Essential oils and its bioactive compounds modulating cytokines: A systematic review on anti-asthmatic and immunomodulatory properties.
Asthma, the main inflammatory chronic condition affecting the respiratory system, is characterized by hyperresponsiveness and reversible airway obstruction, recruitment of inflammatory cells and excessive production of mucus. Cytokines as biochemical messengers of immune cells, play an important role in the regulation of allergic inflammatory and infectious airway processes. Essential oils of plant origin are complex mixtures of volatile and semi volatile organic compounds that determine the specific aroma of plants and are categorized by their biological activities. We reviewed whether essential oils and their bioactive compounds of plant origin could modulate cytokines' immune responses and improve asthma therapy in experimental systems in vitro and in vivo. Electronic and manual search of articles in English available from inception up to November 2018 reporting the immunomodulatory activity of essential oils and their bioactive compounds for the management of asthma. We used PubMed, EMBASE, Scopus and Web of Science. Publications reporting preclinical experiments where cytokines were examined to evaluate the consequence of anti-asthmatic therapy were included. 914 publications were identified and 13 were included in the systematic review. Four articles described the role of essential oils and their bioactive compounds on bronchial asthma using cell lines; nine in vivo studies evaluated the anti-inflammatory efficacy and immunomodulating effects of essential oil and their secondary metabolites on cytokines production and inflammatory responses. The most important immunopharmacological mechanisms reported were the regulation of cytokine production, inhibition of reactive oxygen species accumulation, inactivation of eosinophil migration and remodeling of the airways and lung tissue, modulation of FOXP3 gene expression, regulation of inflammatory cells in the airways and decreasing inflammatory mediator expression levels. Plant derived essential oils and related active compounds have potential therapeutic activity for the treatment of asthma by modulating the release of pro-inflammatory (TNF-α, IL-1β, IL-8), Th17 (IL-17), anti-inflammatory (IL-10), Th1 (IFN-γ, IL-2, IL-12) and Th2 (IL-4, IL-5, IL-6, IL-13) cytokines and the suppression of inflammatory cell accumulation.


Relationship of weight, height, and body mass index with fracture risk at different sites in postmenopausal women: the Global Longitudinal study of Osteoporosis in Women (GLOW).
Low body mass index (BMI) is a well-established risk factor for fracture in postmenopausal women. Height and obesity have also been associated with increased fracture risk at some sites. We investigated the relationships of weight, BMI, and height with incident clinical fracture in a practice-based cohort of postmenopausal women participating in the Global Longitudinal study of Osteoporosis in Women (GLOW). Data were collected at baseline and at 1, 2, and 3 years. For hip, spine, wrist, pelvis, rib, upper arm/shoulder, clavicle, ankle, lower leg, and upper leg fractures, we modeled the time to incident self-reported fracture over a 3-year period using the Cox proportional hazards model and fitted the best linear or nonlinear models containing height, weight, and BMI. Of 52,939 women, 3628 (6.9%) reported an incident clinical fracture during the 3-year follow-up period. Linear BMI showed a significant inverse association with hip, clinical spine, and wrist fractures: adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) per increase of 5 kg/m(2) were 0.80 (0.71-0.90), 0.83 (0.76-0.92), and 0.88 (0.83-0.94), respectively (all p < 0.001). For ankle fractures, linear weight showed a significant positive association: adjusted HR per 5-kg increase 1.05 (1.02-1.07) (p < 0.001). For upper arm/shoulder and clavicle fractures, only linear height was significantly associated: adjusted HRs per 10-cm increase were 0.85 (0.75-0.97) (p = 0.02) and 0.73 (0.57-0.92) (p = 0.009), respectively. For pelvic and rib fractures, the best models were for nonlinear BMI or weight (p = 0.05 and 0.03, respectively), with inverse associations at low BMI/body weight and positive associations at high values. These data demonstrate that the relationships between fracture and weight, BMI, and height are site-specific. The different associations may be mediated, at least in part, by effects on bone mineral density, bone structure and geometry, and patterns of falling.


Cord-blood transplants from unrelated donors in patients with Hurler's syndrome.
Hurler's syndrome (the most severe form of mucopolysaccharidosis type I) causes progressive deterioration of the central nervous system and death in childhood. Allogeneic bone marrow transplantation before the age of two years halts disease progression and prolongs life, but many children lack a bone marrow donor. We investigated the feasibility of using cord-blood transplants from unrelated donors and a myeloablative preparative regimen that did not involve total-body irradiation in young children with Hurler's syndrome. Between December 1995 and October 2002, 20 consecutive children with Hurler's syndrome received busulfan, cyclophosphamide, and antithymocyte globulin before receiving cord-blood transplants from unrelated donors. The children were subsequently evaluated for engraftment, adverse effects, and effects on disease symptoms. Cord-blood donors had normal alpha-L-iduronidase activity (mean number of cells, 10.53x10(7) per kilogram of body weight) and were discordant for up to three of six HLA markers. Neutrophil engraftment occurred a median of 24 days after transplantation. Five patients had grade II or grade III acute graft-versus-host disease; none had extensive chronic graft-versus-host disease. Seventeen of the 20 children were alive a median of 905 days after transplantation, with complete donor chimerism and normal peripheral-blood alpha-L-iduronidase activity (event-free survival rate, 85 percent). Transplantation improved neurocognitive performance and decreased somatic features of Hurler's syndrome. Cord blood from unrelated donors appears to be an excellent source of stem cells for transplantation in patients with Hurler's syndrome. Sustained engraftment can be achieved without total-body irradiation. Cord-blood transplantation favorably altered the natural history of Hurler's syndrome and thus may be important to consider in young children with this form of the disease.


Computed tomography perfusion imaging denoising using gaussian process regression.
Brain perfusion weighted images acquired using dynamic contrast studies have an important clinical role in acute stroke diagnosis and treatment decisions. However, computed tomography (CT) images suffer from low contrast-to-noise ratios (CNR) as a consequence of the limitation of the exposure to radiation of the patient. As a consequence, the developments of methods for improving the CNR are valuable. The majority of existing approaches for denoising CT images are optimized for 3D (spatial) information, including spatial decimation (spatially weighted mean filters) and techniques based on wavelet and curvelet transforms. However, perfusion imaging data is 4D as it also contains temporal information. Our approach using gaussian process regression (GPR), which takes advantage of the temporal information, to reduce the noise level. Over the entire image, GPR gains a 99% CNR improvement over the raw images and also improves the quality of haemodynamic maps allowing a better identification of edges and detailed information. At the level of individual voxel, GPR provides a stable baseline, helps us to identify key parameters from tissue time-concentration curves and reduces the oscillations in the curve. GPR is superior to the comparable techniques used in this study.


Solid-state solar modules based on mesoscopic organometal halide perovskite: a route towards the up-scaling process.
We fabricated the first solid state modules based on organometal halide perovskite CH3NH3PbI3-xClx using Spiro-OMeTAD and poly(3-hexylthiophene) as hole transport materials. Device up-scaling was performed using innovative procedures to realize large-area cells and the integrated series-interconnections. The perovskite-based modules show a maximum conversion efficiency of 5.1% using both poly(3-hexylthiophene) and Spiro-OMeTAD. A long-term stability test was performed (in air, under AM1.5G, 1 Sun illumination conditions) using both materials showing different behaviour under continuous light stress. Whilst the poly(3-hexylthiophene)-based module efficiency drops by about 80% with respect to the initial value after 170 hours, the Spiro-based module shows a promising long-term stability maintaining more than 60% of its initial efficiency after 335 hours.


Submicrometer infrared surface imaging using a scanning-probe microscope and an optical parametric oscillator laser.
Submicrometer IR surface imaging was performed with a resolution better than the diffraction limit. The apparatus was based on an IR optical parametric oscillator laser and a commercial atomic force microscope and used, as the detection mechanism, induced resonant oscillations in an atomic force microscopy (AFM) cantilever. For the first time to our knowledge this was achieved with top-down illumination and a benchtop IR source, thus extending the range of potential applications of this technique. IR absorption and AFM topography images of polystyrene beads were recorded simultaneously with an image resolution of 200 nm.


Development of a complex amino acid supplement, Fatigue Reviva™, for oral ingestion: initial evaluations of product concept and impact on symptoms of sub-health in a group of males.
A new dietary supplement, Fatigue Reviva™, has been recently developed to address issues related to amino acid depletion following illness or in conditions of sub-health where altered amino acid homeostasis has been associated with fatigue. Complex formulations of amino acids present significant challenges due to solubility and taste constraints. This initial study sets out to provide an initial appraisal of product palatability and to gather pilot evidence for efficacy. Males reporting symptoms of sub-health were recruited on the basis of being free from any significant medical or psychological condition. Each participant took an amino acid based dietary supplement (Fatigue Reviva™) daily for 30 days. Comparisons were then made between pre- and post-supplement general health symptoms and urinary amino acid profiles. Seventeen men took part in the study. Following amino acid supplementation the total Chalder fatigue score improved significantly (mean ± SEM, 12.5 ± 0.9 versus 10.0 ± 1.0, P<0.03). When asked whether they thought that the supplement had improved their health, 65% of participants responded positively. A subgroup of participants reported gastrointestinal symptoms which were attributed to the supplement and which were believed to result from the component fructooligosaccharide. Analysis of urinary amino acids revealed significant alterations in the relative abundances of a number of amino acids after supplementation including an increase in valine, isoleucine and glutamic acid and reduced levels of glutamine and ornithine. Discriminant function analysis of the urinary amino acid data revealed significant differences between the pre- and post-supplement urine excretion profiles. The results indicated that Fatigue Reviva™ was palatable and that 65% of the study group reported that they felt the product had improved their health. The product could provide an effective tool for the management of unexplained fatigue and symptoms of sub-health. Further product development may yield additional options for those patients susceptible to fructooligosaccharide.


Approach to multiple pulmonary nodules: a case report and review of literature.
Chest X-ray and CT examinations often find pulmonary nodules that could be malignant or benign. A case is presented and discussed here in order to improve diagnosis and management of pulmonary nodules. A 62-year-old lady was found to have multiple pulmonary nodules by X-ray when she complained of a cough and fever. This was confirmed by a CT scan. Fine needle aspiration (FNA) of one of the lung lesions reported scant atypical epithelial cells that stained positive for TTF-1 and cytokeratin 7, but negative for cytokeratin 20. Thus, it was suspicious for large cell carcinoma. A videothoracoscopic lung biopsy and histopathology were applied and showed a necrotic nodule with surrounding chronic inflammation and macrophage response, with no evidence of malignant cells. Atypical reactive pneumocytes at the periphery of the lesion (an old infarct) were probably equivalent to the atypical cells seen on cytology. This result changed the diagnosis of our patient from a malignant condition to a benign process. Thus, CT and FNA may give a false positive. A second pathological opinion is very useful for the right diagnosis and management, as shown in our case.


BRO1, a novel gene that interacts with components of the Pkc1p-mitogen-activated protein kinase pathway in Saccharomyces cerevisiae.
Yeast cells with mutations in BRO1 display phenotypes similar to those caused by deletion of BCK1, a gene encoding a MEK kinase that functions in a mitogen-activated protein kinase pathway mediating maintenance of cell integrity. bro1 cells exhibit a temperature-sensitive growth defect that is suppressed by the addition of osmotic stabilizers or Ca2+ to the growth medium or by additional copies of the BCK1 gene. At permissive temperatures, bro1 mutants are sensitive to caffeine and respond abnormally to nutrient limitation. A null mutation in BRO1 is synthetically lethal with null mutations in BCK1, MPK1, which encodes a mitogen-activated protein kinase that functions downstream of Bck1p, or PKC1, a gene encoding a protein kinase C homolog that activates Bck1p. Analysis of the isolated BRO1 gene revealed that it encodes a novel, 97-kDa polypeptide which contains a putative SH3 domain-binding motif and is homologous to a protein of unknown function in Caenorhabditis elegans.


Differences in the temporal dynamics of phenotypic selection among fitness components in the wild.
The balance of selection acting through different fitness components (e.g. fecundity, mating success, survival) determines the potential tempo and trajectory of adaptive evolution. Yet the extent to which the temporal dynamics of phenotypic selection may vary among fitness components is poorly understood. Here, we compiled a database of 3978 linear selection coefficients from temporally replicated studies of selection in wild populations to address this question. Across studies, we find that multi-year selection through mating success and fecundity is stronger than selection through survival, but varies less in direction. We also report that selection through mating success varies more in long-term average strength than selection through either survival or fecundity. The consistency in direction and stronger long-term average strength of selection through mating success and fecundity suggests that selection through these fitness components should cause more persistent directional evolution relative to selection through survival. Similar patterns were apparent for the subset of studies that evaluated the temporal dynamics of selection on traits simultaneously using several different fitness components, but few such studies exist. Taken together, these results reveal key differences in the temporal dynamics of selection acting through different fitness components, but they also reveal important limitations in our understanding of how selection drives adaptive evolution.


Local control of hepatic phenotype with growth factor-encoded surfaces.
The goal of the present study was to modulate the phenotype expression of hepatocytes in vitro on surfaces imprinted with growth factors (GFs). Hepatocyte growth factor (HGF) or transforming-growth factor-β1 (TGF-β1) were mixed with collagen (I) and robotically printed onto standard glass slides to create arrays of 300 μm or 500 μm diameter spots. Primary rat hepatocytes were seeded on top of the arrays, forming clusters corresponding in size to the underlying protein spots. The TGF-β1 spots appeared to downregulate markers of hepatic (epithelial) phenotype while upregulating expression of mesenchymal markers. Conversely, hepatocytes cultured on HGF spots maintained high level of epithelial markers. When hepatocytes were seeded onto alternating spots of HGF and TGF-β1, their phenotype was found to depend on center-to-center distance between the spots. At shorter distances cross-expression of epithelial and mesenchymal markers was observed while at distances exceeding 1.25 mm divergence of phenotypes, epithelial on HGF and mesenchymal on TGF-β was seen. Overall, our results demonstrate that GF-encoded surfaces can modulate phenotype within groups of cells cultured on the same surface. Given the importance of phenotype switching in development, fibrosis and cancer, this platform may be used to gain useful insights into the mechanisms of processes such as epithelial-to-mesenchymal transition or stem cell fate selections.


The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study.
To determine whether there is a link between hypoglycaemia and mortality among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Retrospective epidemiological analysis of data from the ACCORD trial. Setting Diabetes clinics, research clinics, and primary care clinics. Patients were eligible for the ACCORD study if they had type 2 diabetes, a glycated haemoglobin (haemoglobin A(1C)) concentration of 7.5% or more during screening, and were aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of subclinical disease or two additional cardiovascular risk factors. Intervention Intensive (haemoglobin A(1C) <6.0%) or standard (haemoglobin A(1C) 7.0-7.9%) glucose control. Symptomatic, severe hypoglycaemia, manifest as either blood glucose concentration of less than 2.8 mmol/l (<50 mg/dl) or symptoms that resolved with treatment and that required either the assistance of another person or medical assistance, and all cause and cause specific mortality, including a specific assessment for involvement of hypoglycaemia. 10 194 of the 10 251 participants enrolled in the ACCORD study who had at least one assessment for hypoglycaemia during regular follow-up for vital status were included in this analysis. Unadjusted annual mortality among patients in the intensive glucose control arm was 2.8% in those who had one or more episodes of hypoglycaemia requiring any assistance compared with 1.2% for those with no episodes (53 deaths per 1924 person years and 201 deaths per 16 315 person years, respectively; adjusted hazard ratio (HR) 1.41, 95% CI 1.03 to 1.93). A similar pattern was seen among participants in the standard glucose control arm (3.7% (21 deaths per 564 person years) v 1.0% (176 deaths per 17 297 person years); adjusted HR 2.30, 95% CI 1.46 to 3.65). On the other hand, among participants with at least one hypoglycaemic episode requiring any assistance, a non-significantly lower risk of death was seen in those in the intensive arm compared with those in the standard arm (adjusted HR 0.74, 95% 0.46 to 1.23). A significantly lower risk was observed in the intensive arm compared with the standard arm in participants who had experienced at least one hypoglycaemic episode requiring medical assistance (adjusted HR 0.55, 95% CI 0.31 to 0.99). Of the 451 deaths that occurred in ACCORD up to the time when the intensive treatment arm was closed, one death was adjudicated as definitely related to hypoglycaemia. Symptomatic, severe hypoglycaemia was associated with an increased risk of death within each study arm. However, among participants who experienced at least one episode of hypoglycaemia, the risk of death was lower in such participants in the intensive arm than in the standard arm. Symptomatic, severe hypoglycaemia does not appear to account for the difference in mortality between the two study arms up to the time when the ACCORD intensive glycaemia arm was discontinued. NCT00000620.


Identification of differentially expressed mRNA transcripts in drug-resistant versus parental human melanoma cell lines.
Malignant melanoma resistance to chemotherapy remains a major limitation to treatment. Our aim was to identify genes associated with drug resistance, in order to better understand the molecular events underlying the drug-resistant phenotype. A human melanoma cell line and its drug-resistant variants obtained by selection with MNNG or 6-thioguanine were used. Alterations in gene expression were characterized by differential display reverse transcription-polymerase chain reaction (DDRT-PCR). Prominent mRNA fragments present in selected variants and not in the parental cells were identified and characterized by cloning and sequencing. Differential expression was confirmed by real-time RT-PCR. Three functionally distinct transcriptional products were demonstrated: the chaperonin subunit TCP 1-zeta-6A (CCT6A), the hyaluronan receptor CD44 and LPPR-2, the lipid phosphate phosphatase-related protein type-2. Genes with altered expression were identified in drug-resistant variants. The identified molecules may provide new insights into the molecular basis for melanoma resistance to chemotherapy.


Development of the knowledge-based and empirical combined scoring algorithm (KECSA) to score protein-ligand interactions.
We describe a novel knowledge-based protein-ligand scoring function that employs a new definition for the reference state, allowing us to relate a statistical potential to a Lennard-Jones (LJ) potential. In this way, the LJ potential parameters were generated from protein-ligand complex structural data contained in the Protein Databank (PDB). Forty-nine (49) types of atomic pairwise interactions were derived using this method, which we call the knowledge-based and empirical combined scoring algorithm (KECSA). Two validation benchmarks were introduced to test the performance of KECSA. The first validation benchmark included two test sets that address the training set and enthalpy/entropy of KECSA. The second validation benchmark suite included two large-scale and five small-scale test sets, to compare the reproducibility of KECSA, with respect to two empirical score functions previously developed in our laboratory (LISA and LISA+), as well as to other well-known scoring methods. Validation results illustrate that KECSA shows improved performance in all test sets when compared with other scoring methods, especially in its ability to minimize the root mean square error (RMSE). LISA and LISA+ displayed similar performance using the correlation coefficient and Kendall τ as the metric of quality for some of the small test sets. Further pathways for improvement are discussed for which would allow KECSA to be more sensitive to subtle changes in ligand structure.


Microbial trench-based optofluidic system for reagentless determination of phenolic compounds.
Phenolic compounds are one of the main contaminants of soil and water due to their toxicity and persistence in the natural environment. Their presence is commonly determined with bulky and expensive instrumentation (e.g. chromatography systems), requiring sample collection and transport to the laboratory. Sample transport delays data acquisition, postponing potential actions to prevent environmental catastrophes. This article presents a portable, miniaturized, robust and low-cost microbial trench-based optofluidic system for reagentless determination of phenols in water. The optofluidic system is composed of a poly(methyl methacrylate) structure, incorporating polymeric optical elements and miniaturized discrete auxiliary components for optical transduction. An electronic circuit, adapted from a lock-in amplifier, is used for system control and interfering ambient light subtraction. In the trench, genetically modified bacteria are stably entrapped in an alginate hydrogel for quantitative determination of model phenol catechol. Alginate is also acting as a diffusion barrier for compounds present in the sample. Additionally, the superior refractive index of the gel (compared to water) confines the light in the lower level of the chip. Hence, the optical readout of the device is only altered by changes in the trench. Catechol molecules (colorless) in the sample diffuse through the alginate matrix and reach bacteria, which degrade them to a colored compound. The absorbance increase at 450 nm reports the presence of catechol simply, quickly (~10 min) and quantitatively without addition of chemical reagents. This miniaturized, portable and robust optofluidic system opens the possibility for quick and reliable determination of environmental contamination in situ, thus mitigating the effects of accidental spills.


Adolescent alcohol use is positively associated with later depression in a population-based U.K. cohort.
Alcohol use and internalizing problems are often positively associated during adolescence and adulthood. However, the basis of this relationship remains poorly understood, and longitudinal data collected in population-based samples could improve the development of etiological models. Using a prospective population-based U.K. cohort, the current study examined the relationship between frequency of drinking during adolescence (ages 13-15, N = 7,100) with problems with depression and anxiety at average age 17 years 10 months (n = 4,292). Analyses were conducted separately by sex and adjusted by the inclusion of potential individual- and familial-level confounders. Among boys, drinking frequency was positively associated with later depression but not anxiety. This association was robust to adjustment for covariates/confounders. Among girls, drinking frequency was related to later depression and anxiety in univariable analyses. In multivariable analyses, only the association with depression remained after adjustment for covariates/confounders. RESULTS were comparable across sexes, although the effect size of drinking frequency was higher among boys. Higher adolescent alcohol use, even at sub-clinical levels, is associated with an increased risk of later problems with depression but may not be associated with an aggregate measure of anxiety. Future research should consider the possibility of differential relationships between multiple measures of adolescent alcohol use and distinct internalizing outcomes later in development.


Transition metal-catalyzed ketone-directed or mediated C-H functionalization.
Transition metal-catalyzed C-H functionalization has evolved into a prominent and indispensable tool in organic synthesis. While nitrogen, phosphorus and sulfur-based functional groups (FGs) are widely employed as effective directing groups (DGs) to control the site-selectivity of C-H activation, the use of common FGs (e.g. ketone, alcohol and amine) as DGs has been continuously pursued. Ketones are an especially attractive choice of DGs and substrates due to their prevalence in various molecules and versatile reactivity as synthetic intermediates. Over the last two decades, transition metal-catalyzed C-H functionalization that is directed or mediated by ketones has experienced vigorous growth. This review summarizes these advancements into three major categories: use of ketone carbonyls as DGs, direct β-functionalization, and α-alkylation/alkenylation with unactivated olefins and alkynes. Each of these subsections is discussed from the perspective of strategic design and reaction discovery.


Genetic screening.
Current approaches to genetic screening include newborn screening to identify infants who would benefit from early treatment, reproductive genetic screening to assist reproductive decision making, and family history assessment to identify individuals who would benefit from additional prevention measures. Although the traditional goal of screening is to identify early disease or risk in order to implement preventive therapy, genetic screening has always included an atypical element-information relevant to reproductive decisions. New technologies offer increasingly comprehensive identification of genetic conditions and susceptibilities. Tests based on these technologies are generating a different approach to screening that seeks to inform individuals about all of their genetic traits and susceptibilities for purposes that incorporate rapid diagnosis, family planning, and expediting of research, as well as the traditional screening goal of improving prevention. Use of these tests in population screening will increase the challenges already encountered in genetic screening programs, including false-positive and ambiguous test results, overdiagnosis, and incidental findings. Whether this approach is desirable requires further empiric research, but it also requires careful deliberation on the part of all concerned, including genomic researchers, clinicians, public health officials, health care payers, and especially those who will be the recipients of this novel screening approach.


Disorder and defects are not intrinsic to boron carbide.
A unique combination of useful properties in boron-carbide, such as extreme hardness, excellent fracture toughness, a low density, a high melting point, thermoelectricity, semi-conducting behavior, catalytic activity and a remarkably good chemical stability, makes it an ideal material for a wide range of technological applications. Explaining these properties in terms of chemical bonding has remained a major challenge in boron chemistry. Here we report the synthesis of fully ordered, stoichiometric boron-carbide B13C2 by high-pressure-high-temperature techniques. Our experimental electron-density study using high-resolution single-crystal synchrotron X-ray diffraction data conclusively demonstrates that disorder and defects are not intrinsic to boron carbide, contrary to what was hitherto supposed. A detailed analysis of the electron density distribution reveals charge transfer between structural units in B13C2 and a new type of electron-deficient bond with formally unpaired electrons on the C-B-C group in B13C2. Unprecedented bonding features contribute to the fundamental chemistry and materials science of boron compounds that is of great interest for understanding structure-property relationships and development of novel functional materials.


Lessons for addressing noncommunicable diseases within a primary health-care system from the Ballabgarh project, India.
Most patients with noncommunicable diseases (NCDs) can be managed appropriately at the primary care level, using a simplified standard protocol supported by low-cost drugs. The primary care response to common NCDs is often unstructured and inadequate in low- and middle-income countries. This study assessed the feasibility of integration of NCD prevention and control within the primary health-care system of India. This study was done among 12 subcentres, 2 primary health centres (PHCs) and one subdistrict hospital in a block in north India. All 28 multipurpose health workers of these subcentres underwent 3-day training for delivering the package of NCD interventions as a part of their routine functioning. A time-motion study was conducted before and after this, to assess the workload on a sample of the workers with and without the NCD work. Screening for risk assessment was done at domiciliary level as well as at health-facility level (opportunistic screening), and the cost was estimated based on standard costing procedures. Individuals who screened positive were investigated with electrocardiography and fasting blood sugar. PHCs were strengthened with provision of essential medicines and technologies. After training, 6% of the time of workers (n = 7) was spent in the NCD-related activities, and introduction of NCD activities did not impact the coverage of other major national health programmes. Loss during referral of "at-risk" subjects (37.5% from home to subcentre and 33% from subcentre to PHC) resulted in screening efficiency being lowest at domiciliary level (1.3 cases of NCDs identified per 1000 screened). In comparison to domiciliary screening (₹21 830.6; US$ 363.8 per case identified), opportunistic screening at subdistrict level (₹794.6; US$ 13.2) was 27.5 times and opportunistic screening at PHC (₹1457.5; US$ 24.3) was 15.0 times lower. There was significant utilization of NCD services provided at PHCs, including counselling. Opportunistic screening appears to be feasible and a cost-effective strategy for risk screening. It is possible to integrate NCD prevention and control into primary health care in India.


Natural selection in a bangladeshi population from the cholera-endemic ganges river delta.
As an ancient disease with high fatality, cholera has likely exerted strong selective pressure on affected human populations. We performed a genome-wide study of natural selection in a population from the Ganges River Delta, the historic geographic epicenter of cholera. We identified 305 candidate selected regions using the composite of multiple signals (CMS) method. The regions were enriched for potassium channel genes involved in cyclic adenosine monophosphate-mediated chloride secretion and for components of the innate immune system involved in nuclear factor κB (NF-κB) signaling. We demonstrate that a number of these strongly selected genes are associated with cholera susceptibility in two separate cohorts. We further identify repeated examples of selection and association in an NF-κB/inflammasome-dependent pathway that is activated in vitro by Vibrio cholerae. Our findings shed light on the genetic basis of cholera resistance in a population from the Ganges River Delta and present a promising approach for identifying genetic factors influencing susceptibility to infectious diseases.


Talaromyces marneffei activates the AIM2-caspase-1/-4-GSDMD axis to induce pyroptosis in hepatocytes.
Talaromyces marneffei tends to induce systemic infection in immunocompromised individuals, which is one of the causes of the high mortality. The underlying molecular mechanisms of T.marneffei-induced abnormal liver function are still poorly understood. In this study, we found that T.marneffei-infected patients could develop abnormal liver function, evidenced by reduced albumin and increased levels of aspartate aminotransferase (AST) and AST/alanine aminotransferase (ALT). T. marneffei-infected mice exhibited similar characteristics. In vitro investigations showed that T.marneffei induced the death of AML-12 cells. Furthermore, we determined that T.marneffei infection induced pyroptosis in hepatocytes of C57BL/6J mice and AML-12 cells, demonstrated by the increase of AIM2, caspase-1/-4, Gasdermin D(GSDMD) and pyroptosis-related cytokines in T.marneffei-infected mice/cells. Importantly, cell death was markedly suppressed in the presence of VX765 (an inhibitor of caspase-1/-4). Furthermore, in the presence of VX765, T.marneffei-induced pyroptosis was blocked. Nevertheless, necroptosis and apoptosis were also detected in infected animal model at 14 days post-infection. In conclusion, T.marneffei induces pyroptosis in hepatocytes through activation of the AIM2-caspase-1/-4-GSDMD axis, which may be an important cause of liver damage, and other death pathways including necroptosis and apoptosis may also be involved in the later stage of infection.


Bisphosphonate therapy ameliorates hearing loss in mice lacking osteoprotegerin.
Three auditory ossicles including the malleus, incus, and stapes conduct sound in the middle ear from the tympanic membrane to the inner ear. Auditory ossicles are massively resorbed by osteoclasts in Opg(-/-) mice, which lack osteoprotegerin (OPG), a soluble decoy receptor for the osteoclastogenic cytokine RANKL. Opg(-/-) mice exhibit progressive hearing loss and are a model for juvenile Paget's disease. However, effects of antiresorptive treatment on auditory ossicles and on hearing function in Opg(-/-) mice are unknown. We intraperitoneally injected Opg(-/-) mice with bisphosphonate risedronate 5 d/wk for 9 wk. Morphology of auditory ossicles was examined microscopically, radiographically, and histologically. Hearing function was monitored by measuring the auditory brain stem response (ABR). Control Opg(-/-) mice exhibited thinning of all three ossicles and tibia. In contrast, risedronate treatment significantly inhibited bone loss in auditory ossicles as well as in long bones of Opg(-/-) mice. Bony fusion of the junction between the stapes and the otic capsule was reduced after treatment. Moreover, ABR measurement showed that hearing in Opg(-/-) mice was significantly improved by risedronate treatment. These data suggest that hearing loss in pathologies characterized by excessive resorption of the auditory ossicles may be prevented by bisphosphonates.


Longitudinal profile of retinal ganglion cell damage assessed with blue-light confocal scanning laser ophthalmoscopy after ischaemic reperfusion injury.
To longitudinally investigate retinal ganglion cell (RGC) expression of Thy-1, a cell-surface glycoprotein specifically expressed in RGCs, with a blue-light confocal scanning laser ophthalmoscope, following retinal ischaemia induced by acute elevation of intraocular pressure. A blue-light confocal scanning laser ophthalmoscope (bCSLO, 460 nm excitation and 490 nm detection) was used to image Thy1-cyan fluorescent protein (CFP) mice before and weekly for 4 weeks after transiently elevating the intraocular pressure to 115 mm Hg for 45 min (n = 4) or 90 min (n = 5) to induce ischaemic injury. Corresponding retinal areas before and after the intraocular pressure (IOP) elevation, during the period of ischaemic reperfusion, were compared, and the fluorescent spots (Thy-1 expressing RGCs) were counted. The longitudinal profile of CFP-expressing RGCs was modelled with a linear regression equation. The spatial distribution of RGC damage was analysed in the superior, nasal, inferior and temporal quadrants of the retina. No significant change was found at 4 weeks after 45 min of IOP elevation (n = 4, p = 0.465). The average RGC densities before and 4 weeks after IOP elevation were 1660 (SD 242) cells/mm2 and 1624 (209) cells/mm2, respectively. However, significant loss of CFP-expressing RGCs was detected at 1 week following 90 min of IOP elevation (n = 5, p<0.001). After this initial RGC loss, no significant change was detected subsequently. The proportion of RGC fluorescence remaining was variable and ranged from 14.5% to 79.5% at 4 weeks after the IOP elevation. The average RGC densities before and 4 weeks after IOP elevation were 1443 (162) cells/mm2 and 680 (385) cells/mm2, respectively. Diffuse loss of fluorescent RGCs was observed in the spatial distribution analysis. The longitudinal profile of Thy-1 expressing RGC fluorescence loss after ischaemic injury is non-progressive and unrelated to the duration of reperfusion.


Perioperative management for orthopaedic patients with sickle cell anaemia.
To compare outcomes of 2 types of perioperative optimisation for patients with sickle cell anaemia (SCA) undergoing various orthopaedic surgeries. 12 female and 11 male patients aged 13 to 40 (mean, 18) years with SCA underwent 31 separate orthopaedic procedures for osteonecrosis of the femoral head. They were referred to a haematologist for 2 types of perioperative optimisation, based on the choice of the attending paediatrician. In the aggressive management group, patients received packed red blood cells preoperatively to increase the haemoglobin level to 9 to 11 g/dl and to lower the haemoglobin S level to <30%. Fresh frozen plasma was given when their Factor VII level was <30%. In the conservative management group, patients received packed red blood cells preoperatively to increase the haemoglobin level to a minimum of 10 g/dl. Fresh frozen plasma or packed red blood cells were given intra-operatively only when excessive bleeding occurred. The length of hospital stay, the number of perioperative complications, the number of transfusions, and episodes of alloimmunisation and/or vaso-occlusive crises in the two groups were compared. No patient in the aggressive management group received supplemental oxygen or had an estimated intra-operative blood loss of >400 ml. Three patients in the conservative management group received multiple intra- and post-operative transfusions and supplemental oxygen. Both aggressive and conservative protocols may be safely used in SCA patients. The more aggressive protocol resulted in lower rates for postoperative complications, transfusions, and resorting to supplemental oxygen.


Educational inequalities in diabetes mortality across Europe in the 2000s: the interaction with gender.
To evaluate educational inequalities in diabetes mortality in Europe in the 2000s, and to assess whether these inequalities differ between genders. Data were obtained from mortality registries covering 14 European countries. To determine educational inequalities in diabetes mortality, age-standardised mortality rates, mortality rate ratios, and slope and relative indices of inequality were calculated. To assess whether the association between education and diabetes mortality differs between genders, diabetes mortality was regressed on gender, educational rank and 'gender × educational rank'. An inverse association between education and diabetes mortality exists in both genders across Europe. Absolute educational inequalities are generally larger among men than women; relative inequalities are generally more pronounced among women, the relative index of inequality being 2.8 (95 % CI 2.0-3.9) in men versus 4.8 (95 % CI 3.2-7.2) in women. Gender inequalities in diabetes mortality are more marked in the highest than the lowest educated. Education and diabetes mortality are inversely related in Europe in the 2000s. This association differs by gender, indicating the need to take the socioeconomic and gender dimension into account when developing public health policies.


Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
This guideline focuses on long-term administration of antithrombotic drugs designed for primary and secondary prevention of cardiovascular disease, including two new antiplatelet therapies. The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. We present 23 recommendations for pertinent clinical questions. For primary prevention of cardiovascular disease, we suggest low-dose aspirin (75-100 mg/d) in patients aged > 50 years over no aspirin therapy (Grade 2B). For patients with established coronary artery disease, defined as patients 1-year post-acute coronary syndrome, with prior revascularization, coronary stenoses > 50% by coronary angiogram, and/or evidence for cardiac ischemia on diagnostic testing, we recommend long-term low-dose aspirin or clopidogrel (75 mg/d) (Grade 1A). For patients with acute coronary syndromes who undergo percutaneous coronary intervention (PCI) with stent placement, we recommend for the first year dual antiplatelet therapy with low-dose aspirin in combination with ticagrelor 90 mg bid, clopidogrel 75 mg/d, or prasugrel 10 mg/d over single antiplatelet therapy (Grade 1B). For patients undergoing elective PCI with stent placement, we recommend aspirin (75-325 mg/d) and clopidogrel for a minimum duration of 1 month (bare-metal stents) or 3 to 6 months (drug-eluting stents) (Grade 1A). We suggest continuing low-dose aspirin plus clopidogrel for 12 months for all stents (Grade 2C). Thereafter, we recommend single antiplatelet therapy over continuation of dual antiplatelet therapy (Grade 1B). Recommendations continue to favor single antiplatelet therapy for patients with established coronary artery disease. For patients with acute coronary syndromes or undergoing elective PCI with stent placement, dual antiplatelet therapy for up to 1 year is warranted.


Systematic evaluation of the impact of ChIP-seq read designs on genome coverage, peak identification, and allele-specific binding detection.
Chromatin immunoprecipitation followed by sequencing (ChIP-seq) experiments revolutionized genome-wide profiling of transcription factors and histone modifications. Although maturing sequencing technologies allow these experiments to be carried out with short (36-50 bps), long (75-100 bps), single-end, or paired-end reads, the impact of these read parameters on the downstream data analysis are not well understood. In this paper, we evaluate the effects of different read parameters on genome sequence alignment, coverage of different classes of genomic features, peak identification, and allele-specific binding detection. We generated 101 bps paired-end ChIP-seq data for many transcription factors from human GM12878 and MCF7 cell lines. Systematic evaluations using in silico variations of these data as well as fully simulated data, revealed complex interplay between the sequencing parameters and analysis tools, and indicated clear advantages of paired-end designs in several aspects such as alignment accuracy, peak resolution, and most notably, allele-specific binding detection. Our work elucidates the effect of design on the downstream analysis and provides insights to investigators in deciding sequencing parameters in ChIP-seq experiments. We present the first systematic evaluation of the impact of ChIP-seq designs on allele-specific binding detection and highlights the power of pair-end designs in such studies.


MicroSCALE screening reveals genetic modifiers of therapeutic response in melanoma.
Cell microarrays are a promising tool for performing large-scale functional genomic screening in mammalian cells at reasonable cost, but owing to technical limitations they have been restricted for use with a narrow range of cell lines and short-term assays. Here, we describe MicroSCALE (Microarrays of Spatially Confined Adhesive Lentiviral Features), a cell microarray-based platform that enables application of this technology to a wide range of cell types and longer-term assays. We used MicroSCALE to uncover kinases that when overexpressed partially desensitized B-RAFV600E-mutant melanoma cells to inhibitors of the mitogen-activated protein kinase kinase kinase (MAPKKK) RAF, the MAPKKs MEK1 and 2 (MEK1/2, mitogen-activated protein kinase kinase 1 and 2), mTOR (mammalian target of rapamycin), or PI3K (phosphatidylinositol 3-kinase). These screens indicated that cells treated with inhibitors acting through common mechanisms were affected by a similar profile of overexpressed proteins. In contrast, screens involving inhibitors acting through distinct mechanisms yielded unique profiles, a finding that has potential relevance for small-molecule target identification and combination drugging studies. Further, by integrating large-scale functional screening results with cancer cell line gene expression and pharmacological sensitivity data, we validated the nuclear factor κB pathway as a potential mediator of resistance to MAPK pathway inhibitors. The MicroSCALE platform described here may enable new classes of large-scale, resource-efficient screens that were not previously feasible, including those involving combinations of cell lines, perturbations, and assay outputs or those involving limited numbers of cells and limited or expensive reagents.


People who are transgender: mental health concerns.
The aim of the study was to elicit the views and opinions of transgender people in relation to mental health concerns. Four people who identified as transgender participated in semi-structured interviews. The main results showed that challenges existed for people around mental health issues. Mental health nurses can play a key role in the provision of psychosocial supports to transgender people and their families. Government policy makers are becoming increasingly interested in the views and experiences of people who utilize mental health services to inform rights-based and socially inclusive health and social care initiatives. However, very little information exists in the available literature about transgender people in this regard. The current research was part of a larger mixed methods study that used surveys and in-depth semi-structured interviews. This paper reports on the findings from the interview data that relate to the unique mental health experiences of the people whom identified as transgender (n = 4). The data were subject to thematic analysis, and the main themes that emerged included service experiences, treatment issues, other supports, and hopes and aspirations. Participants identified challenges and opportunities for enhancing mental health service provision for transgender people and their families. Some of the highlighted concerns related to practitioner attributes and relevant psychosocial supports. Mental health nurses are well placed to use their knowledge and therapeutic skills to support people who identify as transgender and significant people in their lives.


Setting research priorities on multiple micronutrient supplementation in pregnancy.
Prenatal micronutrient deficiencies are associated with negative maternal and birth outcomes. Multiple micronutrient supplementation (MMS) during pregnancy is a cost-effective intervention to reduce these adverse outcomes. However, important knowledge gaps remain in the implementation of MMS interventions. The Child Health and Nutrition Research Initiative (CHNRI) methodology was applied to inform the direction of research and investments needed to support the implementation of MMS interventions for pregnant women in low- and middle-income countries (LMIC). Following CHNRI methodology guidelines, a group of international experts in nutrition and maternal health provided and ranked the research questions that most urgently need to be resolved for prenatal MMS interventions to be successfully implemented. Seventy-three research questions were received, analyzed, and reorganized, resulting in 35 consolidated research questions. These were scored against four criteria, yielding a priority ranking where the top 10 research options focused on strategies to increase antenatal care attendance and MMS adherence, methods needed to identify populations more likely to benefit from MMS interventions and some discovery issues (e.g., potential benefit of extending MMS through lactation). This exercise prioritized 35 discrete research questions that merit serious consideration for the potential of MMS during pregnancy to be optimized in LMIC.


Decoding the Vertical Phase Separation and Its Impact on C8-BTBT/PS Transistor Properties.
Disentangling the details of the vertical distribution of small semiconductor molecules blended with polystyrene (PS) and the contact properties are issues of fundamental value for designing strategies to optimize small-molecule:polymer blend organic transistors. These questions are addressed here for ultrathin blends of 2,7-dioctyl[1]benzothieno[3,2-b][1]benzothiophene (C8-BTBT) and PS processed by a solution-shearing technique using three different blend composition ratios. We show that friction force microscopy (FFM) allows the determination of the lateral and vertical distribution of the two materials at the nanoscale. Our results demonstrate a three-layer stratification of the blend: a film of C8-BTBT of few molecular layers with crystalline order sandwiched between a PS-rich layer at the bottom (a few nm thick) acting as a passivating dielectric layer and a PS-rich skin layer on the top (∼1 nm) conferring stability to the devices. Kelvin probe force microscopy (KPFM) measurements performed in operating organic field-effect transistors (OFETs) reveal that the devices are strongly contact-limited and suggest contact doping as a route for device optimization. By excluding the effect of the contacts, field-effect mobility values in the channel as high as 10 cm2 V-1 s-1 are obtained. Our findings, obtained via a combination of FFM and KPFM, provide a satisfactory explanation of the different electrical performances of the OFETs as a function of the blend composition ratio and by doping the contacts.


Very high frequency oscillations (VHFO) as a predictor of movement intentions.
Gamma band (30-80 Hz) oscillations arising in neuronal ensembles are thought to be a crucial component of the neural code. Recent studies in animals suggest a similar functional role for very high frequency oscillations (VHFO) in the range 80-200 Hz. Since some intracerebral studies in humans link VHFO to epileptogenesis, it remains unclear if VHFO appear in the healthy human brain and if so which is their role. This study uses EEG recordings from twelve healthy volunteers, engaged in a visuo-motor reaction time task, to show that VHFO are not necessarily pathological but rather code information about upcoming movements. Oscillations within the range (30-200 Hz) occurring in the period between stimuli presentation and the fastest hand responses allow highly accurate (>96%) prediction of the laterality of the responding hand in single trials. Our results suggest that VHFO belong in functional terms to the gamma band that must be considerably enlarged to better understand the role of oscillatory activity in brain functioning. This study has therefore important implications for the recording and analysis of electrophysiological data in normal subjects and patients.


Management of Crohn's disease in adults.
Guidelines for clinical practice are intended to suggest preferable approaches to particular medical problems as established by interpretation and collation of scientifically valid research, derived from extensive review of published literature. When data that will withstand objective scrutiny are not available, a recommendation may be made based on a consensus of experts. Guidelines are intended to apply to the clinical situation for all physicians without regard to specialty. Guidelines are intended to be flexible, not necessarily indicating the only acceptable approach, and should be distinguished from standards of care that are inflexible and rarely violated. Given the wide range of choices in any health-care problem, the physician should select the course best suited to the individual patient and the clinical situation presented. These guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee. Expert opinion is solicited from the outset for the document. The quality of evidence upon which a specific recommendation is based is as follows: Grade A: Homogeneous evidence from multiple well-designed randomized (therapeutic) or cohort (descriptive) controlled trials, each involving a number of participants to be of sufficient statistical power. Grade B: Evidence from at least one large well-designed clinical trial with or without randomization, from cohort or case-control analytic studies, or well-designed meta-analysis. Grade C: Evidence based on clinical experience, descriptive studies, or reports of expert committees. The Committee reviews guidelines in depth, with participation from experienced clinicians and others in related fields. The final recommendations are based on the data available at the time of the production of the document and may be updated with pertinent scientific developments at a later time.


The benefits of health information technology: a review of the recent literature shows predominantly positive results.
An unprecedented federal effort is under way to boost the adoption of electronic health records and spur innovation in health care delivery. We reviewed the recent literature on health information technology to determine its effect on outcomes, including quality, efficiency, and provider satisfaction. We found that 92 percent of the recent articles on health information technology reached conclusions that were positive overall. We also found that the benefits of the technology are beginning to emerge in smaller practices and organizations, as well as in large organizations that were early adopters. However, dissatisfaction with electronic health records among some providers remains a problem and a barrier to achieving the potential of health information technology. These realities highlight the need for studies that document the challenging aspects of implementing health information technology more specifically and how these challenges might be addressed.


Targeting transcription regulation in cancer with a covalent CDK7 inhibitor.
Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state.


Sizzled: a secreted Xwnt8 antagonist expressed in the ventral marginal zone of Xenopus embryos.
An expression cloning screen was used to isolate a novel gene homologous to the extracellular cysteine-rich domain of frizzled receptors. The gene (which we called sizzled for secreted frizzled) was shown to encode a soluble secreted protein, containing a functional signal sequence but no transmembrane domains. Sizzled (szl) is capable of inhibiting Xwnt8 as assayed by (1) dose-dependent inhibition of siamois induction by Xwnt8 in animal caps, (2) rescue of embryos ventralized by Xwnt8 DNA and (3) inhibition of XmyoD expression in the marginal zone. Szl can dorsalize Xenopus embryos if expressed after the midblastula transition, strengthening the idea that zygotic expression of wnts and in particular of Xwnt8 plays a role in antagonizing dorsal signals. It also suggests that inhibiting ventralizing wnts parallels the opposition of BMPs by noggin and chordin. szl expression is restricted to a narrow domain in the ventral marginal zone of gastrulating embryos. szl thus encodes a secreted antagonist of wnt signaling likely involved in inhibiting Xwnt8 and XmyoD ventrally and whose restricted expression represents a new element in the molecular pattern of the ventral marginal zone.


Quality of couples' relationship and adjustment to metastatic breast cancer.
This study examined mood disturbance among women with metastatic breast cancer in relationship to partnership status, relationship quality, and partner's coping and mood disturbance. These associations were examined within a total sample of 125 metastatic breast cancer patients and a subsample of 48 of these patients and their partners. Partnered and single women were indistinguishable in mood disturbance when household income was statistically controlled. Results also showed that patients were less distressed when they rated the relationship higher in Cohesion--Expression and in Conflict and when their partners reported lower mood disturbance. One possible implication of these results is that in relationships in which a woman has metastatic cancer, she may benefit from open engagement of difficulties and conflict. Furthermore, alleviating her distress may be better achieved by focus on the couple relationship rather than her individual coping.


Synthesis of dendritic polyglycerol anions and their efficiency toward L-selectin inhibition.
A versatile route for the synthesis of highly functionalized, polyanionic macromolecules based on dendritic polyglycerol was applied by means of the Huisgen-Sharpless-Meldal 1,3-dipolar cycloaddition ("click-reaction") of polyglycerolazide precursors and alkyne-functionalized anions such as sulfonates, carboxylates, phosphonates, and bisphosphonates. In addition, the corresponding polyglycerol phosphate has been synthesized via direct hydroxyl interconversion of polyglycerol to the corresponding phosphate with a degree of functionalization >80% by analogy to the synthesis of previously reported polyglycerol sulfates (dPGS). On the basis of the finding that dPGS exhibits high affinity for L- and P-selectin, the potential of these novel polyanionic, multivalent macromolecules of varying anionic nature as L-selectin inhibitors has been evaluated in vitro by means of a competitive concentration dependent binding assay. Affinity of all polyanions toward L-selectin was demonstrated with distinct IC(50) values ranging from the low nanomolar to the high micromolar range. The efficiency of L-selectin inhibition increases in the order carboxylate < phosphate < phosphonate ≈ sulfonate < bisphosphonate < sulfate. Additional DLS and ζ-potential measurements of these polyanions were performed to correlate their binding affinity toward L-selectin with their anionic nature. However, a direct correlation of effective charge and particle size with the determined IC(50) values turned out to require further in-depth studies on the microstructure of the polyanions but clearly indicate an exceptional position of dPGS among the studied dendritic polyelectrolytes.


ROCK Inhibitor Y-27632 Promotes Human Retinal Pigment Epithelium Survival by Altering Cellular Biomechanical Properties.
Dysfunction or death of retinal pigment epithelial (RPE) cells is a common pathogenesis of various types of retinal degenerative diseases. Recent reports indicated that ROCK pathway inhibitors regulate cell proliferation or apoptosis in a celltype- dependent manner. Here, we aim to investigate the effect of ROCK inhibitor Y- 27632 on the human retinal pigment epithelium (RPE) in vitro. Cell proliferation and apoptosis were analyzed by CCK-8 and flow cytometry respectively. Cell proliferation markers were detected by immunofluorescence and western blot. Cell morphology was evaluated using scanning electron microscopy. The topography and biomechanical properties of living cells were assessed using atomic force microscope (AFM). In addition, cytoskeleton and epithelial-mesenchymal transition (EMT) markers were detected by western blot and immunofluorescence. 30µM Y-27632 significantly promoted cell proliferation and decreased apoptosis. Compared with control group, human retinal pigment epithelial cell line ARPE-19 cells treated with 30µM Y-27632 exhibited significantly decreased cytomembrane roughness (Ra: 41.04±1.63nm vs. 24.41±0.75nm, P<0.01; Rq: 51.56±2.03nm vs. 30.81±0.95nm, P<0.01) and increased elasticity modulus (16.66±0.83KPa vs. 32.55±1.48KPa, P<0.01). In addition, the inhibition of ROCK activity by Y-27632 caused cell elongation and reorganization of microfilaments and microtubules of cytoskeletons. Taken together, our data demonstrated that Y-27632 could alter biomechanical properties and reorganized cytoskeletons to promote RPE cell survival. These results are an important step toward the future application of Y-27632 in retinal degenerative diseases.


Practice and drop-out effects during a 17-year longitudinal study of cognitive aging.
Interpretations of longitudinal studies of cognitive aging are misleading unless effects of practice and selective drop-out are considered. A random effects model taking practice and drop-out into account analyzed data from four successive presentations of each of two intelligence tests, two vocabulary tests, and two verbal memory tests during a 17-year longitudinal study of 5,899 community residents whose ages ranged from 49 to 92 years. On intelligence tests, substantial practice effects counteracted true declines observed over 3 to 5 years of aging and remained significant even with intervals of 7 years between successive assessments. Adjustment for practice and drop-out revealed accelerating declines in fluid intelligence and cumulative learning, linear declines in verbal free recall, and no substantial change in vocabulary. Socioeconomic status and basal levels of general fluid ability did not affect rates of decline. After further adjustment for demographics, variability between individuals was seen to increase as the sample aged.


Applying the RE-AIM Framework to Inform the Development of a Multiple Sclerosis Falls-Prevention Intervention.
Successfully addressing the problem of falls among people with multiple sclerosis (MS) will require the translation of research findings into practice change. This process is not easy but can be facilitated by using frameworks such as RE-AIM during the process of planning, implementing, and evaluating MS falls-prevention interventions. RE-AIM stands for Reach, Effectiveness, Adoption, Implementation, and Maintenance. Since its initial publication in 1999, the RE-AIM framework has become widely recognized across a range of disciplines as a valuable tool to guide thinking about the development and evaluation of interventions intended for widespread dissemination. For this reason, it was selected by the International MS Falls Prevention Research Network to structure initial discussions with clinicians, people with MS, and representatives of professional and MS societies about the factors we need to consider in the development of an MS falls-prevention intervention for multisite testing that we hope will someday be disseminated widely. Through a combination of small-group work and large-group discussion, participants discussed four of the five RE-AIM elements. A total of 17 recommendations were made to maximize the reach (n = 3), adoption (n = 5), implementation (n = 4), and maintenance (n = 5) of the intervention the Network is developing. These recommendations are likely to be useful for any MS rehabilitation researcher who is developing and testing interventions that he or she hopes will be widely disseminated.


The transcriptional regulators SteA and StuA contribute to keratin degradation and sexual reproduction of the dermatophyte Arthroderma benhamiae.
Most superficial fungal infections are caused by dermatophytes, a specialized group of filamentous fungi which exclusively infect keratinized host structures such as hair, skin and nails. Since little is known about the molecular basis of pathogenicity and sexual reproduction in dermatophytes, here we functionally addressed two central transcriptional regulators, SteA and StuA. In the zoophilic species Arthroderma benhamiae a strategy for targeted genetic manipulation was recently established, and moreover, the species is teleomorphic and thus allows performing assays based on mating. By comparative genome analysis homologs of the developmental regulators SteA and StuA were identified in A. benhamiae. Knock-out mutants of the corresponding genes as well as complemented strains were generated and phenotypically characterized. In contrast to A. benhamiae wild type and complemented strains, both mutants failed to produce sexual reproductive structures in mating experiments. Analysis of growth on keratin substrates indicated that loss of steA resulted in the inability of ΔsteA mutants to produce hair perforation organs, but did not affect mycelia formation during growth on hair and nails. By contrast, ΔstuA mutants displayed a severe growth defect on these substrates, but were still able to produce hair perforations. Hence, formation of hair perforation organs and fungal growth on hair per se are differentially regulated processes. Our findings on the major role of SteA and StuA during sexual development and keratin degradation in A. benhamiae provide insights into their role in dermatophytes and further enhance our knowledge of basic biology and pathogenicity of these fungi.


An EMG-to-force processing approach for determining ankle muscle forces during normal human gait.
Muscle forces move our limbs. These forces must be estimated with indirect techniques, as direct measurements are neither generally possible nor practical. An electromyography (EMG)-to-force processing technique was developed. Ankle joint moments and, by extension, ankle muscle forces were calculated. The ankle moment obtained by inverse dynamics was calculated for ten normal adults during free speed gait. There was close correlation between inverse dynamics ankle moments and moments determined by the EMG-to-force processing approach. Muscle forces were determined. The gait peak Achilles tendon force occurred in late single limb support. Peak force observed (2.9 kN) closely matched values obtained where force transducers were used to obtain in vivo muscle forces (2.6 kN). The EMG-to-force processing model presented here appears to be a practical means to determine in vivo muscle forces.


Far beyond the usual biomarkers in breast cancer: a review.
Research investigating biomarkers for early detection, prognosis and the prediction of treatment responses in breast cancer is rapidly expanding. However, no validated biomarker currently exists for use in routine clinical practice, and breast cancer detection and management remains dependent on invasive procedures. Histological examination remains the standard for diagnosis, whereas immunohistochemical and genetic tests are utilized for treatment decisions and prognosis determinations. Therefore, we conducted a comprehensive review of literature published in PubMed on breast cancer biomarkers between 2009 and 2013. The keywords that were used together were breast cancer, biomarkers, diagnosis, prognosis and drug response. The cited references of the manuscripts included in this review were also screened. We have comprehensively summarized the performance of several biomarkers for diagnosis, prognosis and predicted drug responses of breast cancer. Finally, we have identified 15 biomarkers that have demonstrated promise in initial studies and several miRNAs. At this point, such biomarkers must be rigorously validated in the clinical setting to be translated into clinically useful tests for the diagnosis, prognosis and prediction of drug responses of breast cancer.


An Annual Plant Growth Proxy in the Mojave Desert Using MODIS-EVI Data.
In the arid Mojave Desert, the phenological response of vegetation is largely dependent upon the timing and amount of rainfall, and maps of annual plant cover at any one point in time can vary widely. Our study developed relative annual plant growth models as proxies for annual plant cover using metrics that captured phenological variability in Moderate-Resolution Imaging Spectroradiometer (MODIS) Enhanced Vegetation Index (EVI) satellite images. We used landscape phenologies revealed in MODIS data together with ecological knowledge of annual plant seasonality to develop a suite of metrics to describe annual growth on a yearly basis. Each of these metrics was applied to temporally-composited MODIS-EVI images to develop a relative model of annual growth. Each model was evaluated by testing how well it predicted field estimates of annual cover collected during 2003 and 2005 at the Mojave National Preserve. The best performing metric was the spring difference metric, which compared the average of three spring MODIS-EVI composites of a given year to that of 2002, a year of record drought. The spring difference metric showed correlations with annual plant cover of R² = 0.61 for 2005 and R² = 0.47 for 2003. Although the correlation is moderate, we consider it supportive given the characteristics of the field data, which were collected for a different study in a localized area and are not ideal for calibration to MODIS pixels. A proxy for annual growth potential was developed from the spring difference metric of 2005 for use as an environmental data layer in desert tortoise habitat modeling. The application of the spring difference metric to other imagery years presents potential for other applications such as fuels, invasive species, and dust-emission monitoring in the Mojave Desert.


Cystic fibrosis program directors' attitudes toward sexual and reproductive health in young women with CF.
Advancements in therapy have led to dramatic increases in the life expectancy of patients with cystic fibrosis (CF). As survival improves, young women with CF will have expectations for their sexual and reproductive health (SRH) futures similar to their counterparts without CF. As they face unique CF-specific SRH concerns, they may rely on CF care providers for disease-specific SRH care provision. The purpose of this study was to investigate the attitudes of CF providers toward female SRH and perceived barriers in the current CF care model. U.S. CF program directors (n = 16) participated in qualitative interviews investigating attitudes and barriers to female CF SRH care. Interviews were audio-recorded, transcribed, and coded using a thematic analysis approach. Participants (nine pediatric, five adult, and two combined) all agreed CF providers have a fundamental role in CF female SRH care. Most respondents named lack of time and patient and provider discomfort as significant barriers to effective SRH communication. Other reported barriers included: lack of training in SRH, family members in the room, low priority of SRH in setting of other CF issues, and lack of adequate rapport with patients. This is the first study to assess the attitudes and experiences of CF care providers toward SRH discussion and care among female CF patients. Despite their perceived fundamental role in CF female SRH care, CF providers face significant barriers. Investment in provider training is needed to better address the complex SRH needs of young female patients.


Biodiversity effects in the wild are common and as strong as key drivers of productivity.
More than 500 controlled experiments have collectively suggested that biodiversity loss reduces ecosystem productivity and stability. Yet the importance of biodiversity in sustaining the world's ecosystems remains controversial, largely because of the lack of validation in nature, where strong abiotic forcing and complex interactions are assumed to swamp biodiversity effects. Here we test this assumption by analysing 133 estimates reported in 67 field studies that statistically separated the effects of biodiversity on biomass production from those of abiotic forcing. Contrary to the prevailing opinion of the previous two decades that biodiversity would have rare or weak effects in nature, we show that biomass production increases with species richness in a wide range of wild taxa and ecosystems. In fact, after controlling for environmental covariates, increases in biomass with biodiversity are stronger in nature than has previously been documented in experiments and comparable to or stronger than the effects of other well-known drivers of productivity, including climate and nutrient availability. These results are consistent with the collective experimental evidence that species richness increases community biomass production, and suggest that the role of biodiversity in maintaining productive ecosystems should figure prominently in global change science and policy.


Why do scientists disagree? Explaining and improving measures of the perceived causes of scientific disputes.
There has been increasing attention to understanding how laypeople explain disagreements among scientists. In this article, we evaluate the factorial validity and scale/item functioning of a Science Dispute Reasons scale (Study 1) and test specific hypotheses about demographic, individual difference, and topic-related variables that may explain why some reasons are perceived to be more likely than others (Study 2). The final scale included 17 items grouped into three reason factors (Process/Competence, Interests/Values, and Complexity/Uncertainty), which is largely consistent with previous research. We find a mixed pattern of global and specific impacts on reason likelihood ratings from a range of variables including political ideology and conspiracist ideation (primary mediated through perceived credibility of science), science knowledge, and topic-related variables such as knowledge of and care about the dispute in question. Overall, science dispute reasons appear to be more strongly driven by attitudes and worldviews as opposed to objective knowledge and skills. These findings represent progress in understanding lay perceptions of the causes of scientific disputes, although much work remains. We discuss the implications of this work and directions for future research.


Incorporation of tetanus-epitope into virus-like particles achieves vaccine responses even in older recipients in models of psoriasis, Alzheimer's and cat allergy.
Monoclonal antibodies are widely used to treat non-infectious conditions but are costly. Vaccines could offer a cost-effective alternative but have been limited by sub-optimal T-cell stimulation and/or weak vaccine responses in recipients, for example, in elderly patients. We have previously shown that the repetitive structure of virus-like-particles (VLPs) can effectively bypass self-tolerance in therapeutic vaccines. Their efficacy could be increased even further by the incorporation of an epitope stimulating T cell help. However, the self-assembly and stability of VLPs from envelope monomer proteins is sensitive to geometry, rendering the incorporation of foreign epitopes difficult. We here show that it is possible to engineer VLPs derived from a non human-pathogenic plant virus to incorporate a powerful T-cell-stimulatory epitope derived from Tetanus toxoid. These VLPs (termed CMVTT) retain self-assembly as well as long-term stability. Since Th cell memory to Tetanus is near universal in humans, CMVTT-based vaccines can deliver robust antibody-responses even under limiting conditions. By way of proof of concept, we tested a range of such vaccines against chronic inflammatory conditions (model: psoriasis, antigen: interleukin-17), neurodegenerative (Alzheimer's, β-amyloid), and allergic disease (cat allergy, Fel-d1), respectively. Vaccine responses were uniformly strong, selective, efficient in vivo, observed even in old mice, and employing low vaccine doses. In addition, randomly ascertained human blood cells were reactive to CMVTT-VLPs, confirming recognition of the incorporated Tetanus epitope. The CMVTT-VLP platform is adaptable to almost any antigen and its features and performance are ideally suited for the design of vaccines delivering enhanced responsiveness in aging populations.


Alcoholic Liver Disease: High Risk or Low Risk for Developing Hepatocellular Carcinoma?
In this review we critically assess the literature to evaluate the level of risk posed by alcohol as both a primary etiology of hepatocellular carcinoma (HCC) and as a cofactor in its development. Although there have been conflicting findings, based on the body of evidence to date, it appears that the linkage between compensated alcoholic liver disease-associated cirrhosis and HCC is best characterized as medium-high risk, with the risk increasing with age and with quantity and duration of alcohol consumption and is more pronounced in females. While abstinence is the most effective way to reduce HCC risk, its effect seems largely dependent on the severity of liver damage at the point of cessation. Alcohol clearly interacts with other etiologies and conditions including viral hepatitis B and C, hereditary hemochromatosis, diabetes, and obesity to increase the risk for developing HCC, either synergistically or additively. Continued progress in genetics, especially through mechanistic-based and genome-wide association studies may ultimately identify which single nucleotide polymorphisms are risk factors for the onset of alcoholic liver disease and its progression to HCC and lead to the development of targeted therapeutics which may help providers better manage at-risk patients.


The Problem of Pain in Systemic Lupus Erythematosus: An Explication of the Role of Biopsychosocial Mechanisms.
To define biopsychosocial mechanisms of pain that go above and beyond disease activity and organ damage in systemic lupus erythematosus (SLE). We conducted a cross-sectional analysis of patient-reported data in a population-based registry of 766 people with SLE. Predictors of pain intensity and interference were examined using hierarchical linear regression. We built 2 main hierarchical regression models with pain intensity and interference as outcomes, both regressed on disease activity and organ damage. For each model, we sought to establish the relationship between pain outcomes and the primary exposures using sequential steps comprising the inclusion of each construct in 6 stages: demographic, socioeconomic, physical, psychological, behavioral, and social factors. We also conducted sensitivity analyses eliminating all overt aspects of pain in the disease activity measure and reestimated the models. Disease activity and organ damage explained 32-33% of the variance in pain intensity and interference. Sociodemographic factors accounted for an additional 4-9% of variance in pain outcomes, whereas psychosocial/behavioral factors accounted for the final 4% of variance. In the sensitivity analyses, we found that disease activity and organ damage explained 25% of the variance in pain outcomes. Disease activity only explained 33% of the variance in pain outcomes. However, there was an attenuation in these associations after accounting for psychosocial/behavioral factors, highlighting their roles in modifying the relationship between disease activity and pain. These findings suggest that multilevel interventions may be needed to tackle the negative effect of pain in SLE.


Structure of the Receptor-Binding Carboxy-Terminal Domain of the Bacteriophage T5 L-Shaped Tail Fibre with and without Its Intra-Molecular Chaperone.
Bacteriophage T5, a Siphovirus belonging to the order Caudovirales, has a flexible, three-fold symmetric tail, to which three L-shaped fibres are attached. These fibres recognize oligo-mannose units on the bacterial cell surface prior to infection and are composed of homotrimers of the pb1 protein. Pb1 has 1396 amino acids, of which the carboxy-terminal 133 residues form a trimeric intra-molecular chaperone that is auto-proteolyzed after correct folding. The structure of a trimer of residues 970-1263 was determined by single anomalous dispersion phasing using incorporated selenomethionine residues and refined at 2.3 Å resolution using crystals grown from native, methionine-containing, protein. The protein inhibits phage infection by competition. The phage-distal receptor-binding domain resembles a bullet, with the walls formed by partially intertwined beta-sheets, conferring stability to the structure. The fold of the domain is novel and the topology unique to the pb1 structure. A site-directed mutant (Ser1264 to Ala), in which auto-proteolysis is impeded, was also produced, crystallized and its 2.5 Å structure solved by molecular replacement. The additional chaperone domain (residues 1263-1396) consists of a central trimeric alpha-helical coiled-coil flanked by a mixed alpha-beta domain. Three long beta-hairpin tentacles, one from each chaperone monomer, extend into long curved grooves of the bullet-shaped domain. The chaperone-containing mutant did not inhibit infection by competition.


High-temperature beverages and foods and esophageal cancer risk--a systematic review.
Coffee, tea and maté may cause esophageal cancer (EC) by causing thermal injury to the esophageal mucosa. If so, the risk of EC attributable to thermal injury could be large in populations in which these beverages are commonly consumed. In addition, these drinks may cause or prevent EC via their chemical constituents. Therefore, a large number of epidemiologic studies have investigated the association of an indicator of amount or temperature of use of these drinks or other hot foods and beverages with risk of EC. We conducted a systematic review of these studies and report the results for amount and temperature of use separately. By searching PubMed and the ISI, we found 59 eligible studies. For coffee and tea, there was little evidence for an association between amount of use and EC risk; however, the majority of studies showed an increased risk of EC associated with higher drinking temperature which was statistically significant in most of them. For maté drinking, the number of studies was limited, but they consistently showed that EC risk increased with both amount consumed and temperature, and these 2 were independent risk factors. For other hot foods and drinks, over half of the studies showed statistically significant increased risks of EC associated with higher temperature of intake. Overall, the available results strongly suggest that high-temperature beverage drinking increases the risk of EC. Future studies will require standardized strategies that allow for combining data and results should be reported by histological subtypes of EC.


Analysis of secretory, immunostaining and clinical characteristics of human "functionless" pituitary adenomas: transdifferentiation or gonadotropinomas?
In this study, the central technique of in vitro culture has been used to further investigate whether LH/FSH-expressing, but clinically "functionless" pituitary adenomas are gonadotropinomas or whether their hormone secretion is due to transdifferentiation events. 664 "functionless" pituitary adenomas were examined for hormone secretion by in vitro culture and for hormone content by immunostaining. The results were correlated with the clinical findings. 40 % of the tumours (n = 263) secreted at least one of the gonadotropins alone, 8 % (n = 53) exhibited various patterns of anterior pituitary hormones, whilst the remaining 52 % of tumours were not associated with any hormone. In the secretory tumours, immunostaining revealed only a few scattered hormone-containing cells (5 to 15 %). Mild hyperprolactinaemia was observed in some cases, presumably because of pressure effects of the tumours. The majority of the patients suffered clear cut hypopituitarism (p < 0.05). Pre-operatively, gonadotropin hypersecretion was observed in 3 cases, but only one of these secreted hormones in culture. Interestingly, a higher proportion of tumours removed from patients with hypopituitarism showed secretory activity in vitro than those tumours removed from patients showing no hormonal dysfunction or hyperprolactinaemia. We conclude that the term "gonadotropinoma" to describe functionless pituitary tumours associated with LH and/or FSH secretion is a misnomer, because the presence of LH and/or FSH confirmed by in vitro methods in the present series is a result of only a few scattered cells. We suggest that primary pituitary tumour cells differentiate into a secretory type (transdifferentiation), possibly in response to altered serum hormone levels such as decreased steroids. Further work is required to identify the factors which trigger the altered cells' characteristics.


Effects of high-density lipoproteins on storage at 4 degrees C of fowl spermatozoa.
Qualitative and quantitative characterization of lipoproteins found in seminal plasma from domestic cocks was performed after isolation by density gradient ultracentrifugation. Trigyceride-rich lipoproteins (very low, intermediate- and low density lipoproteins) were not detectable in seminal plasma. High-density lipoproteins (HDL), identified on the basis of size, chemical composition and protein moiety, were present at a concentration of 66 micrograms/ml. A fraction possibly corresponding to VHDL (very high density lipoproteins, 77% protein, 23% lipid) was also detected but appeared contaminated by a protein-rich opalescent material. Since HDL contains mostly phospholipid and cholesterol, the physiological role of these lipoproteins on the storage of fowl spermatozoa was studied. Replacing seminal plasma with a solution containing chicken HDL at physiological concentration (66 micrograms/ml) had no effect on fertilizing ability of spermatozoa stored at 4 degrees C for 24 h. However, higher concentrations of HDL (560 micrograms/ml) had deleterious effects on spermatozoa stored in vitro.


Identification and molecular genetic analysis of replication functions of the bacteriocinogenic plasmid pIP404 from Clostridium perfringens.
The replication functions of the bacteriocinogenic plasmid pIP404, from Clostridium perfringens, were localized to a 2.8-kb EcoRI-EcoRV fragment by cloning into a vector deficient for replication in Bacillus subtilis. This fragment contains two genes, cop and rep, which encode proteins and an 800-bp noncoding segment of complex structure consisting of multiple tandemly repeated sequences. The Cop protein is involved in copy number control, whereas the rep gene product is essential for plasmid replication. By deletion analysis the minimal origin of replication was defined as the rep gene plus most of the repeated sequences. A powerful promoter producing a 150-nucleotide RNA molecule, RNA1, that could act as an anti-sense RNA to the rep gene was detected in the "origin-like" region. In contrast to most other small plasmids of gram-positive bacteria, pIP404, and its derivatives, does not appear to replicate via a single stranded intermediate in either C. perfringens or B. subtilis.


Survey on Wireless Technology Trade-Offs for the Industrial Internet of Things.
Aside from vast deployment cost reduction, Industrial Wireless Sensor and Actuator Networks (IWSAN) introduce a new level of industrial connectivity. Wireless connection of sensors and actuators in industrial environments not only enables wireless monitoring and actuation, it also enables coordination of production stages, connecting mobile robots and autonomous transport vehicles, as well as localization and tracking of assets. All these opportunities already inspired the development of many wireless technologies in an effort to fully enable Industry 4.0. However, different technologies significantly differ in performance and capabilities, none being capable of supporting all industrial use cases. When designing a network solution, one must be aware of the capabilities and the trade-offs that prospective technologies have. This paper evaluates the technologies potentially suitable for IWSAN solutions covering an entire industrial site with limited infrastructure cost and discusses their trade-offs in an effort to provide information for choosing the most suitable technology for the use case of interest. The comparative discussion presented in this paper aims to enable engineers to choose the most suitable wireless technology for their specific IWSAN deployment.


Energy Efficiency of Inference Algorithms for Clinical Laboratory Data Sets: Green Artificial Intelligence Study.
The use of artificial intelligence (AI) in the medical domain has attracted considerable research interest. Inference applications in the medical domain require energy-efficient AI models. In contrast to other types of data in visual AI, data from medical laboratories usually comprise features with strong signals. Numerous energy optimization techniques have been developed to relieve the burden on the hardware required to deploy a complex learning model. However, the energy efficiency levels of different AI models used for medical applications have not been studied. The aim of this study was to explore and compare the energy efficiency levels of commonly used machine learning algorithms-logistic regression (LR), k-nearest neighbor, support vector machine, random forest (RF), and extreme gradient boosting (XGB) algorithms, as well as four different variants of neural network (NN) algorithms-when applied to clinical laboratory datasets. We applied the aforementioned algorithms to two distinct clinical laboratory data sets: a mass spectrometry data set regarding Staphylococcus aureus for predicting methicillin resistance (3338 cases; 268 features) and a urinalysis data set for predicting Trichomonas vaginalis infection (839,164 cases; 9 features). We compared the performance of the nine inference algorithms in terms of accuracy, area under the receiver operating characteristic curve (AUROC), time consumption, and power consumption. The time and power consumption levels were determined using performance counter data from Intel Power Gadget 3.5. The experimental results indicated that the RF and XGB algorithms achieved the two highest AUROC values for both data sets (84.7% and 83.9%, respectively, for the mass spectrometry data set; 91.1% and 91.4%, respectively, for the urinalysis data set). The XGB and LR algorithms exhibited the shortest inference time for both data sets (0.47 milliseconds for both in the mass spectrometry data set; 0.39 and 0.47 milliseconds, respectively, for the urinalysis data set). Compared with the RF algorithm, the XGB and LR algorithms exhibited a 45% and 53%-60% reduction in inference time for the mass spectrometry and urinalysis data sets, respectively. In terms of energy efficiency, the XGB algorithm exhibited the lowest power consumption for the mass spectrometry data set (9.42 Watts) and the LR algorithm exhibited the lowest power consumption for the urinalysis data set (9.98 Watts). Compared with a five-hidden-layer NN, the XGB and LR algorithms achieved 16%-24% and 9%-13% lower power consumption levels for the mass spectrometry and urinalysis data sets, respectively. In all experiments, the XGB algorithm exhibited the best performance in terms of accuracy, run time, and energy efficiency. The XGB algorithm achieved balanced performance levels in terms of AUROC, run time, and energy efficiency for the two clinical laboratory data sets. Considering the energy constraints in real-world scenarios, the XGB algorithm is ideal for medical AI applications.


Identifying the approaches used by audiologists to address the psychosocial needs of their adult clients.
To identify the approaches taken by audiologists to address their adult clients' psychosocial needs related to hearing loss. A participatory mixed methods design. Participants generated statements describing the ways in which the psychosocial needs of their adult clients with hearing loss are addressed, and then grouped the statements into themes. Data were obtained using face-to-face and online structured questions. Concept mapping techniques were used to identify key concepts and to map each of the concepts relative to each other. An international sample of 65 audiologists. Ninety-three statements were generated and grouped into seven conceptual clusters: Client Empowerment; Use of Strategies and Training to Personalise the Rehabilitation Program; Facilitating Peer and Other Professional Support; Providing Emotional Support; Improving Social Engagement with Technology; Including Communication Partners; and Promoting Client Responsibility. Audiologists employ a wide range of approaches in their attempt to address the psychosocial needs associated with hearing loss experienced by their adult clients. The approaches described were mostly informal and provided in a non-standardised way. The majority of approaches described were not evidence-based, despite the availability of several options that are evidence-based, thus highlighting the implementation gap between research and clinical practice.


A mechanical pencil lead-supported carbon nanotube/Au nanodendrite structure as an electrochemical sensor for As(iii) detection.
A mechanical pencil lead (MPL), an easily obtainable carbon-based material with a consistent size, was used as a frame to construct an MPL-supported carbon nanotube/Au nanodendrite (MPL-CNT/AuND) sensor through simple electrodeposition of Au onto the MPL in the presence of CNTs. A nanodendrite structure was adopted to ensure large numbers of active electrochemical sites because of its hierarchical structure with well-aligned terraces; the CNTs were used to firmly adhere the fabricated Au nanodendrites to the MPL surface to ensure ruggedness. The MPL-CNT/AuND structure was used to measure As3+ samples in a concentration range from 0.5 to 80 ppb using anodic stripping voltammetry (ASV). The variation in peak intensities was linear (R2: 0.997), and the limit of detection (LOD) was 0.4 ppb. The average relative standard deviation (RSD) of the peak intensities from the voltammograms of each sample collected using three separately prepared MPL-CNT/AuNDs was 8.7%, thereby demonstrating good sensor-to-sensor reproducibility. Furthermore, when three As3+ samples prepared in tap water were measured, the accuracy was maintained without noticeable degradation and the response was steady up to 50-cycle measurements.