distribution (DSD) from the Deepwater Horizon (DWH) blowout is an important step in predicting the fate and transport of the released oil. Due to the absence of measurements of the DSD from the DWH incident, we considered herein hypothetical scenarios of releases that explore the realistic parameter space using a thoroughly calibrated DSD model, VDROP-J, and we attempted to provide bounds on the range of droplet sizes from the DWH blowout within 200 m of the wellhead. The scenarios include conditions without and with the presence of dispersants, different dispersant treatment efficiencies, live oil and dead oil properties, and varying oil flow rate, gas flow rate, and orifice diameter. The results, especially for dispersant-treated oil, are very different from recent modeling studies in the literature.


Resources for genetic and genomic studies of Xenopus.
The National Institutes of Health Xenopus Initiative is a concerted effort to interact with the Xenopus research community to identify the community's needs; to devise strategies to meet those needs; and to support, oversee, and coordinate the resulting projects. This chapter provides a brief description of several genetic and genomic resources generated by this initiative and explains how to access them. The resources described in this chapter are (1) complementary deoxyribonucleic acid (cDNA) libraries and expressed sequence tag (EST) sequences; (2) UniGene clusters; (3) full-insert cDNA sequences; (4) a genetic map; (5) genomic libraries; (6) a physical map; (7) genome sequence; (8) microarrays; (9) mutagenesis and phenotyping; and (10) bioinformatics. The descriptions presented here were based on data that were available at the time of manuscript submission. Because these are ongoing projects, they are constantly generating new data and analyses. The Web sites cited in each subheading present current data and analyses.


Nitric oxide synthase gene therapy rapidly reduces adhesion molecule expression and inflammatory cell infiltration in carotid arteries of cholesterol-fed rabbits.
Hypercholesterolemia reduces nitric oxide bioavailability, manifested by reduced endothelium-dependent vascular relaxation, and also induces vascular adhesion molecule expression and inflammatory cell infiltration. We have previously shown that gene therapy with NO synthase in hypercholesterolemic rabbits substantially reverses the deficit in vascular relaxation. In the present study, we show that NO synthase gene therapy rapidly and substantially reduces vascular adhesion molecule expression, lipid deposition, and inflammatory cell infiltration. Thirty male New Zealand White rabbits were maintained on a 1% cholesterol diet for 11 to 13 weeks, then underwent carotid artery gene transfer with Ad.nNOS or Ad.betaGal (recombinant adenoviruses expressing neuronal NO synthase or beta-galactosidase, respectively), or received medium alone in a sham procedure. Arteries were harvested at 1 and 3 days after gene transfer, and the following parameters were determined by immunohistochemical and image-analysis techniques: intercellular adhesion molecule-1, vascular cell adhesion molecule-1, lipid deposition by oil red O staining, lymphocyte infiltration (CD43-positive cells), and monocyte infiltration (RAM-11-positive cells). In Ad.nNOS-treated arteries, all markers were significantly decreased relative to Ad. betaGal or sham-treated arteries within 3 days after gene transfer. Ad.nNOS had a particularly striking impact on monocyte infiltration; as early as 24 hours after gene transfer, Ad.nNOS-treated arteries had >3-fold fewer monocytes than Ad.betaGal- or sham-treated arteries. NO synthase gene therapy rapidly ameliorates several markers of atherosclerosis in the cholesterol-fed rabbit.


Sex Differences in the Sympathetic Neural Recruitment and Hemodynamic Response to Head-Up Tilt in Older Hypertensives.
This study tested the hypothesis that older hypertensive women display augmented pressor responses and aberrant sympathetic neural discharge patterning in response to orthostatic stress versus older hypertensive men. We evaluated, in older hypertensive and normotensive men and women (n=12 each group), blood pressure, heart rate, cardiac index (acetylene rebreathing), total peripheral resistance, and muscle sympathetic nerve activity (microneurography) at baseline (supine; 3 minutes) and during graded head-up tilt (30° for 5 minutes and 60° for 20 minutes). Sympathetic action potential discharge patterns were studied using wavelet-based methodology. In the upright posture, systolic and diastolic blood pressure responses were greater in hypertensive women versus hypertensive men and normotensive women (P<0.05). No differences existed in the heart rate, stroke index, or cardiac index response between groups; however, the total peripheral resistance response throughout graded head-up tilt was markedly greater in hypertensive women (P<0.01). Yet, the increase in integrated muscle sympathetic nerve activity burst frequency and burst incidence were similar between hypertensive women and men in the supine and upright postures. However, the increase in the mean action potential content per integrated burst and recruitment of previously dormant, larger-sized action potentials during 60° head-up tilt was greater in hypertensive women versus hypertensive men and normotensive women (P<0.001). Therefore, total sympathetic action potential firing frequency was markedly greater in hypertensive women throughout 60° head-up tilt (P<0.001). In conclusion, older hypertensive women displayed exaggerated pressor and peripheral vasoconstrictor responses to orthostasis versus hypertensive men, under conditions of augmented and aberrant sympathetic neural recruitment, rather than increased burst frequency, in the upright posture.


Associations between neuromuscular function and levels of physical activity differ for boys and girls during puberty.
To compare the associations between neuromuscular performance and anthropometric characteristics with habitual levels of physical activity in boys and girls during the initial stages of puberty. In a cross-sectional study of 72 healthy children (39 boys and 33 girls) ranging in age from 8 to 14 years, sex differences in anthropometric and motor performance characteristics were compared at 3 Tanner stages (T1-T3). Outcome variables included dual-energy x-ray absorptiometry measurements of body composition, assessments of neuromuscular function, and levels of physical activity (steps/day) measured by accelerometry. Physical activity was lower in girls than boys at T2 and T3, but there was no sex difference at T1. Physical activity increased with Tanner stage for boys but did not differ between Tanner stages in girls. Physical activity at each Tanner stage was strongly associated (R(2) > 0.85) with neuromuscular characteristics for both boys and girls, but percentage of body fat also was associated with physical activity for T3 girls. The attenuated gains in neuromuscular function experienced by girls in early stages of puberty were strongly associated with lower levels of physical activity, whereas the increase in physical activity exhibited by boys was mostly related to increases in the strength and endurance of leg muscles. Because sedentary activity is a known contributor to the development of obesity and type 2 diabetes in youth, this study helps to identify possible contributors to decreases in physical activity in young girls and provides potential targets for early intervention.


Aberrant structures of fecal bacterial community in allergic infants profiled by 16S rRNA gene pyrosequencing.
We investigated the correlation between fecal bacteria composition in early infancy and the prevalence of allergic diseases in late infancy. The fecal microbiota in the first 2 months was profiled using the 16S rRNA V6 short-tag sequences in the community and statistically compared between two groups of subjects who did and did not show allergic symptoms in the first 2 years (n = 11 vs. 11). In the allergic group, genus Bacteroides at 1 month and genera Propionibacterium and Klebsiella at 2 months were more abundant, and genera Acinetobacter and Clostridium at 1 month were less abundant than in the nonallergic group. Allergic infants who showed high colonization of Bacteroides and/or Klebsiella showed less colonization of Clostridium perfringens/butyricum, suggesting antagonism between these bacterial groups in the gastrointestinal tract. It was also remarkable that the relative abundance of total Proteobacteria, excluding genus Klebsiella, was significantly lower in the allergic than in the nonallergic group at the age of 1 month. These results indicate that pyrosequence-based 16S rRNA gene profiling is valid to find the intestinal microbiotal disorder that correlates with allergy development in later life.


Nasal delivery of chitosan/alginate nanoparticle encapsulated bee (Apis mellifera) venom promotes antibody production and viral clearance during porcine reproductive and respiratory syndrome virus infection by modulating T cell related responses.
In this study, we administered specially developed chitosan/alginate nanoparticle encapsulated BV (CH/AL-BV) which has slow-releasing properties and mucosal adhesiveness to pig via nasal route and evaluate whether it can facilitate systemic immune response and improve clearance of porcine reproductive and respiratory syndrome virus (PRRSV). The CH/AL-BV-administered group with PRRSV vaccination showed significantly enhanced Th1-related responses including a high population of CD4+ T lymphocyte and cytokine mRNA levels including interferon-gamma (IFN-γ) and interleukin (IL)-12 and increased PRRSV-specific IgG levels. In the PRRSV challenge experiment, the CH/AL-BV group showed a significant decrease of viral burden in the sera and tissues (lung and bronchial lymph node) and mild interstitial pneumonia signs on both lung gross examination and microscopic evaluation with high levels of PRRSV-specific IgG and viral neutralizing antibody. CH/AL-BV also effectively induced not only Th1-related immune responses including increase in portion of CD4+ T lymphocyte, cytokines (IFN-γ and IL-12), and transcriptional factors (STAT4 and T-bet), but also stimulated IFN-γ-secreting cell families such as CD4+ T lymphocytes and Th/memory cells. Interestingly, the CH/AL-BV group showed decrease in PRRSV-specific immune-suppressive actions, including the T regulatory cell population and its related cytokines (IL-10 and TGF-β) and transcriptional factors (STAT5 and Foxp3). Therefore, nasal-delivered CH/AL-BV may effectively induce non-specific immune stimulating actions, particularly those related to Th1 responses and viral clearance activities against PRRSV infection. Based on these results, CH/AL-BV could be a promising strategy for overcoming the disadvantages of classical PRRSV vaccination and can be applied as a preventive agent against PRRSV and other viral diseases, particularly those with immune-suppressive characteristics.


Protein folding in the central cavity of the GroEL-GroES chaperonin complex.
The chaperonin GroEL is able to mediate protein folding in its central cavity. GroEL-bound dihydrofolate reductase assumes its native conformation when the GroES cofactor caps one end of the GroEL cylinder, thereby discharging the unfolded polypeptide into an enclosed cage. Folded dihydrofolate reductase emerges upon ATP-dependent GroES release. Other proteins, such as rhodanese, may leave GroEL after having attained a conformation that is committed to fold. Incompletely folded polypeptide rebinds to GroEL, resulting in structural rearrangement for another folding trial in the chaperonin cavity.


Design of an all-optical fractional-order differentiator with terahertz bandwidth based on a fiber Bragg grating in transmission.
All-optical fractional-order temporal differentiators with bandwidths reaching terahertz (THz) values are demonstrated with transmissive fiber Bragg gratings. Since the designed fractional-order differentiator is a minimum phase function, the reflective phase of the designed function can be chosen arbitrarily. As examples, we first design several 0.5th-order differentiators with bandwidths reaching the THz range for comparison. The reflective phases of the 0.5th-order differentiators are chosen to be linear phase, quadratic phase, cubic phase, and biquadratic phase, respectively. We find that both the maximum coupling coefficient and the spatial resolution of the designed grating increase when the reflective phase varies from quadratic function to cubic function to biquadratic function. Furthermore, when the reflective phase is chosen to be a quadratic function, the obtained grating coupling coefficient and period are more likely to be achieved in practice. Then we design fractional-order differentiators with different orders when the reflective phase is chosen to be a quadratic function. We see that when the designed order of the differentiator increases, the obtained maximum coupling coefficient also increases while the oscillation of the coupling coefficient decreases. Finally, we give the numerical performance of the designed 0.5th-order differentiator by showing its temporal response and calculating its cross-correlation coefficient.


Vocabulary Acquisition and Usage for Late Talkers: The Feasibility of a Caregiver-Implemented Telehealth Model.
This feasibility study examined a caregiver-implemented telehealth model of the Vocabulary Acquisition and Usage for Late Talkers (VAULT) protocol. We asked whether caregivers could reach fidelity on VAULT, if the protocol was socially and ecologically valid, and if late-talking toddlers could learn new words with this model. Five late-talking monolingual and bilingual toddlers and four caregivers participated. The caregiver-related research questions involved measurements taken at multiple time points and replication across subjects but did not follow a specific research design. The toddler-related research questions included elements of a single-case design. Caregivers completed self-paced online training modules and then provided 8 weeks of VAULT to their children with remote coaching. Fidelity data were collected during coached sessions and through rating scales. Social and ecological validity data were collected via surveys and interviews. Children's word learning was measured before, during, and after treatment via production of targets and controls and via standardized vocabulary inventories. Caregivers demonstrated high fidelity to VAULT throughout treatment. They reported being comfortable with many aspects of VAULT. Feedback was mixed regarding the time required. Many reported their child was talking more as a result of the program. Visual analysis revealed that toddlers learned more target than control words, which was corroborated by Tau-U and d effect size analyses. A caregiver-implemented telehealth model of VAULT was feasible, was socially and ecologically valid, and benefited toddlers, making this a worthwhile model for future studies to examine. https://doi.org/10.23641/asha.21753872.


Does inhaled salbutamol before surfactant therapy have any beneficial effect?
Çelik HT, Yurdakök M, Korkmaz A, Yiğit Ş. Does inhaled salbutamol before surfactant therapy have any beneficial effect? Turk J Pediatr 2018; 60: 669-674. Beta (β)2 adrenergic receptors are present in alveolar type II cells. Previously, the beneficial effects of inhaled salbutamol treatment on respiratory outcomes were shown in premature infants with transient tachypnea of the newborn. We hypothesized that inhaled salbutamol would increase the effects of surfactant on oxygenation in premature infants with respiratory distress syndrome (RDS). Inhaled salbutamol (0.15 mg/kg) or normal saline solution (0.30 ml/ kg) was administered as a single dose by micropump nebulizer 10 minutes before the first dose of surfactant (Poractant alfa) treatment in 40 infants with gestational ages ranging from 26 to 36 weeks. The effects of salbutamol therapy were evaluated by determining the duration of respiratory support, number of doses of surfactant, respiratory rate, heart rate, fraction of inspired oxygen, and partial pressure of arterial oxygen before and after salbutamol nebulization. No statistically significant difference was detected between the two groups in duration of respiratory support, number of doses of surfactant, respiratory rate, fraction of inspired oxygen, or partial pressure of arterial oxygen. In this study, no significant effect of inhaled salbutamol treatment on the surfactant therapy in premature infants with RDS was detected.


IL-38 overexpression induces anti-inflammatory effects in mice arthritis models and in human macrophages in vitro.
Interleukin (IL)-38 is a newly characterised cytokine that belongs to the IL-1 family. This cytokine is expressed in the rheumatoid arthritis (RA) synovial tissue and IL-38 deficient mice have exacerbated arthritis. Here, we analysed the effect of IL-38 overexpression in the joints of arthritic mice, in human macrophages and synovial fibroblasts in vitro. Articular injections of an adeno-associated virus (AAV) 2/8 encoding IL-38 were performed in collagen-induced arthritis (CIA), K/BxN serum transfer-induced arthritis (STIA) and antigen-induced arthritis (AIA) in mice. The effect of IL-38 overexpression was evaluated through clinical scores, immunohistochemistry, microCT, Luminex and RT-qPCR analysis. THP-1 macrophages were transduced with a lentiviral vector to overexpress IL-38. Clinical inflammatory scores were significantly decreased after AAV IL-38 injection in joints of mice with CIA and STIA, but not AIA. This decrease was accompanied by reduced macrophage infiltration and a decreased expression of Th17 cytokines (IL-17, IL-23, IL-22) and TNFα. However, IL-38 overexpression had no effect on cartilage or bone destruction. In vitro, the THP-1 monocytic cell line expressed less IL-6, TNFα and IL-23 after IL-38 overexpression. Conditioned media from these cells, containing released IL-38, also exert an anti-inflammatory effect on human primary macrophages and synovial fibroblasts from patients with RA. This study shows for the first time that IL-38 overexpression attenuates the severity of experimental arthritis. IL-38 may exert its anti-inflammatory effects by decreasing the production of proinflammatory cytokines by macrophages and synovial fibroblasts. This effect can lead to the development of novel treatment strategies in arthritis.


New direct-acting antivirals' combination for the treatment of chronic hepatitis C.
Chronic hepatitis C is one of the leading causes of chronic liver disease, with approximately 170 million people infected worldwide. The severity of disease varies from asymptomatic chronic infection to cirrhosis and hepatocellular carcinoma (HCC). Sustained virological response (SVR) is long lasting, associated with a reduced risk of cirrhosis and HCC. In the near future, standard of care (SOC) treatment of hepatitis C virus (HCV) will include the addition of direct-acting antivirals (DAAs) with a protease inhibitor to the pegylated interferon (PEG-IFN) plus ribavirin (RBV). In HCV genotype 1 patients, promising results have been reported when the protease inhibitor telaprevir or boceprevir is added to the SOC, increasing SVR rates from less than 50% (PEG-IFN plus RBV) to 70% (in patients treated with a triple combination of PEG-IFN, RBV plus a protease inhibitor). The future management of patients with these new molecules will require good clinical practice, knowledge of indications, prediction of side effects and monitoring for antiviral resistance. Certain major medical needs are still unmet, requiring studies in special populations (human immunodeficiency virus-HCV-coinfected patients, transplanted patients, etc.) in genotype non-1 patients and in absolute non-responders. Combinations of antivirals with additive potency that lack cross resistance and with a good safety profile may provide new regimens in the future to make HCV the first chronic viral infection eradicated worldwide with a finite duration of combination DAA therapy without IFN. There is ongoing development of new molecules such as HCV enzyme inhibitors. The aim of this review is to summarize the results obtained with DAAs: protease and polymerase inhibitors.


Vibration monitoring by using a dynamic proximity sensor with interferometric encoding.
An optical sensor for the dynamic measurement of proximity is presented. The sensor combines an extrinsic geometric transducer with interferometric encoding for high vibration sensitivity. Static calibration showed a unique variation in interference contrast over at least 60 fringes, leading to a measurement range of 20 mum and a resolution of at least 0.033mum. Dynamic excitation by using low-amplitude vibrations at 3.6 kHz showed a similar contrast variation, verifying fringe discrimination up to the sixth order. With verification of dynamic performance over all 60 fringes, the sensor should offer a low-cost approach to vibration monitoring in electrical switchgear.


Structure-function analysis of the DNA-binding domain of a transmembrane transcriptional activator.
The transmembrane DNA-binding protein CadC of E. coli, a representative of the ToxR-like receptor family, combines input and effector domains for signal sensing and transcriptional activation, respectively, in a single protein, thus representing one of the simplest signalling systems. At acidic pH in a lysine-rich environment, CadC activates the transcription of the cadBA operon through recruitment of the RNA polymerase (RNAP) to the two cadBA promoter sites, Cad1 and Cad2, which are directly bound by CadC. However, the molecular details for its interaction with DNA have remained elusive. Here, we present the crystal structure of the CadC DNA-binding domain (DBD) and show that it adopts a winged helix-turn-helix fold. The interaction with the cadBA promoter site Cad1 is studied by using nuclear magnetic resonance (NMR) spectroscopy, biophysical methods and functional assays and reveals a preference for AT-rich regions. By mutational analysis we identify amino acids within the CadC DBD that are crucial for DNA-binding and functional activity. Experimentally derived structural models of the CadC-DNA complex indicate that the CadC DBD employs mainly non-sequence-specific over a few specific contacts. Our data provide molecular insights into the CadC-DNA interaction and suggest how CadC dimerization may provide high-affinity binding to the Cad1 promoter.


Health of US parents with and without disabilities.
The health of parents with disabilities is not well understood. Existing research has used small, non-representative samples. The lack of research using national representative data has hindered advocacy and policy-making efforts. In the present study, we used nationally-representative data to examine the prevalence rates of chronic physical health conditions among parents with disabilities and compared them to parents without disabilities. We analyzed pooled and linked data from the 2007-2011 Medical Expenditure Panel Survey and the corresponding National Health Interview Survey. We conducted logistic regression analyses to examine age-adjusted health differences of US parents with and without disabilities, controlling for covariates. Outcome measures included obesity, arthritis, asthma, cancer, heart disease, diabetes, emphysema, high cholesterol, hypertension, and stroke. After controlling for all model covariates and adjusting for age, parents with disabilities had significantly higher odds (aOR ranging from 1.69 to 4.82) of having each of the chronic conditions (P < 0.001). Parents with disabilities also have significant higher odds of having 2 conditions (aOR = 1.63), 3 conditions (aOR = 2.44), and 4 or more conditions (aOR = 5.56). Parents with disabilities have significantly poorer health than parents without disabilities.


Covalently linking CuInS2 quantum dots with a Re catalyst by click reaction for photocatalytic CO2 reduction.
Covalently linking photosensitizers and catalysts in an inorganic-organic hybrid photocatalytic system is beneficial for efficient electron transfer between these components. However, general and straightforward methods to covalently attach molecular catalysts on the surface of inorganic semiconductors are rare. In this work, a classic rhenium bipyridine complex (Re catalyst) has been successfully covalently linked to the low toxicity CuInS2 quantum dots (QDs) by click reaction for photocatalytic CO2 reduction. Covalent bonding between the CuInS2 QDs and the Re catalyst in the QD-Re hybrid system is confirmed by UV-visible absorption spectroscopy, Fourier-transform infrared spectroscopy and energy-dispersive X-ray measurements. Time-correlated single photon counting and ultrafast time-resolved infrared spectroscopy provide evidence for rapid photo-induced electron transfer from the QDs to the Re catalyst. Upon photo-excitation of the QDs, the singly reduced Re catalyst is formed within 300 fs. Notably, the amount of reduced Re in the linked hybrid system is more than that in a sample where the QDs and the Re catalyst are simply mixed, suggesting that the covalent linkage between the CuInS2 QDs and the Re catalyst indeed facilitates electron transfer from the QDs to the Re catalyst. Such an ultrafast electron transfer in the covalently linked CuInS2 QD-Re hybrid system leads to enhanced photocatalytic activity for CO2 reduction, as compared to the conventional mixture of the QDs and the Re catalyst.


Subcellular localization of blood group Leb carbohydrate antigen (MSN-1-reactive antigen) in endometrial cancer cells.
MSN-1 is a monoclonal antibody, which was raised by immunizing mice with a human endometrial cancer cell line, SNG-II. The MSN-1 specifically recognizes a blood group carbohydrate antigen, Leb. We investigated the subcellular and suborganellar localization of the MSN-1-reactive carbohydrate antigens in the endometrial adenocarcinomas and the normal endometria using immunofluorescence microscopy, confocal laser scanning microscopy, and immunoelectron microscopy. In normal endometrium, the apical plasma membranes of endometrial glandular cells were weekly positive. In contrast, in endometrial adenocarcinoma specimens, the apical plasma membranes, the lateral plasma membranes, intracytoplasmic vesicular structures, and the Golgi apparatus were strongly positive. We also found that there are differences in the manner of the distribution of the MSN-1 antigen within the Golgi apparatus between the normal and tumor samples; namely, in the endometrial adenocarcinoma cells the antigens are found abundantly throughout the Golgi apparatus or tend to be located not only at the trans side but also close to the cis side, while the localization of this antigen in normal counterpart is restricted to the trans-Golgi cisternae. These findings imply that aberrant glycosylation occurs in endometrial adenocarcinomas, presumably as a result of abnormal expression of some glycosyltransferases involving the expression of the Leb carbohydrate antigen in the Golgi apparatus.


Adolescent alcohol consumption: biomarkers PEth and FAEE in relation to interview and questionnaire data.
The aim of this study was to investigate the congruence of biomarkers, questionnaires, and interviews as instruments to assess adolescent alcohol consumption. The methodology used was a cross-sectional study with a randomized sample. Four different methods were used to estimate high adolescent alcohol consumption. The concordance of the results was investigated. Surveys were performed, and biological specimens were collected at all schools in the county of Västmanland, Sweden, in 2001. Eighty-one boys and 119 girls from a population of 16- and 19-year-old adolescents were randomly selected from quartiles of volunteers representing various degrees of psychosocial risk behaviors. Using a questionnaire (for a 1-hour session) and in-depth interviews, subjects were assessed regarding their alcohol-use habits. Blood and hair samples were analyzed for phosphatidylethanol (PEth) and fatty acid ethyl esters (FAEEs), respectively. High alcohol consumption was underreported in the questionnaire compared with the interviews. PEth and FAEE analyses weakly confirmed the self-reports, and the results of the two biochemical tests did not overlap. The PEth blood test was the most specific but the least sensitive, whereas the FAEE hair test revealed low specificity and an overrepresentation of positive results in girls. The expected higher self-report of high alcohol consumption by interview rather than by questionnaire was confirmed partly because of the influence of a bogus pipeline procedure. The absence of overlap between PEth and FAEE results and their poor agreement with self-reports suggested that biomarkers are unsuitable as screening tools for alcohol consumption in adolescents.


Clinicopathologic review of pulmonary silicone embolism with special emphasis on the resultant histologic diversity in the lung--a review of five cases.
It is known that the subcutaneous injection of silicone can lead to severe pulmonary complications, followed in some patients by respiratory failure. Currently, silicone is being increasingly applied in the field of plastic surgery and, unfortunately, the illicit injection of silicone fluid by uncertified practitioners is not uncommon in Korea. We offer a critical pathologic review of 5 cases of pulmonary silicone embolism following illegal injection to the vaginal wall, four of which were fatal and came to legal autopsy. Our findings again confirm that subcutaneously injected silicone can gain access to the pulmonary vascular tree and cause pulmonary embolism. The histologic changes observed in the lung are variable and include four patterns i.e., the mere presence of silicone emboli, congestion and hemorrhage, acute pneumonitis, and diffuse alveolar damage despite the severe critical course in all cases. We were unable to find any histologic pattern that correlates well with the clinical course. Apart from producing emboli in the pulmonary vessels, subcutaneous injection of silicone can obviously cause serious pulmonary disease due to its ability to induce acute to induce acute pneumonitis and even possibly acute respiratory distress syndrome.


Comparative Analyses of Medicinal Chemistry and Cheminformatics Filters with Accessible Implementation in Konstanz Information Miner (KNIME).
High-throughput virtual screening (HTVS) is, in conjunction with rapid advances in computer hardware, becoming a staple in drug design research campaigns and cheminformatics. In this context, virtual compound library design becomes crucial as it generally constitutes the first step where quality filtered databases are essential for the efficient downstream research. Therefore, multiple filters for compound library design were devised and reported in the scientific literature. We collected the most common filters in medicinal chemistry (PAINS, REOS, Aggregators, van de Waterbeemd, Oprea, Fichert, Ghose, Mozzicconacci, Muegge, Egan, Murcko, Veber, Ro3, Ro4, and Ro5) to facilitate their open access use and compared them. Then, we implemented these filters in the open platform Konstanz Information Miner (KNIME) as a freely accessible and simple workflow compatible with small or large compound databases for the benefit of the readers and for the help in the early drug design steps.


An acute application of transcranial random noise stimulation does not enhance motor skill acquisition or retention in a golf putting task.
Transcranial random noise stimulation (tRNS) is a brain stimulation technique that has been shown to increase motor performance in simple motor tasks. The purpose was to determine the influence of tRNS on motor skill acquisition and retention in a complex golf putting task. Thirty-four young adults were randomly assigned to a tRNS group or a SHAM stimulation group. Each subject completed a practice session followed by a retention session. In the practice session, subjects performed golf putting trials in a baseline test block, four practice blocks, and a post test block. Twenty-four hours later subjects completed the retention test block. The golf putting task involved performing putts to a small target located 3 m away. tRNS or SHAM was applied during the practice blocks concurrently with the golf putting task. tRNS was applied over the first dorsal interosseus muscle representation area of the motor cortex for 20 min at a current strength of 2 mA. Endpoint error and endpoint variance were reduced across the both the practice blocks and the test blocks, but these reductions were not different between groups. These findings suggest that an acute application of tRNS failed to enhance skill acquisition or retention in a golf putting task.


Differences in patterns of infection and inflammation for corticosteroid treatment and chemotherapy in experimental invasive pulmonary aspergillosis.
Aspergillus fumigatus causes invasive pulmonary aspergillosis (IPA). This disease is one of the most life-threatening opportunistic infections in immunocompromised patients. The type of immunosuppressive regimen under which IPA occurs has rarely been investigated. In this study, we evaluated various parameters of the innate immune response during the progression of murine IPA induced by the intratracheal administration of A. fumigatus conidia as a function of two immunosuppressive treatments: a corticosteroid and a chemotherapeutic agent. We compared host responses various times after infection in terms of survival, pulmonary production of pro- and anti-inflammatory cytokines, cellular trafficking in the airways, lung injury, respiratory distress, and fungal development. We found that IPA pathogenesis involved predominantly fungal development in mice treated by chemotherapy and an adverse host response in mice treated with a corticosteroid. These previously unrecognized differences should be taken into account in evaluations of the pathogenesis of IPA in animal models.


Parameterized SVM for personalized drug concentration prediction.
This paper proposes a parameterized Support Vector Machine (ParaSVM) approach for modeling the Drug Concentration to Time (DCT) curves. It combines the merits of Support Vector Machine (SVM) algorithm that considers various patient features and an analytical model that approximates the predicted DCT points and enables curve calibrations using occasional real Therapeutic Drug Monitoring (TDM) measurements. The RANSAC algorithm is applied to construct the parameter library for the relevant basis functions. We show an example of using ParaSVM to build DCT curves and then calibrate them by TDM measurements on imatinib case study.


The Complexities of Interpreting Reversible Elevated Serum Creatinine Levels in Drug Development: Does a Correlation with Inhibition of Renal Transporters Exist?
In humans, creatinine is formed by a multistep process in liver and muscle and eliminated via the kidney by a combination of glomerular filtration and active transport. Based on current evidence, creatinine can be taken up into renal proximal tubule cells by the basolaterally localized organic cation transporter 2 (OCT2) and the organic anion transporter 2, and effluxed into the urine by the apically localized multidrug and toxin extrusion protein 1 (MATE1) and MATE2K. Drug-induced elevation of serum creatinine (SCr) and/or reduced creatinine renal clearance is routinely used as a marker for acute kidney injury. Interpretation of elevated SCr can be complex, because such increases can be reversible and explained by inhibition of renal transporters involved in active secretion of creatinine or other secondary factors, such as diet and disease state. Distinction between these possibilities is important from a drug development perspective, as increases in SCr can result in the termination of otherwise efficacious drug candidates. In this review, we discuss the challenges associated with using creatinine as a marker for kidney damage. Furthermore, to evaluate whether reversible changes in SCr can be predicted prospectively based on in vitro transporter inhibition data, an in-depth in vitro-in vivo correlation (IVIVC) analysis was conducted for 16 drugs with in-house and literature in vitro transporter inhibition data for OCT2, MATE1, and MATE2K, as well as total and unbound maximum plasma concentration (Cmax and Cmax,u) data measured in the clinic.


Plasmodium falciparum: a method for the amplification of S antigens and its application to laboratory and field samples.
Polymerase chain reaction amplification of several polymorphic genes has been used to study the population biology of Plasmodium falciparum. S antigen is particularly suitable for such studies, but difficulties in the amplification of this gene have precluded its use. Here we describe a simple method for the amplification of S antigen and show why previous attempts may have been unsuccessful. Data are presented from both laboratory and field isolates.


What is data ethics?
This theme issue has the founding ambition of landscaping data ethics as a new branch of ethics that studies and evaluates moral problems related to data (including generation, recording, curation, processing, dissemination, sharing and use), algorithms (including artificial intelligence, artificial agents, machine learning and robots) and corresponding practices (including responsible innovation, programming, hacking and professional codes), in order to formulate and support morally good solutions (e.g. right conducts or right values). Data ethics builds on the foundation provided by computer and information ethics but, at the same time, it refines the approach endorsed so far in this research field, by shifting the level of abstraction of ethical enquiries, from being information-centric to being data-centric. This shift brings into focus the different moral dimensions of all kinds of data, even data that never translate directly into information but can be used to support actions or generate behaviours, for example. It highlights the need for ethical analyses to concentrate on the content and nature of computational operations-the interactions among hardware, software and data-rather than on the variety of digital technologies that enable them. And it emphasizes the complexity of the ethical challenges posed by data science. Because of such complexity, data ethics should be developed from the start as a macroethics, that is, as an overall framework that avoids narrow, ad hoc approaches and addresses the ethical impact and implications of data science and its applications within a consistent, holistic and inclusive framework. Only as a macroethics will data ethics provide solutions that can maximize the value of data science for our societies, for all of us and for our environments.This article is part of the themed issue 'The ethical impact of data science'.


Ca removal and Mg recovery from flue gas desulfurization (FGD) wastewater by selective precipitation.
Selective removal of Ca and recovery of Mg by precipitation from flue gas desulfurization (FGD) wastewater has been investigated. Thermodynamic analysis of four possible additives, Na2CO3, Na2C2O4, NaF and Na2SO4, indicated that both carbonate and oxalate could potentially provide effective separation of Ca via precipitation from Mg in FGD wastewater. However, it was found experimentally that the carbonate system was not as effective as oxalate in this regard. The oxalate system performed considerably better, with Ca removal efficiency of 96% being obtained, with little Mg inclusion at pH 6.0 when the dosage was ×1.4 the stoichiometric requirement. On this basis, the subsequent recovery process for Mg was carried out using NaOH with two-step precipitation. The product was confirmed to be Mg(OH)2 (using X-ray diffraction and thermo gravimetric analysis) with elemental analysis suggesting a purity of 99.3 wt.%.


Temporal and Spatial Changes in the Pea Black Spot Disease Complex in Western Australia.
Black spot (also referred to as Ascochyta blight, Ascochyta foot rot and black stem, and Ascochyta leaf and pod spot) is a devastating disease of pea (Pisum sativum) caused by one or more pathogenic fungi, including Didymella pinodes, Ascochyta pisi, and Phoma pinodella. Surveys were conducted across pea-growing regions of Western Australia in 1984, 1987, 1989, 1996, 2010, and 2012. In total, 1,872 fungal isolates were collected in association with pea black spot disease symptoms. Internal transcribed spacer regions from representative isolates, chosen based on morphology, were sequenced to aid in identification. In most years and locations, D. pinodes was the predominant pathogen in the black spot complex. From 1984 to 2012, four new pathogens associated with black spot symptoms on leaves or stems (P. koolunga, P. herbarum, Boeremia exigua var. exigua, and P. glomerata) were confirmed. This study is the first to confirm P. koolunga in association with pea black spot symptoms in field pea in Western Australia and show that, by 2012, it was widely present in new regions. In 2012, P. koolunga was more prevalent than D. pinodes in Northam and P. pinodella in Esperance. P. herbarum and B. exigua var. exigua were only recorded in 2010. Although A. pisi was reported in Western Australia in 1912 and again in 1968 and is commonly associated with pea black spot in other states of Australia and elsewhere, it was not recorded in Western Australia from 1984 to 2012. It is clear that the pathogen population associated with the pea black spot complex in Western Australia has been dynamic across time and geographic location. This poses a particular challenge to development of effective resistance against the black spot complex, because breeding programs are focused almost exclusively on resistance to D. pinodes, largely ignoring other major pathogens in the disease complex. Furthermore, development and deployment of effective host resistance or fungicides against just one or two of the pathogens in the disease complex could radically shift the make-up of the population toward pathogen species that are least challenged by the host resistance or fungicides, creating an evolving black spot complex that remains ahead of breeding and other management efforts.


Marital resemblance for obsessive-compulsive, anxious and depressive symptoms in a population-based sample.
Resemblance between spouses can be due to phenotypic assortment, social homogamy and/or marital interaction. A significant degree of assortment can have consequences for the genetic architecture of a population. We examined the existence and cause(s) of assortment for obsessive-compulsive (OC), anxious and depressive symptoms in a population-based twin-family sample. OC, anxious and depressive symptoms were measured in around 1400 twin-spouse pairs and >850 parent pairs. Correlations of twins and their spouse, twin and co-twin's spouse, spouses of both twins and parents of twins were obtained to consider phenotypic assortment versus social homogamy as possible causes of marital resemblance. The association of length of relationship with marital resemblance was also investigated. Finally, we examined whether within-trait or cross-trait processes play a primarily role in marital resemblance. Small but significant within-trait correlations of between 0.1 and 0.2 were seen for spouse similarity in OC, anxious and depressive symptoms. Cross-correlations were significant but lower. There was no correlation between length of relationship and marital resemblance. From the pattern of correlations for twin-spouse, co-twin-spouse and spouses of both twins, phenotypic assortment could not be distinguished from social homogamy. Both within- and cross-assortment processes play a role in marital resemblance. Small within- and across-trait correlations exist for OC, anxious and depressive symptoms. No evidence for marital interaction was found. Spouse correlations are small, which makes it difficult to distinguish between social homogamy and phenotypic assortment. It is unlikely that correlations of this size will have a large impact on genetic studies.


Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex.
SCF complexes are the largest family of E3 ubiquitin-protein ligases and mediate the ubiquitination of diverse regulatory and signalling proteins. Here we present the crystal structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF complex, which shows that Cul1 is an elongated protein that consists of a long stalk and a globular domain. The globular domain binds the RING finger protein Rbx1 through an intermolecular beta-sheet, forming a two-subunit catalytic core that recruits the ubiquitin-conjugating enzyme. The long stalk, which consists of three repeats of a novel five-helix motif, binds the Skp1-F boxSkp2 protein substrate-recognition complex at its tip. Cul1 serves as a rigid scaffold that organizes the Skp1-F boxSkp2 and Rbx1 subunits, holding them over 100 A apart. The structure suggests that Cul1 may contribute to catalysis through the positioning of the substrate and the ubiquitin-conjugating enzyme, and this model is supported by Cul1 mutations designed to eliminate the rigidity of the scaffold.


Detection of clonal rearrangement of T-cell receptor genes in the diagnosis of primary cutaneous CD30 lymphoproliferative disorders.
Detection of clonality has been reported to be a helpful tool in the diagnosis of cutaneous lymphomas. Monoclonal rearrangement of T-cell receptor genes (TCR) was reported in fresh frozen tissue of lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large-cell lymphoma (ALCL), but the diagnostic value of T-cell clonality in formalin-fixed, paraffin-embedded biopsies has so far not been assessed. Detection of clonal rearrangement of TCRgamma genes by highly sensitive polymerase chain reaction-based automated high-resolution fragment analysis (AHRFA) in archival LyP (n = 18) and ALCL (n = 17) tissue. Detection of clonality differed significantly among the histologic forms of LyP as well as between LyP and ALCL with clonality found in none of the 10 biopsies of LyP type A and B, in 4/8 (50%) of the LyP type C specimens, and in 11/17 (65%) of ALCL cases. T-cell clonality can only be found in a minority (four of 18; 22%) of archival LyP specimens, even when employing a highly sensitive detection method and is thus of limited diagnostic value. Final diagnosis of LyP has to be based mainly on clinical, histologic, and immunohistochemical findings rather than on results of clonality studies.


Patient-related and radiographic predictors of inferior health-related quality-of-life measures in adult patients with nonoperative spinal deformity.
Patients with nonoperative (N-Op) adult spinal deformity (ASD) have inferior long-term spinopelvic alignment and clinical outcomes. Predictors of lower quality-of-life measures in N-Op populations have yet to be sufficiently investigated. The aim of this study was to identify patient-related factors and radiographic parameters associated with inferior health-related quality-of-life (HRQOL) scores in N-Op ASD patients. N-Op ASD patients with complete radiographic and outcome data at baseline and 2 years were included. N-Op patients and operative (Op) patients were propensity score matched for baseline disability and deformity. Patient-related factors and radiographic alignment parameters (pelvic tilt [PT], sagittal vertical axis [SVA], pelvic incidence [PI]-lumbar lordosis [LL] mismatch, mismatch between cervical lordosis and T1 segment slope [TS-CL], cervical-thoracic pelvic angle [PA], and others) at baseline and 2 years were analyzed as predictors for moderate to severe 2-year Oswestry Disability Index (ODI > 20) and failing to meet the minimal clinically importance difference (MCID) for 2-year Scoliosis Research Society Outcomes Questionnaire (SRS) scores (< 0.4 increase from baseline). Conditional inference decision trees identified predictors of each HRQOL measure and established cutoffs at which factors have a global effect. Random forest analysis (RFA) generated 5000 conditional inference trees to compute a variable importance table for top predictors of inferior HRQOL. Statistical significance was set at p < 0.05. Six hundred sixty-two patients with ASD (331 Op patients and 331 N-Op patients) with complete radiographic and HRQOL data at their 2-year follow-up were included. There were no differences in demographics, ODI, and Schwab deformity modifiers between groups at baseline (all p > 0.05). N-Op patients had higher 2-year ODI scores (27.9 vs 20.3, p < 0.001), higher rates of moderate to severe disability (29.3% vs 22.4%, p = 0.05), lower SRS total scores (3.47 vs 3.91, p < 0.001), and higher rates of failure to reach SRS MCID (35.3% vs 15.7%, p < 0.001) than Op patients at 2 years. RFA ranked the top overall predictors for moderate to severe ODI at 2 years for N-Op patients as follows: 1) frailty index > 2.8, 2) BMI > 35 kg/m2, T4PA > 28°, and 4) Charlson Comorbidity Index > 1. Top radiographic predictors were T4PA > 28° and C2-S1 SVA > 93 mm. RFA also ranked the top overall predictors for failure to reach 2-year SRS MCID for N-Op patients, as follows: 1) T12-S1 lordosis > 53°, 2) cervical SVA (cSVA) > 28 mm, 3) C2-S1 angle > 14.5°, 4) TS-CL > 12°, and 5) PT > 23°. The top radiographic predictors were T12-S1 Cobb angle, cSVA, C2-S1 angle, and TS-CL. When controlling for baseline deformity in N-Op versus Op patients, subsequent deterioration in frailty, BMI, and radiographic progression over a 2-year follow-up were found to drive suboptimal patient-reported outcome measures in N-Op cohorts as measured by validated ODI and SRS clinical instruments.


The utility of health states after stroke: a systematic review of the literature.
To perform decision analyses that include stroke as one of the possible health states, the utilities of stroke states must be determined. We reviewed the literature to obtain estimates of the utility of stroke and explored the impact of the study population and the elicitation method. We searched various databases for articles reporting empirical assessment of utilities. Mean utilities of major stroke (Rankin Scale 4 to 5) and minor stroke (Rankin Scale 2 to 3) were calculated, stratified by study population and elicitation method. Additionally, the modified Rankin Scale was mapped onto the EuroQol classification system. Utilities were obtained from 23 articles. Patients at risk for stroke assigned utilities of 0.26 and 0.55 to major and minor stroke, respectively. Stroke survivors assigned higher utilities to both major (0.41) and minor stroke (0.72). The EuroQol completed by stroke survivors revealed a utility of 0.32 and 0.71 for major and minor stroke, respectively. Utilities elicited by the Standard Gamble were generally higher, while those obtained by the Visual Analogue Scale were lower than the Time Trade Off values. Remaining variation between utilities may be caused by differences in definitions of the health states. The mapped EuroQol indicated a utility of 0.64 for minor stroke and a value just below zero for major stroke. For minor stroke, a utility between 0.50 and 0.70 seems to be reasonable for both decision analyses and cost-effectiveness studies. The utility of major stroke may range between 0 and 0.30 and may possibly be negative.


Investigating the Role of Friendship Interventions on the Mental Health Outcomes of Adolescents: A Scoping Review of Range and a Systematic Review of Effectiveness.
Friendships are crucial in adolescent development. This paper presents a scoping review, followed by a systematic review, to assess friendship interventions and their impacts on the mental health outcomes of adolescents aged 12-24 years. Studies were included if they incorporated a friend or authentic social group in an intervention dedicated to improving mental health outcomes and well-being. Twenty-four studies were included in the scoping review, and eighteen in the systematic review. Data from 12,815 adolescents were analysed; three prominent themes emerged. The most common theme was promoting mental health literacy, followed by supporting help-seeking, and friendship-building/combating isolation. Most evaluations focused on the individual who had received the intervention, rather than their wider friends who would have been potential contacts and experienced any altered interactions. Of the studies focusing on friendship-building, all had positive short-term outcomes but inconclusive long-term effects. Two studies recruited friends from an individual's authentic social group. While opportunities for improving mental health literacy and help-seeking emerged as key themes, the role of friends in mental health interventions has only been included in a small number of studies. Given that friends are a key point of contact for many adolescents, a better understanding of their domains of influence, particularly on mental health, will potentially enhance interventions.


Detecting geospatial patterns of Plasmodium falciparum parasite migration in Cambodia using optimized estimated effective migration surfaces.
Understanding the genetic structure of natural populations provides insight into the demographic and adaptive processes that have affected those populations. Such information, particularly when integrated with geospatial data, can have translational applications for a variety of fields, including public health. Estimated effective migration surfaces (EEMS) is an approach that allows visualization of the spatial patterns in genomic data to understand population structure and migration. In this study, we developed a workflow to optimize the resolution of spatial grids used to generate EEMS migration maps and applied this optimized workflow to estimate migration of Plasmodium falciparum in Cambodia and bordering regions of Thailand and Vietnam. The optimal density of EEMS grids was determined based on a new workflow created using density clustering to define genomic clusters and the spatial distance between genomic clusters. Topological skeletons were used to capture the spatial distribution for each genomic cluster and to determine the EEMS grid density; i.e., both genomic and spatial clustering were used to guide the optimization of EEMS grids. Model accuracy for migration estimates using the optimized workflow was tested and compared to grid resolutions selected without the optimized workflow. As a test case, the optimized workflow was applied to genomic data generated from P. falciparum sampled in Cambodia and bordering regions, and migration maps were compared to estimates of malaria endemicity, as well as geographic properties of the study area, as a means of validating observed migration patterns. Optimized grids displayed both high model accuracy and reduced computing time compared to grid densities selected in an unguided manner. In addition, EEMS migration maps generated for P. falciparum using the optimized grid corresponded to estimates of malaria endemicity and geographic properties of the study region that might be expected to impact malaria parasite migration, supporting the validity of the observed migration patterns. Optimized grids reduce spatial uncertainty in the EEMS contours that can result from user-defined parameters, such as the resolution of the spatial grid used in the model. This workflow will be useful to a broad range of EEMS users as it can be applied to analyses involving other organisms of interest and geographic areas.


Impact of travel time and rurality on presentation and outcomes of symptomatic colorectal cancer: a cross-sectional cohort study in primary care.
Several studies have reported a survival disadvantage for rural dwellers who develop colorectal cancer, but the underlying mechanisms remain obscure. Delayed presentation to GPs may be a contributory factor, but evidence is lacking. To examine the association between rurality and travel time on diagnosis and survival of colorectal cancer in a cohort from northeast Scotland. The authors used a database linking GP records to routine data for patients diagnosed between 1997 and 1998, and followed up to 2011. Primary outcomes were alarm symptoms, emergency admissions, stage, and survival. Travel time in minutes from patients to GP was estimated. Logistic and Cox regression were used to model outcomes. Interaction terms were used to determine if travelling time impacted differently on urban versus rural patients. Rural patients and patients travelling farther to the GP had better 3-year survival. When the travel outcome associations were explored using interaction terms, the associations differed between rural and urban areas. Longer travel in urban areas significantly reduced the odds of emergency admissions (odds ratio [OR] 0.62, P<0.05), and increased survival (hazard ratio 0.75, P<0.05). Longer travel also increased the odds of presenting with alarm symptoms in urban areas; this was nearly significant (OR 1.34, P = 0.06). Presence of alarm symptoms reduced the likelihood of emergency admissions (OR 0.36, P<0.01). Living in a rural area, and travelling farther to a GP in urban areas, may reduce the likelihood of emergency admissions and poor survival. This may be related to how patients present with alarm symptoms.


Assessment of Immunogenicity and Neutralisation Efficacy of Viral-Vectored Vaccines Against Chikungunya Virus.
Chikungunya virus (CHIKV) has caused extensive outbreaks in several countries within the Americas, Asia, Oceanic/Pacific Islands, and Europe. In humans, CHIKV infections cause a debilitating disease with acute febrile illness and long-term polyarthralgia. Acute and chronic symptoms impose a major economic burden to health systems and contribute to poverty in affected countries. An efficacious vaccine would be an important step towards decreasing the disease burden caused by CHIKV infection. Despite no licensed vaccine is yet available for CHIKV, there is strong evidence of effective asymptomatic viral clearance due to neutralising antibodies against the viral structural proteins. We have designed viral-vectored vaccines to express the structural proteins of CHIKV, using the replication-deficient chimpanzee adenoviral platform, ChAdOx1. Expression of the CHIKV antigens results in the formation of chikungunya virus-like particles. Our vaccines induce high frequencies of anti-chikungunya specific T-cell responses as well as high titres of anti-CHIKV E2 antibodies with high capacity for in vitro neutralisation. Our results indicate the potential for further clinical development of the ChAdOx1 vaccine platform in CHIKV vaccinology.