History of medication-assisted treatment and its association with initiating others into injection drug use in San Diego, CA.
Medication-assisted treatment (MAT) remains the gold standard for the treatment of opioid use disorder. MAT also reduces the frequency of injecting among people who inject drugs (PWID). Relatedly, data suggest that PWID play a key role in the initiation of others into drug injecting by exposing injecting practices to injection-naïve drug users. Our primary objective was to test whether a history of MAT enrollment is associated with a reduced odds of PWID providing injection initiation assistance. Preventing Injecting by Modifying Existing Responses (PRIMER; NIDA DP2-DA040256-01), is a multi-site cohort study assessing the impact of socio-structural factors on the risk that PWID provide injection initiation assistance. Data were drawn from a participating cohort of PWID in San Diego, CA. The primary outcome was reporting ever providing injection initiation assistance; the primary predictor was reporting ever being enrolled in MAT. Logistic regression was used to model associations between MAT enrollment and ever initiating others into injecting while adjusting for potential confounders. Participants (n = 354) were predominantly male (n = 249, 70%). Thirty-eight percent (n = 135) of participants reported ever initiating others into injection drug use. In multivariate analysis, participants who reported a history of MAT enrollment had significantly decreased odds of ever providing injection initiation assistance (Adjusted Odds Ratio [AOR]: 0.62, 95% Confidence Interval [CI]: 0.39-0.99). These preliminary findings suggest an association between MAT enrollment and a lower odds that male PWID report providing injection initiation assistance to injection-naïve drug users. Further research is needed to identify the pathways by which MAT enrollment may impact the risk that PWID initiate others into drug injecting.


Increased persistence of lung gene expression using plasmids containing the ubiquitin C or elongation factor 1alpha promoter.
For effective gene therapy of chronic disease, persistent transgene expression at therapeutic levels is required. Clinical studies of airway gene transfer in patients with cystic fibrosis (CF) have resulted in short-lived transgene expression. We used intra-nasal dosing of naked plasmid DNA to the murine lung as a model for investigating the duration of airway gene transfer from a series of reporter expression plasmids. Transgene expression was transient when mediated by the viral promoters CMV, RSV and SV40, falling to less than 10% of peak expression after 2 weeks, although the presence of the adenoviral E4ORF3 gene in cis, resulted in extended duration of reporter activity from the CMV promoter. Transient expression from these promoters was not due to loss of the vector as determined by quantitative TaqMan PCR analysis. However, use of the promoters from the human polybiquitin C (UbC) and the elongation factor 1alpha (EF1alpha) genes resulted in persistent gene expression in the mouse lung. The UbC promoter directed high-level reporter activity which was maintained for up to 8 weeks and was still detectable 6 months after a single administration. Such persistent airway transgene expression from a nonviral vector without the concomitant expression of a potential antigen has not been reported previously. Thus, despite the persistence of vector DNA in vivo, attenuation of promoter function may lead to silencing of transgene expression and careful selection of promoter sequences is recommended for in vivo gene transfer.


Complications of the Fingers and Hand After Arthroscopic Rotator Cuff Repair.
Complications of the fingers and hand that occur after Arthroscopic Rotator Cuff Repair (ARCR) have not been examined in detail. The aim of our study was to evaluate the diagnosis and treatment of complications of the fingers and hand that occur after ARCR and to examine treatment outcomes. The case records of 40 patients (41 shoulders) who underwent ARCR using suture anchors were retrospectively reviewed to investigate complications of the fingers and hand after ARCR. Twelve patients (29%) experienced numbness, pain, edema, and movement limitations of the fingers and hand. These symptoms occurred on average 1.1 months (range, 0.1-2.5 months) after ARCR. The diagnoses were cubital tunnel syndrome in 2 hands, carpal tunnel syndrome in 3 hands, and flexor tenosynovitis (TS) in 10 hands. None of the 10 hands with TS exhibited triggering of the fingers. The mean interval between treatment initiation and symptom resolution was 2.2 months for the 5 hands treated by corticosteroid injection or surgery and 5.9 months for the 7 hands treated by alternating warm and cold baths alone. None of the hands exhibited Complex Regional Pain Syndrome (CRPS). Complications of the fingers and hand after ARCR were observed in 29%. TS was the most frequent complication. When symptoms in the fingers and hand occur after ARCR, rather than immediately suspecting CRPS, TS should be primarily suspected, including when TS symptoms such as triggering are not present, and these patients should be treated proactively using corticosteroid injections or surgery.


Module identification in bipartite and directed networks.
Modularity is one of the most prominent properties of real-world complex networks. Here, we address the issue of module identification in two important classes of networks: bipartite networks and directed unipartite networks. Nodes in bipartite networks are divided into two nonoverlapping sets, and the links must have one end node from each set. Directed unipartite networks only have one type of node, but links have an origin and an end. We show that directed unipartite networks can be conveniently represented as bipartite networks for module identification purposes. We report on an approach especially suited for module detection in bipartite networks, and we define a set of random networks that enable us to validate the approach.


Cloning and functional characterisation of an enzyme involved in the elongation of Delta6-polyunsaturated fatty acids from the moss Physcomitrella patens.
The moss Physcomitrella patens contains high proportions of polyunsaturated very-long-chain fatty acids with up to 20 carbon atoms. Starting from preformed C18 polyunsaturated fatty acids, their biosynthesis involves a sequence of Delta6-desaturation, Delta6-elongation and Delta5-desaturation. In this report we describe for the first time the characterisation of a cDNA (PSE1) of plant origin with homology to the ELO-genes from Saccharomyces cerevisiae, encoding a component of the Delta6-elongase. Functional expression of PSE1 in S. cerevisiae led to the elongation of exogenously supplied Delta6-polyunsaturated fatty acids. By feeding experiments with different trienoic fatty acids of natural and synthetic origin, both substrate specificity and substrate selectivity of the enzyme were investigated. The activity of Pse1, when expressed in yeast, was not sensitive to the antibiotic cerulenin, which is an effective inhibitor of fatty acid synthesis and elongation. Furthermore, the PSE1 gene was disrupted in the moss by homologous recombination. This led to a complete loss of all C20 polyunsaturated fatty acids providing additional evidence for the function of the cDNA as coding for a component of the Delta6-elongase. The elimination of the elongase was not accompanied by a visible alteration in the phenotype, indicating that C20-PUFAs are not essential for viability of the moss under phytotron conditions.


Exploiting fruit byproducts for eco-friendly nanosynthesis: Citrus × clementina peel extract mediated fabrication of silver nanoparticles with high efficacy against microbial pathogens and rat glial tumor C6 cells.
Process byproducts from the fruit industry may represent a cheap and reliable source of green reducing agents to be used in current bio-nanosynthesis. This study reports the use of orange (Citrus × clementina) peel aqueous extract (OPE) for one-pot green synthesis of silver nanoparticles (AgNPs) with high effectiveness against various microbial pathogens as well as rat glial tumor C6 cells. The effects of various operational parameters on the synthesis of AgNPs were systematically investigated. The morphology, particle size, and properties of synthesized AgNPs were characterized using UV-visible spectroscopy, x-ray diffraction, x-ray photoelectron spectroscopy, field emission scanning electron microscopy, energy-dispersive x-ray spectroscopy, and Fourier transform infrared spectroscopy. High-resolution transmission electron microscopy shows that the nanoparticles are mostly spherical in shape and monodispersed, with an average particle size of 15-20 nm. Notably, the OPE-synthesized AgNPs were stable up to 6 months without change in their properties. Low doses of OPE-AgNPs inhibited the growth of human pathogens Escherichia coli, Bacillus cereus, and Staphylococcus aureus. The minimum inhibitory concentration and minimum bactericidal concentration of AgNPs against selected pathogenic bacteria were determined. OPE-AgNPs exhibited strong antioxidant activity in terms of ABTS (2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid)) radical scavenging (IC50 49.6 μg/mL) and DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging (IC50 63.4 μg/mL). OPE-AgNPs showed dose-dependent response against rat glial tumor C6 cells (LD50 60 μg/mL) showing a promising potential as anticancer agents. Overall, the current investigation highlighted a cheap green technology route to synthesize AgNPs using OPE byproducts and could potentially be utilized in biomedical, cosmetic, and pharmaceutical industry.


A Potential Role for the STXBP5-AS1 Gene in Adult ADHD Symptoms.
We aimed to detect Attention-deficit/hyperactivity (ADHD) risk-conferring genes in adults. In children, ADHD is characterized by age-inappropriate levels of inattention and/or hyperactivity-impulsivity and may persists into adulthood. Childhood and adulthood ADHD are heritable, and are thought to represent the clinical extreme of a continuous distribution of ADHD symptoms in the general population. We aimed to leverage the power of studies of quantitative ADHD symptoms in adults who were genotyped. Within the SAGA (Study of ADHD trait genetics in adults) consortium, we estimated the single nucleotide polymorphism (SNP)-based heritability of quantitative self-reported ADHD symptoms and carried out a genome-wide association meta-analysis in nine adult population-based and case-only cohorts of adults. A total of n = 14,689 individuals were included. In two of the SAGA cohorts we found a significant SNP-based heritability for self-rated ADHD symptom scores of respectively 15% (n = 3656) and 30% (n = 1841). The top hit of the genome-wide meta-analysis (SNP rs12661753; p-value = 3.02 × 10-7) was present in the long non-coding RNA gene STXBP5-AS1. This association was also observed in a meta-analysis of childhood ADHD symptom scores in eight population-based pediatric cohorts from the Early Genetics and Lifecourse Epidemiology (EAGLE) ADHD consortium (n = 14,776). Genome-wide meta-analysis of the SAGA and EAGLE data (n = 29,465) increased the strength of the association with the SNP rs12661753. In human HEK293 cells, expression of STXBP5-AS1 enhanced the expression of a reporter construct of STXBP5, a gene known to be involved in "SNAP" (Soluble NSF attachment protein) Receptor" (SNARE) complex formation. In mouse strains featuring different levels of impulsivity, transcript levels in the prefrontal cortex of the mouse ortholog Gm28905 strongly correlated negatively with motor impulsivity as measured in the five choice serial reaction time task (r2 = - 0.61; p = 0.004). Our results are consistent with an effect of the STXBP5-AS1 gene on ADHD symptom scores distribution and point to a possible biological mechanism, other than antisense RNA inhibition, involved in ADHD-related impulsivity levels.


Robust Buchwald-Hartwig amination enabled by ball-milling.
An operationally simple mechanochemical method for the Pd catalysed Buchwald-Hartwig amination of arylhalides with secondary amines has been developed using a Pd PEPPSI catalyst system. The system is demonstrated on 30 substrates and applied in the context of a target synthesis. Furthermore, the performance of the reaction under aerobic conditions has been probed under traditional solution and mechanochemical conditions, the observations are discussed herein.


The effectiveness of a comprehensive geriatric assessment intervention program for frailty in community-dwelling older people: a randomized, controlled trial.
This randomized, controlled trial assessed the effectiveness of comprehensive geriatric assessment (CGA) and subsequent intervention in pre-frail and frail community-dwelling elderly based on the Fried Frailty Criteria (FFC) and the Barthel Index (BI) A total of 310 pre-frail or frail elderly from a single community were identified using the FFC. Of these, 152 were randomly assigned to the intervention group for CGA and appropriate intervention by medication adjustment, exercise instruction, nutrition support, physical rehabilitation, social worker consultation, and specialty referral. Clinical outcome was re-evaluated by the FFC and BI 6 months later. Compared to the control group, the intervention group tended to have a better outcome, with an odds ratio (OR) = 1.19, 95% confidence interval (95% CI) = 0.48-3.04, p = 0.71) and 3.29 (95% CI = 0.65-16.64, p = 0.15), respectively, and were less likely to deteriorate, with an OR = 0.78 (95% CI = 0.34-1.79, p = 0.57) and 0.94 (95% CI = 0.42-2.12, p = 0.88), respectively. Although no significant differences were observed, the CGA and subsequent intervention showed a favorable outcome in frail and pre-frail elderly based on the frailty status and BI. Inability to complete the CGA and poor compliance with the intervention program appear to be the main reasons for unfavorable outcomes.


The genetic architecture of economic and political preferences.
Preferences are fundamental building blocks in all models of economic and political behavior. We study a new sample of comprehensively genotyped subjects with data on economic and political preferences and educational attainment. We use dense single nucleotide polymorphism (SNP) data to estimate the proportion of variation in these traits explained by common SNPs and to conduct genome-wide association study (GWAS) and prediction analyses. The pattern of results is consistent with findings for other complex traits. First, the estimated fraction of phenotypic variation that could, in principle, be explained by dense SNP arrays is around one-half of the narrow heritability estimated using twin and family samples. The molecular-genetic-based heritability estimates, therefore, partially corroborate evidence of significant heritability from behavior genetic studies. Second, our analyses suggest that these traits have a polygenic architecture, with the heritable variation explained by many genes with small effects. Our results suggest that most published genetic association studies with economic and political traits are dramatically underpowered, which implies a high false discovery rate. These results convey a cautionary message for whether, how, and how soon molecular genetic data can contribute to, and potentially transform, research in social science. We propose some constructive responses to the inferential challenges posed by the small explanatory power of individual SNPs.


Image coding using wavelet transform.
A scheme for image compression that takes into account psychovisual features both in the space and frequency domains is proposed. This method involves two steps. First, a wavelet transform used in order to obtain a set of biorthogonal subclasses of images: the original image is decomposed at different scales using a pyramidal algorithm architecture. The decomposition is along the vertical and horizontal directions and maintains constant the number of pixels required to describe the image. Second, according to Shannon's rate distortion theory, the wavelet coefficients are vector quantized using a multiresolution codebook. To encode the wavelet coefficients, a noise shaping bit allocation procedure which assumes that details at high resolution are less visible to the human eye is proposed. In order to allow the receiver to recognize a picture as quickly as possible at minimum cost, a progressive transmission scheme is presented. It is shown that the wavelet transform is particularly well adapted to progressive transmission.


Early brain activity: Translations between bedside and laboratory.
Neural activity is both a driver of brain development and a readout of developmental processes. Changes in neuronal activity are therefore both the cause and consequence of neurodevelopmental compromises. Here, we review the assessment of neuronal activities in both preclinical models and clinical situations. We focus on issues that require urgent translational research, the challenges and bottlenecks preventing translation of biomedical research into new clinical diagnostics or treatments, and possibilities to overcome these barriers. The key questions are (i) what can be measured in clinical settings versus animal experiments, (ii) how do measurements relate to particular stages of development, and (iii) how can we balance practical and ethical realities with methodological compromises in measurements and treatments.


Unwashed wound drainage blood. What are we giving our patients?
Wound drainage blood was collected after total joint arthroplasty was completed in 13 consecutive patients. Peripheral blood samples were collected in the recovery room and at 6 hours postoperatively for all 13 patients. A standard enzyme-linked immunosorbency assay was done to quantify tumor necrosis factor-alpha, interleukin-1 alpha, interleukin-6, and interleukin-8 levels in the samples. At 6 hours postoperatively, the levels of cytokines were elevated significantly in the peripheral and drainage blood serum. In particular, the drainage blood serum had the most dramatic increase for all cytokines, which was significant. Reinfusion of unwashed filtered postoperative wound drainage blood has been shown not to be entirely benign; pyrogenic transfusion reaction is the most commonly reported adverse effect, but hemodynamic instability with hypotension and even myocardial infarction have been reported. The cause of these adverse events has not been defined clearly, but may be secondary to the infusion of cytokines. The present study showed the presence and significant elevation of the cytokine levels in the wound drainage blood. A comprehensive review of the literature revealed that unwashed drainage blood is a relatively dilute blood product lacking normal clotting factors and having numerous other undesirable components that may mitigate against its routine use in lieu of predeposited autologous or homologous blood. This is of interest because there is evidence indicating that wound drainage blood reinfusion may be unnecessary in total joint arthroplasty when autologous blood is available. Use of drains in this surgery also may be unnecessary and has been shown to increase the amount of blood loss and the need for transfusion.


Determination of dimethyl fumarate and other potential allergens in desiccant and antimould sachets.
A method for the determination of dimethyl fumarate (DMF), benzothiazole (BT) and tert-butylphenol (TBP) in desiccant and antimould agents employed for protecting consumer products from humidity and mould has been developed. The method is based on ultrasound-assisted extraction (UAE) followed by GC-MS analysis. Parameters that could affect the extraction of the compounds have been optimised using a multivariate approach. In the final conditions, the extraction is performed using only 0.5 or 1 mL ethyl acetate and applying ultrasound energy for 5 min. Simultaneous extractions could also be carried out in 5 min without losing efficiency. The method was validated showing good linearity (R2 >0.995). Both intra- and inter-day precisions were studied at several concentration levels, being satisfactory in all cases (RSD <10%). Recovery was evaluated in four real desiccant samples at different compound concentrations, ranging between 87% and 109%. Limits of detection and quantification were in the low nanogramme per gramme level, thus allowing the determination of DMF at concentrations well below the limit established by the recent EU Directive (0.1 microg/g). The proposed procedure was applied to the determination of the target compounds in several desiccant and antimould samples. Although most of them were simply labelled as "silica gel", more than 70% of the tested samples contained high amounts of DMF, many of them at the high microgram per gramme level. Many samples also showed the presence of the other two potential allergens. These results demonstrate that the content of the "desiccant" sachets and tablets in consumer products does not usually belong with the label of the desiccant, and hence, the high risk of exposition to the powerful allergen DMF and other potentially harmful chemicals through consumer goods should be a matter of concern.


Compassionate communities and collective memory: a conceptual framework to address the epidemic of loneliness.
In recent years, tackling loneliness has become the focus of increased scholarly debate, social intervention and the development of international policy. One response to the 'epidemic of loneliness' has been the development of the compassionate communities model. The diversity of compassionate communities approaches has led to scholars such as Allan Kellehear (2005; 2017) to highlight a lack of a cohesive underpinning theory to support and drive policy development. In this paper, we propose the use of 'collective memory' as a novel approach to linking loneliness, memory and identity in a way that draws out conceptual links between the role compassionate communities play in tackling social isolation and loneliness. We suggest that the service-led approach that seeks to identify and transpose strategies from one community to another is ineffective; instead, we emphasise the need to develop bespoke community-centred models that can be used by community nurses.


Participatory approaches in the development of health interventions for migrants: a systematic review.
Analysis of participatory approaches to developing health interventions for migrants and how approaches embody core participatory principles of inclusivity and democracy. A systematic review of original articles. Electronic searches within the databases MEDLINE, Embase, Global Health and PsychINFO (from inception-November 2020). Original peer-reviewed articles reporting research to develop and implement a health intervention for migrants, incorporating participatory approaches. We defined migrants as foreign-born individuals. Only articles reporting the full research cycle (inception, design, implementation, analysis, evaluation, dissemination) were included. We extracted information related to who was involved in research (migrants or other non-academic stakeholders), the research stage at which they were involved (inception, design, implementation, analysis, evaluation, dissemination), the method of their involvement and how this aligned with the core principles of participatory research-categorising studies as exhibiting active or pseudo (including proxy and indirect) participation. 1793 publications were screened, of which 28 were included in our analysis. We found substantial variation in the application of participatory approaches in designing health interventions targeting migrants: across 168 individual research stages analysed across the 28 studies, we recorded 46 instances of active participation of migrants, 30 instances of proxy participation and 24 instances of indirect participation. All studies involved non-academic stakeholders in at least one stage of the research, only two studies exhibited evidence of active participation of migrants across all research stages. Evidence is limited due to the variability of terms and approaches used. Important shortfalls in the meaningful inclusion of migrants in developing health interventions exist, suggesting a more rigorous and standardised approach is warranted to better define and deliver participatory research and improve quality. This review followed Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines and is registered on the Open Science Framework (osf.io/2bnz5).


Spontaneous Regression of Cervical Intraepithelial Neoplasia 2: A Meta-analysis.
Cervical intraepithelial neoplasia (CIN) is a precancerous condition that, if progresses, can cause cervical cancer. Less severe forms such as CIN1 regress spontaneously for most of the cases, but for high-grade CIN (CIN2 or CIN3), have higher potentials for progression. Aim of the present study was to obtain reliable estimates of spontaneous regression and progression rates of CIN2. Data were extracted from eligible studies identified after literature search in electronic databases, and meta-analyses were performed by pooling the regression and progression rates reported by these studies. Meta-regression analyses were performed for the identification of factors affecting regression rate. Sixteen studies (1,481 patients; 14.86 months [95% CI 9.25-20.48] follow-up; 28.23 years [95% CI 25.07-31.39] age) were included in the meta-analysis. Overall regression rate in these conservatively observed patients was 42.66% (95% CI 35.41-49.91), but regression rate was higher in studies that recruited patients with CIN2 (50.85% [95% CI 36.11-65.60]) in comparison with those that recruited patients without discrimination of CIN2 with CIN3 (36.31% [95% CI 27.67-44.95]. Progression rate in CIN2 patients was 10.28% [95% CI 3.72-16.84]). Age was significantly negatively associated with regression rate (coefficient -1.72 [-3.53 to 0.10]; p = 0.061). Spontaneous regression rate of CIN2 is considerably high, especially in younger years.


Antitumor effect of novel HSP90 inhibitor NVP-AUY922 against oral squamous cell carcinoma.
Heat-shock protein 90 (HSP90) is a major cellular chaperone protein. HSP90 supports the correct conformation, stabilization, activation, and localization of 'client' oncoproteins, many of which are involved in tumor progression. Therefore, the use of HSP90 inhibitors has become a new strategy in antitumor therapy. However, the effects of an HSP90 inhibitor on oral squamous cell carcinoma are still unclear. NVP-AUY922 (Novartis) is a novel 4,5-diaryloxazole adenosine triphosphate-binding site HSP90 inhibitor. In this study, we investigated the antitumor effect of novel HSP90 inhibitor NVP-AUY922 against oral squamous cell carcinoma. NVP-AUY922 inhibited the proliferation of oral squamous cell carcinoma cells in vitro. NVP-AUY922 caused degradation of client protein inducing ErbB2, p-Akt, p-S6, hypoxia-inducible factor 1-α (HIF1-α) and vascular endothelial growth factor (VEGF) and up-regulation of HSP70 in HSC-2 oral squamous cell carcinoma. NVP-AUY922 increased the expression of cleaved caspase-3 and induced apoptosis in HSC-2 cells. Treatment of NVP-AUY922 induced a robust antitumor response and suppressed p-Akt and VEGF expression in an HSC-2 xenograft model. In summary, NVP-AUY922 exhibits in vitro and in vivo efficiency against oral squamous cell carcinoma, representing a promising therapeutic approach for oral squamous cell carcinoma.


Limitations of cyclosporin A inhibition of the permeability transition in CNS mitochondria.
Activation of the mitochondrial permeability transition may contribute to excitotoxic neuronal death (Ankarcrona et al., 1996; Dubinsky and Levi, 1998). However, cyclosporin A (CsA), a potent inhibitor of the permeability transition in liver mitochondria, only protects against neuronal injury by limited doses of glutamate and selected ischemic paradigms. The lack of consistent CsA inhibition of the mitochondrial permeability transition was analyzed with the use of isolated brain mitochondria. Changes in the permeability of the inner mitochondrial membrane were evaluated by monitoring mitochondrial membrane potential (Deltapsi), using the distribution of tetraphenylphosphonium, and by monitoring mitochondrial swelling, using light absorbance measurements. Metabolic impairments, large Ca(2+) loads, omission of external Mg(2+), or low doses of palmitic acid or the protonophore FCCP exacerbated Ca(2+)-induced sustained depolarizations and swelling and eliminated CsA inhibition. BSA restored CsA inhibition in mitochondria challenged with 50 microm Ca(2+), but not with 100 microm Ca(2+). CsA failed to prevent Ca(2+)-induced depolarization or to repolarize mitochondria when mitochondria were depolarized excessively. Similarly, CsA failed to prevent mitochondrial swelling or PEG-induced shrinkage after swelling when the Ca(2+) challenge produced a strong, sustained depolarization. Thus in brain mitochondria CsA may be effective only as an inhibitor of the permeability transition and the Ca(2+)-activated low permeability state under conditions of partial depolarization. In contrast, ADP plus oligomycin inhibited both permeabilities under all of the conditions that were tested. In situ, the neuroprotective action of CsA may be limited to glutamate challenges sufficiently toxic to induce the permeability transition but not so severe that mitochondrial depolarization exceeds threshold.


Hopanoids play a role in stress tolerance and nutrient storage in the cyanobacterium Nostoc punctiforme.
Hopanes are abundant in ancient sedimentary rocks at discrete intervals in Earth history, yet interpreting their significance in the geologic record is complicated by our incomplete knowledge of what their progenitors, hopanoids, do in modern cells. To date, few studies have addressed the breadth of diversity of physiological functions of these lipids and whether those functions are conserved across the hopanoid-producing bacterial phyla. Here, we generated mutants in the filamentous cyanobacterium, Nostoc punctiforme, that are unable to make all hopanoids (shc) or 2-methylhopanoids (hpnP). While the absence of hopanoids impedes growth of vegetative cells at high temperature, the shc mutant grows faster at low temperature. This finding is consistent with hopanoids acting as membrane rigidifiers, a function shared by other hopanoid-producing phyla. Apart from impacting fitness under temperature stress, hopanoids are dispensable for vegetative cells under other stress conditions. However, hopanoids are required for stress tolerance in akinetes, a resting survival cell type. While 2-methylated hopanoids do not appear to contribute to any stress phenotype, total hopanoids and to a lesser extent 2-methylhopanoids were found to promote the formation of cyanophycin granules in akinetes. Finally, although hopanoids support symbiotic interactions between Alphaproteobacteria and plants, they do not appear to facilitate symbiosis between N. punctiforme and the hornwort Anthoceros punctatus. Collectively, these findings support interpreting hopanes as general environmental stress biomarkers. If hopanoid-mediated enhancement of nitrogen-rich storage products turns out to be a conserved phenomenon in other organisms, a better understanding of this relationship may help us parse the enrichment of 2-methylhopanes in the rock record during episodes of disrupted nutrient cycling.


mglur6b:EGFP Transgenic zebrafish suggest novel functions of metabotropic glutamate signaling in retina and other brain regions.
Metabotropic glutamate receptors (mGluRs) are mainly known for regulating excitability of neurons. However, mGluR6 at the photoreceptor-ON bipolar cell synapse mediates sign inversion through glutamatergic inhibition. Although this is currently the only confirmed function of mGluR6, other functions have been suggested. Here we present Tg(mglur6b:EGFP)zh1, a new transgenic zebrafish line recapitulating endogenous expression of one of the two mglur6 paralogs in zebrafish. Investigating transgene as well as endogenous mglur6b expression within the zebrafish retina indicates that EGFP and mglur6b mRNA are not only expressed in bipolar cells, but also in a subset of ganglion and amacrine cells. The amacrine cells labeled in Tg(mglur6b:EGFP)zh1 constitute a novel cholinergic, non-GABAergic, non-starburst amacrine cell type described for the first time in teleost fishes. Apart from the retina, we found transgene expression in subsets of periventricular neurons of the hypothalamus, Purkinje cells of the cerebellum, various cell types of the optic tectum, and mitral/ruffed cells of the olfactory bulb. These findings suggest novel functions of mGluR6 besides sign inversion at ON bipolar cell dendrites, opening up the possibility that inhibitory glutamatergic signaling may be more prevalent than currently thought. J. Comp. Neurol. 524:2363-2378, 2016. © 2016 Wiley Periodicals, Inc.


Surfactant-associated bacteria in the near-surface layer of the ocean.
Certain marine bacteria found in the near-surface layer of the ocean are expected to play important roles in the production and decay of surface active materials; however, the details of these processes are still unclear. Here we provide evidence supporting connection between the presence of surfactant-associated bacteria in the near-surface layer of the ocean, slicks on the sea surface, and a distinctive feature in the synthetic aperture radar (SAR) imagery of the sea surface. From DNA analyses of the in situ samples using pyrosequencing technology, we found the highest abundance of surfactant-associated bacterial taxa in the near-surface layer below the slick. Our study suggests that production of surfactants by marine bacteria takes place in the organic-rich areas of the water column. Produced surfactants can then be transported to the sea surface and form slicks when certain physical conditions are met. This finding has potential applications in monitoring organic materials in the water column using remote sensing techniques. Identifying a connection between marine bacteria and production of natural surfactants may provide a better understanding of the global picture of biophysical processes at the boundary between the ocean and atmosphere, air-sea exchange of greenhouse gases, and production of climate-active marine aerosols.


Stereoselective Total Synthesis of Macrophage-Produced Prohealing 14,21-Dihydroxy Docosahexaenoic Acids.
Synthesis of 14S,21R- and 14S,21S-dihydroxy-DHA (diHDHA) among the four possible stereoisomers of 14,21-diHDHA was studied. Methyl (R)-lactate (>97% ee), selected as a C20-C22 fragment (DHA numbering), was converted to the C17-C22 phosphonium salt, which was subjected to a Wittig reaction with racemic C16-aldehyde of the C12-C16 part with the TMS and TBS-oxy groups at C12 and C14, yielding the C12-C22 derivative with 14R/S and 21R chirality. Kinetic resolution using Sharpless asymmetric epoxidation of the TBS-deprotected allylic alcohol with l-(+)-DIPT/Ti(O-i-Pr)4 afforded 14S-epoxy alcohol and 14R-allylic alcohol with >99% diastereomeric excess (de) for both. The CN group was introduced to the epoxy alcohol by reaction with Et2AlCN. The 14R-allylic alcohol was also converted to the nitrile via Mitsunobu inversion. Reduction of the nitrile with DIBAL afforded the key aldehyde corresponding to the C11-C22 moiety. The Wittig reaction of this aldehyde with a phosphonium salt of the remaining C1-C10 part followed by functional group manipulation gave 14S,21R-diHDHA. Similarly, ethyl (S)-lactate (>99% ee) was converted to 14S,21S-diHDHA. The chiral LC-UV-MS/MS analysis demonstrated that each of these two 14,21-diHDHAs synthesized using the presented total organic synthesis was highly stereoselective and identical to the macrophage-produced counterpart.


Long-term follow-up of patients with isolated left ventricular noncompaction: role of electrocardiography in predicting poor outcome.
Abnormal baseline electrocardiograms (ECGs) are common in patients with isolated left ventricular noncompaction (IVNC). Whether certain electrocardiographic parameters are associated with a poor clinical outcome, however, remains elusive. The present study was therefore designed to comprehensively assess the predictive value of baseline ECG findings in patients newly diagnosed with IVNC. 74 patients diagnosed with IVNC were included in the analysis. During follow-up, 8 patients (11%) died of a cardiovascular cause or underwent heart transplantation (primary outcome measure). On univariate analysis, several variables, including repolarization abnormalities (ST segment elevation/depression, T-wave inversion) in the inferior leads (5-year estimator: 67.1 ± 10.7% vs. 98 ± 2.2%; P = 0.001), an increase in PQ- (hazard ratio (HR) 1.032, P=0.004) and QTc-duration (HR 1.037, P=0.001), were predictive of cardiovascular death or heart transplantation. On multivariate analysis, only PQ- and QTc-duration and the presence of repolarization abnormalities in the inferior leads remained significantly predictive of a poor outcome. PQ duration, QTc duration, and repolarization abnormalities in the inferior leads are independently predictive of a poor prognosis in IVNC. Further prospective studies are required to conclusively investigate the usefulness of baseline ECG parameters for risk stratification in patients with IVNC.


Production of 2,3-butanediol in Saccharomyces cerevisiae by in silico aided metabolic engineering.
2,3-Butanediol is a chemical compound of increasing interest due to its wide applications. It can be synthesized via mixed acid fermentation of pathogenic bacteria such as Enterobacter aerogenes and Klebsiella oxytoca. The non-pathogenic Saccharomyces cerevisiae possesses three different 2,3-butanediol biosynthetic pathways, but produces minute amount of 2,3-butanediol. Hence, we attempted to engineer S. cerevisiae strain to enhance 2,3-butanediol production. We first identified gene deletion strategy by performing in silico genome-scale metabolic analysis. Based on the best in silico strategy, in which disruption of alcohol dehydrogenase (ADH) pathway is required, we then constructed gene deletion mutant strains and performed batch cultivation of the strains. Deletion of three ADH genes, ADH1, ADH3 and ADH5, increased 2,3-butanediol production by 55-fold under microaerobic condition. However, overproduction of glycerol was observed in this triple deletion strain. Additional rational design to reduce glycerol production by GPD2 deletion altered the carbon fluxes back to ethanol and significantly reduced 2,3-butanediol production. Deletion of ALD6 reduced acetate production in strains lacking major ADH isozymes, but it did not favor 2,3-butanediol production. Finally, we introduced 2,3-butanediol biosynthetic pathway from Bacillus subtilis and E. aerogenes to the engineered strain and successfully increased titer and yield. Highest 2,3-butanediol titer (2.29 . l-1) and yield (0.113 g . g-1) were achieved by Δadh1 Δadh3 Δadh5 strain under anaerobic condition. With the aid of in silico metabolic engineering, we have successfully designed and constructed S. cerevisiae strains with improved 2,3-butanediol production.


The respiratory response to carbon dioxide in humans with unilateral and bilateral resections of the carotid bodies.
The acute hypercapnic ventilatory response (AHCVR) arises from both peripheral and central chemoreflexes. In humans, one technique for identifying the separate contributions of these chemoreflexes to AHCVR has been to associate the rapid component of AHCVR with the peripheral chemoreflex and the slow component with the central chemoreflex. Our first aim was to validate this technique further by determining whether a single slow component was sufficient to describe AHCVR in patients with bilateral carotid body resections (BR) for glomus cell tumours. Our second aim was to determine whether the slow component of AHCVR was diminished following carotid body resection as has been suggested by studies in experimental animals. Seven BR subjects were studied together with seven subjects with unilateral resections (UR) and seven healthy controls. A multifrequency binary sequence in end-tidal PCO2 was employed to stimulate ventilation dynamically under conditions of both euoxia and mild hypoxia. Both two- and one-compartment models of AHCVR were fitted to the data. For BR subjects, the two-compartment model fitted significantly better on 1 out of 13 occasions compared with 22 out of 28 occasions for the other subjects. Average values for the chemoreflex sensitivity of the slow component of AHCVR differed significantly (P < 0.05) between the groups and were 0.95, 1.38 and 1.50 l min-1 Torr-1 for BR, UR and control subjects, respectively. We conclude that, without the peripheral chemoreflex, AHCVR is adequately described by a single slow component and that BR subjects have sensitivities for the slow component that are lower than those of control subjects.


Influence of patients' requests for direct-to-consumer advertised antidepressants: a randomized controlled trial.
Direct-to-consumer (DTC) advertising of prescription drugs in the United States is both ubiquitous and controversial. Critics charge that it leads to overprescribing, while proponents counter that it helps avert underuse of effective treatments, especially for conditions that are poorly recognized or stigmatized. To ascertain the effects of patients' DTC-related requests on physicians' initial treatment decisions in patients with depressive symptoms. Randomized trial using standardized patients (SPs). Six SP roles were created by crossing 2 conditions (major depression or adjustment disorder with depressed mood) with 3 request types (brand-specific, general, or none). Offices of primary care physicians in Sacramento, Calif; San Francisco, Calif; and Rochester, NY, between May 2003 and May 2004. One hundred fifty-two family physicians and general internists recruited from solo and group practices and health maintenance organizations; cooperation rates ranged from 53% to 61%. The SPs were randomly assigned to make 298 unannounced visits, with assignments constrained so physicians saw 1 SP with major depression and 1 with adjustment disorder. The SPs made a brand-specific drug request, a general drug request, or no request (control condition) in approximately one third of visits. Data on prescribing, mental health referral, and primary care follow-up obtained from SP written reports, visit audiorecordings, chart review, and analysis of written prescriptions and drug samples. The effects of request type on prescribing were evaluated using contingency tables and confirmed in generalized linear mixed models that accounted for clustering and adjusted for site, physician, and visit characteristics. Standardized patient role fidelity was excellent, and the suspicion rate that physicians had seen an SP was 13%. In major depression, rates of antidepressant prescribing were 53%, 76%, and 31% for SPs making brand-specific, general, and no requests, respectively (P<.001). In adjustment disorder, antidepressant prescribing rates were 55%, 39%, and 10%, respectively (P<.001). The results were confirmed in multivariate models. Minimally acceptable initial care (any combination of an antidepressant, mental health referral, or follow-up within 2 weeks) was offered to 98% of SPs in the major depression role making a general request, 90% of those making a brand-specific request, and 56% of those making no request (P<.001). Patients' requests have a profound effect on physician prescribing in major depression and adjustment disorder. Direct-to-consumer advertising may have competing effects on quality, potentially both averting underuse and promoting overuse.


Comparison of diffusion tractography and tract-tracing measures of connectivity strength in rhesus macaque connectome.
With the mapping of macroscale connectomes by means of in vivo diffusion-weighted MR Imaging (DWI) rapidly gaining in popularity, one of the necessary steps is the examination of metrics of connectivity strength derived from these reconstructions. In the field of human macroconnectomics the number of reconstructed fiber streamlines (NOS) is more and more used as a metric of cortico-cortical interareal connectivity strength, but the link between DWI NOS and in vivo animal tract-tracing measurements of anatomical connectivity strength remains poorly understood. In this technical report, we communicate on a comparison between DWI derived metrics and tract-tracing metrics of projection strength. Tract-tracing information on projection strength of interareal pathways was extracted from two commonly used macaque connectome datasets, including (1) the CoCoMac database of collated tract-tracing experiments of the macaque brain and (2) the high-resolution tract-tracing dataset of Markov and Kennedy and coworkers. NOS and density of reconstructed fiber pathways derived from DWI data acquired across 10 rhesus macaques was found to positively correlate to tract-tracing based measurements of connectivity strength across both the CoCoMac and Markov dataset (both P < 0.001), suggesting DWI NOS to form a valid method of assessment of the projection strength of white matter pathways. Our findings provide confidence of in vivo DWI connectome reconstructions to represent fairly realistic estimates of the wiring strength of white matter projections. Our cross-modal comparison supports the notion of in vivo DWI to be a valid methodology for robust description and interpretation of brain wiring.


Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption.
Two-sample summary-data Mendelian randomization (MR) incorporating multiple genetic variants within a meta-analysis framework is a popular technique for assessing causality in epidemiology. If all genetic variants satisfy the instrumental variable (IV) and necessary modelling assumptions, then their individual ratio estimates of causal effect should be homogeneous. Observed heterogeneity signals that one or more of these assumptions could have been violated. Causal estimation and heterogeneity assessment in MR require an approximation for the variance, or equivalently the inverse-variance weight, of each ratio estimate. We show that the most popular 'first-order' weights can lead to an inflation in the chances of detecting heterogeneity when in fact it is not present. Conversely, ostensibly more accurate 'second-order' weights can dramatically increase the chances of failing to detect heterogeneity when it is truly present. We derive modified weights to mitigate both of these adverse effects. Using Monte Carlo simulations, we show that the modified weights outperform first- and second-order weights in terms of heterogeneity quantification. Modified weights are also shown to remove the phenomenon of regression dilution bias in MR estimates obtained from weak instruments, unlike those obtained using first- and second-order weights. However, with small numbers of weak instruments, this comes at the cost of a reduction in estimate precision and power to detect a causal effect compared with first-order weighting. Moreover, first-order weights always furnish unbiased estimates and preserve the type I error rate under the causal null. We illustrate the utility of the new method using data from a recent two-sample summary-data MR analysis to assess the causal role of systolic blood pressure on coronary heart disease risk. We propose the use of modified weights within two-sample summary-data MR studies for accurately quantifying heterogeneity and detecting outliers in the presence of weak instruments. Modified weights also have an important role to play in terms of causal estimation (in tandem with first-order weights) but further research is required to understand their strengths and weaknesses in specific settings.


Prevalence of adolescent obesity at a high school in the City of Tshwane.
Obesity has been reported to be on the rise in the world and South Africa is no exception. In recent years obesity has been reported to contribute to the increasing number of people with hypertension and diabetes mellitus. Africa has the fastest growing number of overweight and obese adolescents, with indications that in 2010, it had more than doubled since 1990. Some people might perceive being overweight as being round and healthy which might contribute to the increased rate of obesity in South Africa. Physical and psychological changes that occur during adolescence can also be observed earlier during the preteen years (ages 9-12 years). During this time, peer groups and external appearance are of importance. Physical changes, such as obesity, might be perceived negatively by adolescents, affecting their self-esteem. The purpose of the study was to determine the prevalence of adolescent obesity at a high school in the City of Tshwane. A cross-sectional survey was conducted. Stratified random sampling was used and data were collected from 30% of the total population as recommended by the statistician. Data analysis was performed using descriptive analysis. Validity and reliability were ensured through calibrating the weight-monitoring scale and the measuring tape, which are collection tools. The results identified the prevalence of adolescent obesity at 8.57%. There is evidence of abdominal obesity and waist-hip ratio ≥ 1. The results show that there is a steady increase in obesity levels among adolescents. The poor response of parents was observed and could demonstrate the need to form stronger partnerships for weight reduction interventions. Evidence-based prevalence allowed for conceptualisation of the scope of the obesity epidemic and how children and young people are also affected. To enable proper planning for adolescent obesity interventions, the depth of consequences of obesity for the adolescent cohort should be well defined and clarified.


Ab initio calculations of the electronic properties of polypyridine transition metal complexes and their adsorption on metal surfaces in the presence of solvent and counterions.
Os(II)/(III) and Co(II)/(III) polypyridine complexes in aqueous solution are robust molecular entities both in freely solute state and adsorbed on Au(111)- and Pt(111)-electrode surfaces. This class of robust coordination chemical compounds have recently been characterized by electrochemical scanning tunneling microscopy (in situ STM). The Os-complexes were found to display strong tunneling spectroscopic (STS) features at the level of resolution of the single molecule while STS features of the Co complexes, although clear, were much weaker. The data was framed by concise but phenomenological theory of interfacial electrochemical electron transfer extended to the electrochemical in situ STM configuration. With a view on first-principle insight into the in situ STM behavior of robust redox (as opposed to nonredox) molecules, we present in this report a density functional theory (DFT) study of the complexes in both free and adsorbate state, in either state exposed to both stoichiometric counterions and a large assembly of solvent water molecules. The oxidation states of the complexes were controlled, first by introducing chlorine counter atoms followed by spontaneous attraction of electrons from the complexes, also at first in electrostatically neutral form. Second, the solvent is found to provide strong dielectric screening of this charge transfer process and to be crucial for achieving the full chemically meaningful charge separated ionic oxidation states. The molecular charge and structure of the complexes in the presence of the solvent, are conserved upon adsorption, whereas the structural features of the different oxidation states are completely lost upon adsorption under vacuum conditions. Detailed microscopic insight such as offered by the present study will be important in molecular-based approaches to "smart" redox molecules enclosed in in situ STM or other nanoscale and single-molecules scale configurations in condensed matter environments.


An Improved Red Spectrum of the Methane or T Dwarf SDSS 1624+0029: The Role of the Alkali Metals.
A Keck II low-resolution spectrum shortward of 1 µm is presented for SDSS 1624+0029, the first field methane or T dwarf discovered in the Sloan Digital Sky Survey. Significant flux is detected down to the spectrum's short-wavelength limit of 6200 Å. The spectrum exhibits a broad absorption feature centered at 7700 Å, which we interpret as the K i lambdalambda7665, 7699 resonance doublet. The observed flux declines shortward of 7000 Å, most likely owing to the red wing of the Na i doublet. Both Cs i doublet lines are detected more strongly than in an earlier red spectrum. Neither Li i absorption nor Halpha emission are detected. An exploratory model fit to the spectrum suggests that the shape of the red spectrum can be primarily accounted for by the broad wings of the K i and Na i doublets. This behavior is consistent with the argument proffered by Burrows, Marley, & Sharp that strong alkali absorption is principally responsible for depressing T dwarf spectra shortward of 1 µm. In particular, there seems no compelling reason at this time to introduce dust or an additional opacity source in the atmosphere of the Sloan object. The width of the K i and strengths of the Cs i lines also indicate that the Sloan object is warmer than Gl 229B.


Parcellation of sensorimotor transformations for arm movements.
Pointing to a visual target in 3-dimensional space requires a neural transformation from a visually derived representation of target location to an appropriate pattern of activity in arm muscles. Previous results suggested that 1 step in this process involves a transformation from a representation of target location to a representation of intended arm orientation, and that the neural implementation of this transformation involves a linear approximation to the mathematically exact, nonlinear solution. These results led to the hypothesis that the transformation is parceled into 2 separate channels. In 1 channel a representation of target azimuth is transformed into a representation of arm yaw angles, while in the other channel representations of target distance and target elevation are transformed into a representation of arm elevation angles. The present experiments tested this hypothesis by measuring the errors made by human subjects as they pointed to various parameters of the remembered location of a target in space. The results show that subjects can use the 2 hypothesized channels separately. For example, subjects can accurately point to the target's azimuth while ignoring the target's elevation and distance. The results also show that subjects are unable to point to the target's elevation while ignoring the target's distance, consistent with the hypothesis that information about target elevation and target distance is tied together in the same channel. The parcellation demonstrated in this study is compared to reports of parceled sensorimotor transformation in other vertebrate species.


Long-term effectiveness of treatments for symptomatic convergence insufficiency in children.
To assess the long-term stability of improvements in symptoms and signs in 9- to 17-year-old children enrolled in the Convergence Insufficiency Treatment Trial who were asymptomatic after treatment for convergence insufficiency. Seventy-nine patients who were asymptomatic after a 12-week therapy program for convergence insufficiency were followed for 1 year [33/60 in office-based vergence/accommodative therapy (OBVAT), 18/54 in home-based pencil push-ups (HBPP), 12/57 in home-based computer vergence/accommodative therapy and pencil push-ups (HBCVAT+), and 16/54 in office-based placebo therapy (OBPT)]. Symptoms and clinical signs were measured 6 months and 1 year after completion of the 12-week therapy program. The primary outcome measure was the mean change on the Convergence Insufficiency Symptom Survey (CISS). Secondary outcome measures were near point of convergence, positive fusional vergence at near, and proportions of patients who remained asymptomatic or who were classified as successful or improved based on a composite measure of CISS, near point of convergence, and positive fusional vergence. One-year follow-up visit completion rate was 89% with no significant differences between groups (p = 0.26). There were no significant changes in the CISS in any treatment group during the 1-year follow-up. The percentage who remained asymptomatic in each group was 84.4% (27/32) for OBVAT, 66.7% (10/15) for HBPP, 80% (8/10) for HBCVAT+, and 76.9% (10/13) for OBPT. The percentage who remained either successful or improved 1-year posttreatment was 87.5% (28/32) for OBVAT, 66.6% (10/15) for HBPP, 80% (8/10) for HBCVAT+, and 69.3% (9/13) for OBPT. Most children aged 9 to 17 years who were asymptomatic after a 12-week treatment program of OBVAT for convergence insufficiency maintained their improvements in symptoms and signs for at least 1 year after discontinuing treatment. Although the sample sizes for the home-based and placebo groups were small, our data suggest that a similar outcome can be expected for children who were asymptomatic after treatment with HBPP or HBCVAT+.


Intergenerational family solidarity: value differences between immigrant groups and generations.
Although immigrants may be more dependent on their immediate family for support, they may also experience a wider generation-gap in values regarding intergenerational solidarity, because of processes of acculturation. Based on large scale survey data (N = 2,028), differences between first and second generation immigrants in values regarding intergenerational solidarity were examined among family members in the Netherlands with an immigration background from Turkey, Morocco, Suriname, and The Dutch Antilles. Using a multilevel analytic approach, effects of family and individual characteristics on values regarding intergenerational solidarity were tested, considering the perspectives of two generations. It was found that immigrants with Moroccan and Turkish backgrounds scored higher on values with respect to intergenerational family solidarity than immigrants stemming from Suriname and The Antilles. First generation immigrants placed higher values on family solidarity compared to second generation immigrants. Additionally, religious denomination was a significant predictor of higher values with respect to intergenerational family solidarity. Immigration and acculturation may create great strains in migrant families. Policies to support the fabric of intergenerational solidarity should consider ethnic and religious background and immigration history.


Protective antigenic determinant of streptococcal M protein shared with sarcolemmal membrane protein of human heart.
We present definitive evidence that at least one protective antigenic determinant on type 5 M protein of group A streptococci evokes antibody that is cross-reactive with human heart tissue. One of nine rabbits immunized with a peptide fragment of type 5 M protein (pep M5) produced antibody that cross-reacted by immunofluorescence with sarcolemmal membranes of human heart. The cross-reactive antibody could be removed by absorbing the antiserum with sarcolemmal membranes, types 5 and 19 streptococci, or their pepsin-extracted M proteins, but with no other serotypes tested. Although each of the pep M5 immune sera was opsonic for type 5 streptococci, only the heart-reactive antiserum opsonized type 19 streptococci. The opsonization of type 19 streptococci was abolished by absorbing the antiserum with sarcolemmal membranes isolated from human heart tissue. Purified heart-reactive antibodies eluted from sarcolemmal membranes opsonized both types 5 and 19 streptococci, indicating that the heart cross-reactive determinant of type 5 M protein is cross-protective. The cross-reactive antigen was purified by affinity chromatography from detergent extracts of sarcolemmal membranes and determined to be a complex protein composed of four subunits apparently linked by disulfide bonds.


Modifications in IgG subclasses in the course of immunotherapy with grass pollen.
In this study, we evaluated the evolution of IgG subclasses in the course of immunotherapy, and related this to the clinical evolution. We selected 226 adult patients with sensitivity to grass pollen alone, undergoing immunotherapy for 0-26 months. The following results may be highlighted: 1) IgG1 increased with immunotherapy and reached its peak at 6 months; 2) IgG2 increased significantly, reaching its peak after 24 months of treatment; 3) IgG3, however, did not present significant modifications in the course of immunotherapy; and 4) IgG4 was high in all patients undergoing immunotherapy compared to patients without hyposensitizing treatment, the peak being reached in the group of patients with the longest course of immunotherapy. Only IgG4 showed a positive and significant (p < 0.05) correlation with the degree of clinical recovery reached with immunotherapy.


Ion-solvation structure and battery electrode characteristics of nonflammable organic electrolytes based on tris(trifluoroethyl)phosphate dissolving lithium salts.
The structure and properties of lithium salt solutions based on tris(2,2,2-trifluoroethyl)phosphate (TFEP) solvent have been studied to design a safer electrolyte system for large-sized lithium-ion battery applications. Influences of the ionic structure on the polarization behavior of the LiCoO2 (LCO) positive electrode were investigated. The ionic conductivity and viscosity of the solution consisting of lithium salts dissolved in TFEP, LiX/TFEP (X = PF6, BF4 and TFSA) (TFSA = (CF3SO2)2N), were measured. The results suggest that the ion-solvation structure greatly depends on the anionic species in the salt. Spectroscopic measurements also support the conclusion that the Li+-solvation structure varies with the lithium salts. The differences in the ionic structure of LiX/TFEP influence the electrochemical oxidation potential of the solution and the polarization behavior of the LCO electrode. The overvoltage for Li-desertion/insertion from/into LCO in LiX/TFEP, being much higher than that observed in conventional LIB electrolyte solutions, shows the order of BF4 < PF6 < TFSA. The addition of ethylene carbonate (EC) to LiX/TFEP increases the ionic conductivity, which is probably caused by changes in the Li+-solvation structure in TFEP. The overvoltage for the Li-desertion/insertion of LCO is much lowered by the addition of EC to LiX/TFEP.


Advancing genomic research and reducing health disparities: what can nurse scholars do?
Advances in genomic research are improving our understanding of human diseases and evoking promise of an era of genomic medicine. It is unclear whether genomic medicine may exacerbate or attenuate extant racial group health disparities. We delineate how nurse scholars could engage in the configuration of an equitable genomic medicine paradigm. We identify as legitimate subjects for nursing scholarship the scientific relevance, ethical, and public policy implications for employing racial categories in genomic research in the context of reducing extant health disparities. Since genomic research is largely population specific, current classification of genomic data will center on racial and ethnic groups. Nurse scholars should be involved in clarifying how putative racial group differences should be elucidated in light of the current orthodoxy that genomic solutions may alleviate racial health disparities. Nurse scholars are capable of employing their expertise in concept analysis to elucidate how race is used as a variable in scientific research, and to use knowledge brokering to delineate how race variables that imply human ancestry could be utilized in genomic research pragmatically in the context of health disparities. In an era of genomic medicine, nurse scholars should recognize and understand the challenges and complexities of genomics and race and their relevance to health care and health disparities.


Zinc supplementation reduced DNA breaks in Ethiopian women.
Assessment of zinc status remains a challenge largely because serum/plasma zinc may not accurately reflect an individual's zinc status. The comet assay, a sensitive method capable of detecting intracellular DNA strand breaks, may serve as a functional biomarker of zinc status. We hypothesized that effects of zinc supplementation on intracellular DNA damage could be assessed from samples collected in field studies in Ethiopia using the comet assay. Forty women, from villages where reported consumption of meat was less than once per month and phytate levels were high, received 20 mg zinc as zinc sulfate or placebo daily for 17 days in a randomized placebo-controlled trial. Plasma zinc concentrations were determined by inductively coupled plasma mass spectrometry. Cells from whole blood at the baseline and end point of the study were embedded in agarose, electrophoresed, and stained before being scored by an investigator blinded to the treatments. Although zinc supplementation did not significantly affect plasma zinc, mean (± SEM) comet tail moment measurement of supplemented women decreased from 39.7 ± 2.7 to 30.0 ± 1.8 (P< .005), indicating a decrease in DNA strand breaks in zinc-supplemented individuals. These findings demonstrated that the comet assay could be used as a functional assay to assess the effects of zinc supplementation on DNA integrity in samples collected in a field setting where food sources of bioavailable zinc are limited. Furthermore, the comet assay was sufficiently sensitive to detect changes in zinc status as a result of supplementation despite no significant changes in plasma zinc.


Delayed Intervention of Small Renal Masses on Active Surveillance.
Although surgical excision is the standard of therapy for small renal masses (SRMs), there is a growing recognition of active surveillance as an option in select patients who are poor surgical candidates or who have shorter life expectancy. A number of patients on expectant management, however, subsequently advance to definitive therapy. In this study, we systematically reviewed the literature and performed a pooled analysis of active surveillance series to evaluate the rate and indications for definitive treatment after initiating a period of active surveillance. Fourteen clinical series (1245 patients; 1364 lesions) met our selection criteria. Mean lesion size at presentation was 2.30 ± 0.40 cm with a mean follow-up of 33.6 ± 16.9 months. Collectively, 34.0% of patients underwent delayed intervention, which ranged in individual series from 3.6% to 70.3%. Of patients undergoing delayed intervention, the average time on active surveillance prior to definitive treatment was 27.8 ± 10.6 months. A pooled analysis revealed that 41.0% of patients underwent therapy secondary to tumor growth rate and 51.9% secondary to patient or physician preference in the absence of clinical progression. Overall, 1.1% of all patients progressed to metastatic disease during the average follow-up period. Thus, active surveillance may be an appropriate option for carefully selected patients with SRMs. However, delayed treatment is pursued in a significant percentage of patients within 3 years. Prospective registries and clinical trials with standardized indications for delayed intervention are needed to establish true rates of disease progressions and recommendations for delayed intervention.


Detection of antibodies to varicella zoster virus by radioimmunoassay and enzyme immunoassay techniques.
An enzyme assay for the detection of antibodies to varicella-zoster membrane antigen (IPAMA) and a solid phase radioimmunoassay (RIA) which utilizes infected cell lysates as antigen are described. The results have been compared with those obtained by the indirect fluorescent antibody to membrane antigen (IFAMA) technique. It was found that IPAMA was equal in sensitivity to IFAMA. No cross-reactivity was found with other herpes group viruses. The IPAMA appears to give objective results, is easily and rapidly performed, and is recommended as a routine test for serological diagnosis of varicella-zoster infection. The RIA method is about 100 times more sensitive than IPAMA and IFAMA. The RIA is specific and has the potential of determining lower levels of antibody than other serological methods currently in use.


Mutational analysis of cis elements involved in E2 modulation of human papillomavirus type 16 P97 and type 18 P105 promoters.
cis-Acting elements involved in E2 modulation of human papillomavirus type 16 (HPV-16) P97 promoter activity and HPV-18 P105 promoter activity were examined. In transfected primary human keratinocytes, each promoter had a basal activity that could be repressed by the bovine papillomavirus type 1 E2 gene product. Mutational analysis of the E2-binding sites in the long control region upstream of each promoter revealed that E2 repression was mediated through the E2-binding sites proximal to each promoter. In the context of a mutated E2-binding site at the promoter proximal position, the HPV-16 P97 and HPV-18 P105 promoters could be transactivated by E2. E2-mediated repression of HPV-18 P105 promoter activity was shown to be a transcriptional effect. The interaction of E2 with promoter-proximal E2-binding sites is likely to be important for the controlled expression of viral genes transcribed from the HPV-16 P97 promoter and the HPV-18 P105 promoter in infected human genital epithelial cells.


Effect of a participatory intervention with women's groups on birth outcomes in Nepal: cluster-randomised controlled trial.
Neonatal deaths in developing countries make the largest contribution to global mortality in children younger than 5 years. 90% of deliveries in the poorest quintile of households happen at home. We postulated that a community-based participatory intervention could significantly reduce neonatal mortality rates. We pair-matched 42 geopolitical clusters in Makwanpur district, Nepal, selected 12 pairs randomly, and randomly assigned one of each pair to intervention or control. In each intervention cluster (average population 7000), a female facilitator convened nine women's group meetings every month. The facilitator supported groups through an action-learning cycle in which they identified local perinatal problems and formulated strategies to address them. We monitored birth outcomes in a cohort of 28?931 women, of whom 8% joined the groups. The primary outcome was neonatal mortality rate. Other outcomes included stillbirths and maternal deaths, uptake of antenatal and delivery services, home care practices, infant morbidity, and health-care seeking. Analysis was by intention to treat. The study is registered as an International Standard Randomised Controlled Trial, number ISRCTN31137309. From 2001 to 2003, the neonatal mortality rate was 26.2 per 1000 (76 deaths per 2899 livebirths) in intervention clusters compared with 36.9 per 1000 (119 deaths per 3226 livebirths) in controls (adjusted odds ratio 0.70 [95% CI 0.53-0.94]). Stillbirth rates were similar in both groups. The maternal mortality ratio was 69 per 100000 (two deaths per 2899 livebirths) in intervention clusters compared with 341 per 100000 (11 deaths per 3226 livebirths) in control clusters (0.22 [0.05-0.90]). Women in intervention clusters were more likely to have antenatal care, institutional delivery, trained birth attendance, and hygienic care than were controls. Birth outcomes in a poor rural population improved greatly through a low cost, potentially sustainable and scalable, participatory intervention with women's groups.


Modeling target acquisition tasks associated with security and surveillance.
Military sensor applications include tasks such as the surveillance of activity and searching for roadside explosives. These tasks involve identifying and tracking specific objects in a cluttered scene. Unfortunately, the probability of accomplishing these tasks is not predicted by the traditional detect, recognize, and identify (DRI) target acquisition models. The reason why many security and surveillance tasks are functionally different from the traditional DRI tasks is described. Experiments using characters and simple shapes illustrate the problem with using the DRI model to predict the probability of identifying individual objects. The current DRI model is extended to predict specific object identification by including the frequency spectrum content of target contrast. The predictions of the new model match experimental data.


Race Strategies of Open Water Swimmers in the 5-km, 10-km, and 25-km Races of the 2017 FINA World Swimming Championships.
Despite literature on the pacing strategies of endurance sports, there is an existing lack of knowledge about the swimmers' tactical decisions in the open water races. The aims of the present research were (1) to compare the pacing profiles and tactical strategies of successful elite open water swimmers (men and women) in the 5-km, 10-km, and 25-km races and (2) to relate these pacing strategies to the end race results. Intermediate split times, positions and gaps with leaders of the first ten swimmers classified in the 2017 FINA World Swimming Championships races were collected from the public domain and were related to the finishing positions. Overall swimming velocities of the 5-km races were faster than the 10-km (δ 0.03 ± 0.03 m/s) and the 25-km (δ 0.14 ± 0.01 m/s) events with male swimmers achieving relatively faster mean velocities than females in the 5-km (δ 0.12 ± 0.01 m/s) compared to the 25-km (δ 0.08 ± 0.01 m/s) events. Medallist swimmers achieved moderate faster overall velocities than finalists in the 25-km races (0.01 ± 0.01 m/s) only. Inter-level differences were detected in selected splits for each race distance. Pacing profiles presented lap to lap velocity improvements in the 5-km and men's 10-km races (from +0.02 ± 0.00 to +0.11 ± 0.01 m/s) but also mid-race decreases in the women's 10-km and on the 25-km races. Successful swimmers were located in the leading positions of the 5-km races but at mid-group in the first part of the 10-km and 25-km races, with time gaps with leaders of 15-20 s. Faster lap swimming velocities, mid-race leading positions and shorter time-gaps were only related to the finishing positions in the last lap of the 10-km and in the three last laps of the 25-km events, but also in the first lap of the women's 5-km race. Despite different mid-race positioning, successful open water swimmers typically presented negative pacing profiles, a consistent control of mid-race gaps with leaders (15-20 s maximum) and great spurts (4-6% faster than mean race velocities) at the end of races. Coaches and swimmers should be aware of the different race dynamics depending to the event distance in order to select optimal race strategies.


A computational model of early argument structure acquisition.
How children go about learning the general regularities that govern language, as well as keeping track of the exceptions to them, remains one of the challenging open questions in the cognitive science of language. Computational modeling is an important methodology in research aimed at addressing this issue. We must determine appropriate learning mechanisms that can grasp generalizations from examples of specific usages, and that exhibit patterns of behavior over the course of learning similar to those in children. Early learning of verb argument structure is an area of language acquisition that provides an interesting testbed for such approaches due to the complexity of verb usages. A range of linguistic factors interact in determining the felicitous use of a verb in various constructions-associations between syntactic forms and properties of meaning that form the basis for a number of linguistic and psycholinguistic theories of language. This article presents a computational model for the representation, acquisition, and use of verbs and constructions. The Bayesian framework is founded on a novel view of constructions as a probabilistic association between syntactic and semantic features. The computational experiments reported here demonstrate the feasibility of learning general constructions, and their exceptions, from individual usages of verbs. The behavior of the model over the timecourse of acquisition mimics, in relevant aspects, the stages of learning exhibited by children. Therefore, this proposal sheds light on the possible mechanisms at work in forming linguistic generalizations and maintaining knowledge of exceptions.


Reformulating psychological difficulties in people with Parkinson's disease: the potential of a social relational approach to disablism.
Research investigating the psychological difficulties experienced by people with Parkinson's disease (PD) is dominated by individualistic neurobiological and psychological perspectives. Therefore, this opinion paper draws on a reformulation of the social model of disability, Thomas' (1999) and (2007) social relational approach to disablism, to offer an alternative way of conceptualising psychological difficulties experienced by people with PD. This opinion paper explores the ways in which socially imposed restrictions and stigma may contribute to psychological difficulties by using Thomas' (2007) concept of psychoemotional disablism. By using the lens of psychoemotional disablism, this paper demonstrates that people with PD can be exposed to stigmatising attitudes and interactions which could contribute to restrictions, feelings of shame, and psychological difficulties such as depression. Accordingly, it is argued that further attention to the link between psychological difficulties and social dimensions of disablism in PD is needed in both research arenas and clinical practice to broaden understandings and interventions for people with PD.


Evidence that genetic variation in 5-HT transporter expression is linked to changes in 5-HT2A receptor function.
Variability in expression of the 5-HT transporter (5-HTT) gene in the human population has been associated with a range of behavioural phenotypes. The underlying mechanisms are unclear but may involve changes in 5-HT receptor levels and/or signalling. The present study used a novel 5-HTT overexpressing transgenic mouse to test the hypothesis that variability in 5-HTT expression may alter 5-HT(2A) receptor function. In wildtype mice, the 5-HT(2) receptor agonist DOI increased regional brain mRNA expression of two immediate early genes (c-fos and Arc), and induced head twitches, and both effects were abolished by pre-treatment with the 5-HT(2A) receptor antagonist MDL 100907. In 5-HTT overexpressing mice, DOI induced a greater increase in both c-fos and Arc mRNA expression in cortical brain regions, and more head twitches, compared to wildtype mice. Autoradiographic and in situ hybridisation experiments showed that 5-HT(2A) receptor binding sites and 5-HT(2A) receptor mRNA did not differ between transgenic and wildtype mice. Finally, the transgenic mice had lower regional brain 5-HT levels compared to wildtype mice. This depletion of 5-HT may underpin the increase in 5-HT(2A) receptor function because in wildtype mice 5-HT depletion using the 5-HT synthesis inhibitor, p-chlorophenylalanine, enhanced the head twitch response to DOI. These data demonstrate that elevated 5-HTT expression is accompanied by increased 5-HT(2A) receptor function, an effect possibly mediated by decreased availability of synaptic 5-HT. Variation in levels of 5-HTT expression may therefore be a source of variability in 5-HT(2A) receptor function, which may be an important modifier of 5-HTT-linked phenotypes.


Design of an algorithm for the diagnostic approach of patients with joint pain.
Rheumatic diseases are a reason for frequent consultation with primary care doctors. Unfortunately, there is a high percentage of misdiagnosis. To design an algorithm to be used by primary care physicians to improve the diagnostic approach of the patient with joint pain, and thus improve the diagnostic capacity in four rheumatic diseases. Based on the information obtained from a literature review, we identified the main symptoms, signs, and paraclinical tests related to the diagnosis of rheumatoid arthritis, spondyloarthritis with peripheral involvement, systemic lupus erythematosus with joint involvement, and osteoarthritis. We conducted 3 consultations with a group of expert rheumatologists, using the Delphi technique, to design a diagnostic algorithm that has as a starting point "joint pain" as a common symptom for the four diseases. Thirty-nine rheumatologists from 18 countries of Ibero-America participated in the Delphi exercise. In the first consultation, we presented 94 items to the experts (35 symptoms, 31 signs, and 28 paraclinical tests) candidates to be part of the algorithm; 74 items (25 symptoms, 27 signs, and 22 paraclinical tests) were chosen. In the second consultation, the decision nodes of the algorithm were chosen, and in the third, its final structure was defined. The Delphi exercise lasted 8 months; 100% of the experts participated in the three consultations. We present an algorithm designed through an international consensus of experts, in which Delphi methodology was used, to support primary care physicians in the clinical approach to patients with joint pain. Key Points • We developed an algorithm with the participation of rheumatologists from 18 countries of Ibero-America, which gives a global vision of the clinical context of the patient with joint pain. • We integrated four rheumatic diseases into one tool with one common symptom: joint pain. It is a novel tool, as it is the first algorithm that will support the primary care physician in the consideration of four different rheumatic diseases. • It will improve the correct diagnosis and reduce the number of paraclinical tests requested by primary care physicians, in the management of patients with joint pain. This point was verified in a recently published study in the journal Rheumatology International (reference number 31).


Feature-based learning improves adaptability without compromising precision.
Learning from reward feedback is essential for survival but can become extremely challenging with myriad choice options. Here, we propose that learning reward values of individual features can provide a heuristic for estimating reward values of choice options in dynamic, multi-dimensional environments. We hypothesize that this feature-based learning occurs not just because it can reduce dimensionality, but more importantly because it can increase adaptability without compromising precision of learning. We experimentally test this hypothesis and find that in dynamic environments, human subjects adopt feature-based learning even when this approach does not reduce dimensionality. Even in static, low-dimensional environments, subjects initially adopt feature-based learning and gradually switch to learning reward values of individual options, depending on how accurately objects' values can be predicted by combining feature values. Our computational models reproduce these results and highlight the importance of neurons coding feature values for parallel learning of values for features and objects.


Divergent population structure and climate associations of a chromosomal inversion polymorphism across the Mimulus guttatus species complex.
Chromosomal rearrangement polymorphisms are common and increasingly found to be associated with adaptive ecological divergence and speciation. Rearrangements, such as inversions, reduce recombination in heterozygous individuals and thus can protect favourable allelic combinations at linked loci, facilitating their spread in the presence of gene flow. Recently, we identified a chromosomal inversion polymorphism that contributes to ecological adaptation and reproductive isolation between annual and perennial ecotypes of the yellow monkeyflower, Mimulus guttatus. Here we evaluate the population genetic structure of this inverted region in comparison with the collinear regions of the genome across the M. guttatus species complex. We tested whether annual and perennial M. guttatus exhibit different patterns of divergence for loci in the inverted and noninverted regions of the genome. We then evaluated whether there are contrasting climate associations with these genomic regions through redundancy analysis. We found that the inversion exhibits broadly different patterns of divergence among annual and perennial M. guttatus and is associated with environmental variation across population accessions. This study is the first widespread population genetic survey of the diversity of the M. guttatus species complex. Our findings contribute to a greater understanding of morphological, ecological, and genetic evolutionary divergence across this highly diverse group of closely related ecotypes and species. Finally, understanding species relationships among M. guttatus sp. has hitherto been stymied by accumulated evidence of substantial gene flow among populations as well as designated species. Nevertheless, our results shed light on these relationships and provide insight into adaptation in life history traits within the complex.


CMV retinitis screening and treatment in a resource-poor setting: three-year experience from a primary care HIV/AIDS programme in Myanmar.
Cytomegalovirus retinitis is a neglected disease in resource-poor settings, in part because of the perceived complexity of care and because ophthalmologists are rarely accessible. In this paper, we describe a pilot programme of CMV retinitis management by non-ophthalmologists. The programme consists of systematic screening of all high-risk patients (CD4 <100 cells/mm3) by AIDS clinicians using indirect ophthalmoscopy, and treatment of all patients with active retinitis by intravitreal injection of ganciclovir. Prior to this programme, CMV retinitis was not routinely examined for, or treated, in Myanmar. This is a retrospective descriptive study. Between November 2006 and July 2009, 17 primary care AIDS clinicians were trained in indirect ophthalmoscopy and diagnosis of CMV retinitis; eight were also trained in intravitreal injection. Evaluation of training by a variety of methods documented high clinical competence. Systematic screening of all high-risk patients (CD4 <100 cells/mm3) was carried out at five separate AIDS clinics throughout Myanmar. A total of 891 new patients (1782 eyes) were screened in the primary area (Yangon); the majority of patients were male (64.3%), median age was 32 years, and median CD4 cell count was 38 cells/mm3. CMV retinitis was diagnosed in 24% (211/891) of these patients. Bilateral disease was present in 36% of patients. Patients with active retinitis were treated with weekly intravitreal injection of ganciclovir, with patients typically receiving five to seven injections per eye. A total of 1296 injections were administered. A strategy of management of CMV retinitis at the primary care level is feasible in resource-poor settings. With appropriate training and support, CMV retinitis can be diagnosed and treated by AIDS clinicians (non-ophthalmologists), just like other major opportunistic infections.


Cortico-striatal language pathways dynamically adjust for syntactic complexity: A computational study.
A growing body of literature supports a key role of fronto-striatal circuits in language perception. It is now known that the striatum plays a role in engaging attentional resources and linguistic rule computation while also serving phonological short-term memory capabilities. The ventral semantic and the dorsal phonological stream dichotomy assumed for spoken language processing also seems to play a role in cortico-striatal perception. Based on recent studies that correlate deep Broca-striatal pathways with complex syntax performance, we used a previously developed computational model of frontal-striatal syntax circuits and hypothesized that different parallel language pathways may contribute to canonical and non-canonical sentence comprehension separately. We modified and further analyzed a thematic role assignment task and corresponding reservoir computing model of language circuits, as previously developed by Dominey and coworkers. We examined the models performance under various parameter regimes, by influencing how fast the presented language input decays and altering the temporal dynamics of activated word representations. This enabled us to quantify canonical and non-canonical sentence comprehension abilities. The modeling results suggest that separate cortico-cortical and cortico-striatal circuits may be recruited differently for processing syntactically more difficult and less complicated sentences. Alternatively, a single circuit would need to dynamically and adaptively adjust to syntactic complexity.


Integrated Lateral Flow Device for Flow Control with Blood Separation and Biosensing.
Lateral flow devices are versatile and serve a wide variety of purposes, including medical, agricultural, environmental, and military applications. Yet, the most promising opportunities of these devices for diagnosis might reside in point-of-care (POC) applications. Disposable paper-based lateral flow strips have been of particular interest, because they utilize low-cost materials and do not require expensive fabrication instruments. However, there are constraints on tuning flow rates and immunoassays functionalization in papers, as well as technical challenges in sensors' integration and concentration units for low-abundant molecular detection. In the present work, we demonstrated an integrated lateral flow device that applied the capillary forces with functionalized polymer-based microfluidics as a strategy to realize a portable, simplified, and self-powered lateral flow device (LFD). The polydimethylsiloxane (PDMS) surface was rendered hydrophilic via functionalization with different concentrations of Pluronic F127. Controlled flow is a key variable for immunoassay-based applications for providing enough time for protein binding to antibodies. The flow rate of the integrated LFD was regulated by the combination of multiple factors, including Pluronic F127 functionalized surface properties and surface treatments of microchannels, resistance of the integrated flow resistor, the dimensions of the microstructures and the spacing between them in the capillary pump, the contact angles, and viscosity of the fluids. Various plasma flow rates were regulated and achieved in the whole device. The LFD combined the ability to separate high quality plasma from human whole blood by using a highly asymmetric plasma separation membrane, and created controlled and steady fluid flow using capillary forces produced by the interfacial tensions. Biomarker immunoglobulin G (IgG) detection from plasma was demonstrated with a graphene nanoelectronic sensor integrated with the LFD. The developed LFD can be used as a flexible and versatile platform, and has the potential for detecting circulating biomarkers from whole blood. Sandwich-immunoassays can be performed directly on the LFD by patterning receptors for analytes on a desired substrate, and detections can be performed using a variety of sensing methods including nanoelectronic, colorimetric, or fluorescence sensors. The described bio-sensing technology presents an alternative for POC testing using small samples of human whole blood. It could benefit regions with limited access to healthcare, where delays in diagnosis can lead to quick deterioration of the quality of life and increase the morbidity and mortality.


Challenges in meeting Healthy People 2020 objectives for cancer-related preventive services, National Health Interview Survey, 2008 and 2010.
Healthy People (HP) is the US program that formulates and tracks national health objectives for the nation. The National Health Interview Survey (NHIS) is a designated data source for setting and evaluating several HP targets in cancer. We used data from the 2008 and 2010 NHIS to provide a benchmark for national performance toward meeting HP 2020 cancer-related objectives. HP 2020 cancer screening, provider counseling, and health care access objectives were selected. For each objective, NHIS measures for the overall population and several sociodemographic subgroups were calculated; the findings were compared with established HP 2020 targets. From 2008 to 2010, rates of breast and cervical cancer screening declined slightly while colorectal cancer screening rates increased by 7 percentage points. Rates of cancer screening and provider counseling were below HP targets. Meeting HP targets seems less likely for subgroups characterized by low income, no health insurance, or no usual source of care. Meeting HP targets for access to health services will require an increase of 18 percentage points in the proportion of persons under age 65 with health insurance coverage and an increase of 10 percentage points in the proportion aged 18 to 64 with a usual source of care. Whether HP objectives for cancer screening and health care access are met may depend on implementation of health care reform measures that improve access to and coordination of care. Better integration of clinical health care and community-based efforts for delivering high-quality screening and treatment services and elimination of health disparities are also needed.


Genotype-Phenotype Taxonomy of Hypertrophic Cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression. We enrolled 436 patients with HCM (median age, 60 years; 28.8% women) with clinical, genetic, and imaging data. An independent cohort of 60 patients with HCM from Singapore (median age, 59 years; 11% women) and a reference population from the UK Biobank (n=16 691; mean age, 55 years; 52.5% women) were also recruited. We used machine learning to analyze the 3-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree. Carriers of pathogenic or likely pathogenic variants for HCM had lower left ventricular mass, but greater basal septal hypertrophy, with reduced life span (mean follow-up, 9.9 years) compared with genotype negative individuals (hazard ratio, 2.66 [95% CI, 1.42-4.96]; P<0.002). Four main phenotypic branches were identified using unsupervised learning of 3-dimensional shape: (1) nonsarcomeric hypertrophy with coexisting hypertension; (2) diffuse and basal asymmetrical hypertrophy associated with outflow tract obstruction; (3) isolated basal hypertrophy; and (4) milder nonobstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for pathogenic or likely pathogenic variants, 2.18 [95% CI, 1.93-2.28]; P=0.0001). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalizable to an independent cohort (trustworthiness, M1: 0.86-0.88). We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk, and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.


Perceptions of HIV-related health services in Zambia for people with disabilities who are HIV-positive.
Despite the emerging body of literature on increased vulnerability to HIV among people with disabilities (PWDs), there is a dearth of evidence related to experiences of PWDs who have become HIV-positive. This priority was identified by a disability advocacy organization in Lusaka, Zambia, where the prevalence of HIV and of disability is each approximately 15%. The purpose of this study was to explore perceptions and experiences of HIV-related health services for PWDs who are also living with HIV in Lusaka, Zambia. This qualitative, interpretive study involved in-depth, semi-structured, one-on-one interviews with two groups of participants in Lusaka, Zambia: 21 PWDs who had become HIV-positive, and 11 people working in HIV and/or disability. PWDs had physical, hearing, visual and/or intellectual impairments. Interviews were conducted in English, Nyanja, Bemba or Zambian sign language. Descriptive and thematic analyses were conducted by a multidisciplinary, international research team. Participants described their experiences with HIV-related health services in terms of the challenges they faced. In particular, they encountered three main challenges while seeking care and treatment: (1) disability-related discrimination heightened when seeking HIV services, (2) communication barriers and related concerns with confidentiality, and (3) movement and mobility challenges related to seeking care and collecting antiretroviral therapy. These experiences were further shaped by participants' profound concerns about poverty and unmet basic needs. This study demonstrates how PWDs who are HIV-positive have the same HIV care, treatment and support needs as able-bodied counterparts, but face avoidable barriers to care. Many challenges mirror concerns identified with HIV prevention, suggesting that efforts to promote inclusion and reduce stigma could have widespread benefits. Despite the growing body of literature on increased risk of exposure to HIV among HIV-negative PWDs, this is the first published study to examine perceptions of testing, treatment and other HIV services for PWDs who have become HIV-positive. Findings reveal far-reaching opportunities for improving the quality of care for this population.