sFlt-1/PlGF ratio test for pre-eclampsia: an economic assessment for the UK.
To assess the economic impact of introducing into clinical practice in the UK the soluble fms-like tyrosine kinase (sFlt-1) to placental growth factor (PlGF) ratio test for guiding the management of pre-eclampsia. We used an economic model estimating the incremental value of information, from a UK National Health Service payer's perspective, generated by the sFlt-1/PlGF ratio test, compared with current diagnostic procedures, in guiding the management of women with suspected pre-eclampsia. The economic model estimated costs associated with the diagnosis and management of pre-eclampsia in pregnant women between 24 + 0 and 36 + 6 weeks' gestation, managed in either a 'test' scenario in which the sFlt-1/PlGF test is used in addition to current diagnostic procedures, or a 'no-test' scenario in which clinical decisions are based on current diagnostic procedures alone. Test characteristics and resource use were derived from PROGNOSIS, a non-interventional study in women presenting with clinical suspicion of pre-eclampsia. The main outcome measure from the economic model was the cost per patient per episode of care, from first suspicion of pre-eclampsia to birth. Introduction of the sFlt-1/PlGF ratio test into clinical practice is expected to result in cost savings of £344 per patient compared with a no-test scenario. Savings are generated primarily through an improvement in diagnostic accuracy and subsequent reduction in unnecessary hospitalization. Introducing the sFlt-1/PlGF ratio test into clinical practice in the UK was shown to be cost-saving by reducing unnecessary hospitalization of women at low risk of developing pre-eclampsia. In addition, the test ensures that those women at higher risk are identified and managed appropriately. © 2016 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.


An apolipoprotein AI mimetic peptide: membrane interactions and the role of cholesterol.
The 18-amino acid amphipathic helical peptide Ac-DWFKAFYDKVAEKFKEAF-NH(2) promotes the separation of cholesterol from the phospholipid, resulting in the formation of cholesterol crystallites, even at mole fractions of cholesterol as low as 0.3. The peptide exerts a greater degree of penetration into membranes of pure phosphatidylcholine in the absence of cholesterol than into bilayers of phosphatidylcholine and cholesterol. The circular dichroism spectrum of the peptide in buffer indicates that it self-associates, leading to the formation of structures with higher helical content. However, in the presence of lipid, the peptide remains helical over a larger concentration range. The peptide undergoes a thermal transition on heating. Cholesterol has little effect on the secondary structure of the peptide; however, increased Trp emission intensity in the absence of cholesterol indicates a deeper penetration of the helix upon removal of cholesterol from the membrane. The results with these model systems demonstrate changes in peptide-lipid interactions that may be related to the observed biological properties of this peptide.


Recycling of ash from biomass incinerator in clay matrix to produce ceramic bricks.
The objective of this study is to investigate the effect of incorporation of ash from biomass incinerator as raw material on the production of ceramic bricks for their application in construction. So, for the fabrication of bricks, compositions were prepared with addition of increasing amounts of waste ash (0%, 10%, 20%, 30%, 40% and 50% in wt.) in the clay body. The mixed samples were sintered using conventional powder processing based on powder compaction at 54.5 MPa and firing them at 950 °C without the addition of additives. Effect on apparent density, water absorption and mechanical properties were investigated. The results showed that water absorption increased and apparent density and compressive strength decreased with higher amounts of ash. Bricks with an ash content up to 20% meet the UNE standards compressive strength. As a result, since interesting performances were observed, the potential use of ashes from biomass incinerator up to 20 wt.% in ceramic formulations of industrial interest was confirmed. In this sense, incorporating ashes into clay body reduces environmental problems and total cost of raw material disposition.


Quick and simple; psoas density measurement is an independent predictor of anastomotic leak and other complications after colorectal resection.
Radiologically defined sarcopenia has been shown to predict negative outcomes after cancer surgery, however radiological assessment of sarcopenia often requires additional software and standardisation against anthropomorphic data. Measuring psoas density using hospital Picture Archiving and Communication Systems (PACS), universally available in the UK, may have advantages over methods requiring the use of additional specialist and often costly software. The aim of this study was to assess the association between radiologically defined sarcopenia measured by psoas density and postoperative outcome in patients having a colorectal cancer resection. All patients having a resection for colorectal cancer, discussed by the colorectal multi-disciplinary team in one institution between 1/1/15 and 31/12/15, were retrospectively identified. Mean psoas density at the level of the L3 vertebra was analysed from preoperative computed tomography (CT) scans to define sarcopenia using the Picture Archiving and Communication Systems (PACS). Postoperative complications and mortality were recorded. One hundred and sixty-nine patients had a colorectal resection for cancer and 140 of these had a primary anastomosis. Ninety-day mortality and 1-year mortality were 1.1% and 7.1%, respectively. Eighteen (10.7%) patients suffered a Clavien-Dindo grade 3 or 4 complication of which 6 (33%) were anastomotic leaks. In the whole cohort, sarcopenia was associated with an increased risk of Clavien-Dindo grade 3 or 4 complications [adjusted OR 6.33 (1.65-24.23) p = 0.007]. In those who had an anastomosis, sarcopenia was associated with an increased risk of anastomotic leak [adjusted OR 14.37 (1.37-150.04) p = 0.026]. A quick and easy radiological assessment of sarcopenia by measuring psoas density on preoperative CT scan using software universally available in the UK is highly predictive of postoperative morbidity in colorectal cancer patients.


Evaluation of Leishmania species reactivity in human serologic diagnosis of leishmaniasis.
The sensitivities and specificities of IgG-ELISA and IgG flow cytometry based techniques using different Leishmania species were determined using sera collected from 40 cutaneous or visceral leishmaniasis patients. The flow cytometry technique, using promastigote parasite forms, performed better than total soluble extract IgG-ELISA. At the species level, the use of Leishmania amazonensis and Leishmania major as antigens in enzyme linked immunosorbent assay (ELISA) decreased the overall sensitivity. To assess the specificity of these tests, sera from malaria, toxoplasmosis, amoebiasis, schistosomiasis, and leprosy patients were used. We also included sera from Leishmania non-infected endemic individuals. The cutaneous species displayed a decreased specificity in both assays. Although more sensitive, flow cytometry using promastigote parasite forms generally presented lower levels of specificity when compared with total extract of IgG-ELISA. Overall, the results of the study show the potential of IgG flow cytometry for the diagnosis of leishmaniasis. Although highly sensitive, a refinement of the flow cytometry method should be performed to improve the overall specificity.


Low Interferon Relative-Response to Cytomegalovirus Is Associated with Low Likelihood of Intrauterine Transmission of the Virus.
Congenital Cytomegalovirus (CMV) is a very common intrauterine infection which can cause severe mental and hearing impairments. Notably, only 40% of primarily infected women transmit CMV to the fetus. CMV-specific T-cell response has a role in CMV disease but individual immune heterogeneity precludes reliable correlation between measurable T-cells response and intrauterine transmission. To establish a correlation between maternal T-cells response and fetal CMV transmission using an individual normalized immune response. We analyzed IFN-γ secretion upon whole blood stimulation from primary CMV-infected pregnant women, with either CMV-peptides or PHA-mitogen. We established a new normalization method of individual IFN-γ response to CMV by defining the ratio between specific-CMV response and non-specific mitogen response (defined as IFN-γ relative response, RR), aiming to overcome high person-to-person immune variability. We found a unique subpopulation of women with low IFN-γ RR strongly correlated with absence of transmission. IFN-γ RR lower than 1.8% (threshold determined by ROC analysis) reduces the pre-test probability of transmission from 40% to 8%, revealing an unexpected link between low IFN-γ RR and non-transmission. In pregnant women with primary CMV infection, low IFN-γ RR is associated with low risk of transmission.


Medicinal Plants of the Australian Aboriginal Dharawal People Exhibiting Anti-Inflammatory Activity.
Chronic inflammation contributes to multiple ageing-related musculoskeletal and neurodegenerative diseases, cardiovascular diseases, asthma, rheumatoid arthritis, and inflammatory bowel disease. More recently, chronic neuroinflammation has been attributed to Parkinson's and Alzheimer's disease and autism-spectrum and obsessive-compulsive disorders. To date, pharmacotherapy of inflammatory conditions is based mainly on nonsteroidal anti-inflammatory drugs which in contrast to cytokine-suppressive anti-inflammatory drugs do not influence the production of cytokines such as tumour necrosis factor-α or nitric oxide. However, their prolonged use can cause gastrointestinal toxicity and promote adverse events such as high blood pressure, congestive heart failure, and thrombosis. Hence, there is a critical need to develop novel and safer nonsteroidal anti-inflammatory drugs possessing alternate mechanism of action. In this study, plants used by the Dharawal Aboriginal people in Australia for the treatment of inflammatory conditions, for example, asthma, arthritis, rheumatism, fever, oedema, eye inflammation, and inflammation of bladder and related inflammatory diseases, were evaluated for their anti-inflammatory activity in vitro. Ethanolic extracts from 17 Eucalyptus spp. (Myrtaceae) were assessed for their capacity to inhibit nitric oxide and tumor necrosis factor-α production in RAW 264.7 macrophages. Eucalyptus benthamii showed the most potent nitric oxide inhibitory effect (IC50 5.57 ± 1.4 µg/mL), whilst E. bosistoana, E. botryoides, E. saligna, E. smithii, E. umbra, and E. viminalis exhibited nitric oxide inhibition values between 7.58 and 19.77 µg/mL.


Examining the temporal relationship between criminal justice involvement and sexual risk behaviors among drug-involved men.
Although criminal justice involvement has repeatedly been associated with human immunodeficiency virus (HIV)/sexually transmitted infection prevalence and sexual risk behaviors, few studies have examined whether arrest or incarceration uniquely contributes to sexually risky behavior. We examined the temporal relationship between criminal justice involvement and subsequent sexual HIV risk among men in methadone maintenance treatment in New York City. A random sample of 356 men was interviewed at baseline (time 1), 6-month (time 2), and 12-month (time 3) follow-ups. Propensity score matching, negative binomial, and multiple logistic regression were used to isolate and test the effect of time 2 arrest and incarceration on time 3 sexual risk behaviors. Incidence of time 2 criminal justice involvement was 20.1% for arrest and 9.4% for incarceration in the prior 6 months. Men who were arrested at time 2 demonstrated increased number (adjusted incidence rate ratio [IRR] = 1.62; 95% confidence intervals [CI] = 1.11, 2.37) and proportion (IRR = 1.36; 95% CI = 1.07, 1.72) of unprotected vaginal sex acts at time 3. Men incarcerated at time 2 displayed increased number (IRR = 2.07; 95% CI = 1.23, 3.48) and proportion (IRR = 1.45; 95% CI = 1.06, 1.99) of unprotected vaginal sex acts at time 3. Within this sample of drug-involved men, arrest and incarceration are temporally associated with and may uniquely impact successive sexual risk-taking. Findings underscore the importance of HIV prevention interventions among individuals with low-intensity criminal justice involvement. Developing prevention efforts aimed at short-term incarceration, community reentry, and alternatives to incarceration settings will address a large and under-researched segment of the criminal justice population. Alternative approaches to current criminal justice policy may result in public health benefits.


Reliability analysis framework for computer-assisted medical decision systems.
We present a technique that enhances computer-assisted decision (CAD) systems with the ability to assess the reliability of each individual decision they make. Reliability assessment is achieved by measuring the accuracy of a CAD system with known cases similar to the one in question. The proposed technique analyzes the feature space neighborhood of the query case to dynamically select an input-dependent set of known cases relevant to the query. This set is used to assess the local (query-specific) accuracy of the CAD system. The estimated local accuracy is utilized as a reliability measure of the CAD response to the query case. The underlying hypothesis of the study is that CAD decisions with higher reliability are more accurate. The above hypothesis was tested using a mammographic database of 1337 regions of interest (ROIs) with biopsy-proven ground truth (681 with masses, 656 with normal parenchyma). Three types of decision models, (i) a back-propagation neural network (BPNN), (ii) a generalized regression neural network (GRNN), and (iii) a support vector machine (SVM), were developed to detect masses based on eight morphological features automatically extracted from each ROI. The performance of all decision models was evaluated using the Receiver Operating Characteristic (ROC) analysis. The study showed that the proposed reliability measure is a strong predictor of the CAD system's case-specific accuracy. Specifically, the ROC area index for CAD predictions with high reliability was significantly better than for those with low reliability values. This result was consistent across all decision models investigated in the study. The proposed case-specific reliability analysis technique could be used to alert the CAD user when an opinion that is unlikely to be reliable is offered. The technique can be easily deployed in the clinical environment because it is applicable with a wide range of classifiers regardless of their structure and it requires neither additional training nor building multiple decision models to assess the case-specific CAD accuracy.


Effect of Hydrogen-Rich Water on Radiation-Induced Cognitive Dysfunction in Rats.
The goal of this work was to determine whether hydrogen-rich water (HRW) could attenuate radiation-induced cognitive dysfunction in rats and to explore the underlying mechanisms. Rats received 30 Gy whole-brain irradiation using a 6-MeV electron beam. Either purified water or HRW (0.8-0.9 ppm) was administrated at 10 min prior to irradiation, as well as a daily HRW treatment after irradiation for 30 consecutive days. The Morris water maze was used to test spatial memory in the rats. The concentration of glutathione (GSH), malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG) and the super-oxidedismutase (SOD) activity in cerebral cortex, as well as brain-derived neurotrophic factor (BDNF) level in serum, were measured. Immunofluorescence staining was adopted to detect proliferating cells. The expression of BDNF-TrkB pathway-related genes and proteins were detected using qRT-PCR and Western blot. Models of cognitive dysfunction were successfully established using a 30 Gy dose of ionizing radiation. Compared to the radiation treated group, the radiation-HRW treated group showed significantly decreased escape latency (P < 0.05), but increased retention time, swimming distance of original platform quadrant (P < 0.05) and number of platform crossings (P < 0.05). Furthermore, the SOD, GSH (P < 0.05) and BDNF (P < 0.05) levels in the radiation-HRW treated group were higher compared to the radiation treated group. The MDA and 8-OHdG levels (P < 0.05) were decreased in the radiation-HRW treated group when compared to the radiation treated group. Additionally, treatment with HRW increased the number of BrdU+NeuN+ cells in the radiation treated group. The mRNA and protein levels of BDNF and TrkB (P < 0.05) in radiation-HRW treated group was higher than that in the radiation treated group. Collectively, our study indicates that HRW has a protective effect on radiation-induced cognitive dysfunction, and that the possible mechanisms mainly involve anti-oxidative and anti-inflammatory reactions, and its protection of newborn neurons by regulating the BDNF-TrkB signaling pathway.


The synthesis of amphiphilic polyethyleneimine/calcium phosphate composites for bispecific T-cell engager based immunogene therapy.
Bispecific T-cell engagers (BiTEs) are single chain variable fragments with specific structures, which could connect the surface antigen on cancer cells and CD3 ligands on T cells, and then engage the T cells for cancer immunotherapy. In this report, a novel organic-inorganic hybrid gene delivery system composed of stearic acid modified polyethyleneimine (stPEI) and calcium phosphate (CaP) was used to deliver MC.DNA into cells to express BiTE antibodies. This gene delivery system exhibits high transfection efficiency, long-term effects and low cytotoxicity in vitro. Furthermore, the gene production, anti-IGF1R/CD3 bispecific T-cell engager, exhibited a rapid redirection activity in T cells to induce cancer cell apoptosis. In summary, the results confirmed that stPEI-CaP could be an efficient gene delivery system for BiTE encoding MC.DNA based gene immunotherapy.


Context dependent regulatory patterns of the androgen receptor and androgen receptor target genes.
Expression of the androgen receptor (AR) is associated with androgen-dependent proliferation arrest and terminal differentiation of normal prostate epithelial cells. Additionally, activation of the AR is required for survival of benign luminal epithelial cells and primary cancer cells, thus androgen deprivation therapy (ADT) leads to apoptosis in both benign and cancerous tissue. Escape from ADT is known as castration-resistant prostate cancer (CRPC). In the course of CRPC development the AR typically switches from being a cell-intrinsic inhibitor of normal prostate epithelial cell proliferation to becoming an oncogene that is critical for prostate cancer cell proliferation. A clearer understanding of the context dependent activation of the AR and its target genes is therefore desirable. Immortalized human prostate basal epithelial EP156T cells and progeny cells that underwent epithelial to mesenchymal transition (EMT), primary prostate epithelial cells (PrECs) and prostate cancer cell lines LNCaP, VCaP and 22Rv1 were used to examine context dependent restriction and activation of the AR and classical target genes, such as KLK3. Genome-wide gene expression analyses and single cell protein analyses were applied to study the effect of different contexts. A variety of growth conditions were tested and found unable to activate AR expression and transcription of classical androgen-dependent AR target genes, such as KLK3, in prostate epithelial cells with basal cell features or in mesenchymal type prostate cells. The restriction of androgen- and AR-dependent transcription of classical target genes in prostate basal epithelial cells was at the level of AR expression. Exogenous AR expression was sufficient for androgen-dependent transcription of AR target genes in prostate basal epithelial cells, but did not exert a positive feedback on endogenous AR expression. Treatment of basal prostate epithelial cells with inhibitors of epigenetic gene silencing was not efficient in inducing androgen-dependent transcription of AR target genes, suggesting the importance of missing cofactor(s). Regulatory mechanisms of AR and androgen-dependent AR target gene transcription are insufficiently understood and may be critical for prostate cancer initiation, progression and escape from standard therapy. The present model is useful for the study of context dependent activation of the AR and its transcriptome.


Are we overfeeding hemodialysis patients with protein? Exploring an alternative method to estimate protein needs.
Sufficient protein intake is of great importance in hemodialysis (HD) patients, especially for maintaining muscle mass. Daily protein needs are generally estimated using bodyweight (BW), in which individual differences in body composition are not accounted for. As body protein mass is best represented by fat free mass (FFM), there is a rationale to apply FFM instead of BW. The agreement between both estimations is unclear. Therefore, the aim of this study is to compare protein needs based on either FFM or BW in HD patients. Protein needs were estimated in 115 HD patients by three different equations; FFM, BW and BW adjusted for low or high BMI. FFM was measured by multi-frequency bioelectrical impedance spectroscopy and considered the reference method. Estimations of FFM x 1.5 g/kg and FFM x 1.9 g/kg were compared with (adjusted)BW x 1.2 and x 1.5, respectively. Differences were assessed with repeated measures ANOVA and Bland-Altman plots. Mean protein needs estimated by (adjusted)BW were higher compared to those based on FFM, across all BMI categories (P < 0.01) and most explicitly in obese patients. In females with BMI >30, protein needs were 69 ± 17.4 g/day higher based on BW and 45 ± 9.3 g/day higher based on BMI adjusted BW, compared to FFM. In males with BMI >30, protein needs were 51 ± 20.4 g/day and 23 ± 20.9 g/day higher compared to FFM, respectively. Our data show large differences and possible overestimations of protein needs when comparing BW to FFM. We emphasize the importance of more research and discussion on this topic.


Multidisciplinary Collaboration in the Treatment of Patients With Type 2 Diabetes in Primary Care: Analysis Using Process Mining.
Public health in several countries is characterized by a shortage of professionals and a lack of economic resources. Monitoring and redesigning processes can foster the success of health care institutions, enabling them to provide a quality service while simultaneously reducing costs. Process mining, a discipline that extracts knowledge from information system data to analyze operational processes, affords an opportunity to understand health care processes. Health care processes are highly flexible and multidisciplinary, and health care professionals are able to coordinate in a variety of different ways to treat a diagnosis. The aim of this work was to understand whether the ways in which professionals coordinate their work affect the clinical outcome of patients. This paper proposes a method based on the use of process mining to identify patterns of collaboration between physician, nurse, and dietitian in the treatment of patients with type 2 diabetes mellitus and to compare these patterns with the clinical evolution of the patients within the context of primary care. Clustering is used as part of the preprocessing of data to manage the variability, and then process mining is used to identify patterns that may arise. The method is applied in three primary health care centers in Santiago, Chile. A total of seven collaboration patterns were identified, which differed primarily in terms of the number of disciplines present, the participation intensity of each discipline, and the referrals between disciplines. The pattern in which the three disciplines participated in the most equitable and comprehensive manner had a lower proportion of highly decompensated patients compared with those patterns in which the three disciplines participated in an unbalanced manner. By discovering which collaboration patterns lead to improved outcomes, health care centers can promote the most successful patterns among their professionals so as to improve the treatment of patients. Process mining techniques are useful for discovering those collaborations patterns in flexible and unstructured health care processes.


High-quality permanent draft genome sequence of Rhizobium sullae strain WSM1592; a Hedysarum coronarium microsymbiont from Sassari, Italy.
Rhizobium sullae strain WSM1592 is an aerobic, Gram-negative, non-spore-forming rod that was isolated from an effective nitrogen (N2) fixing root nodule formed on the short-lived perennial legume Hedysarum coronarium (also known as Sulla coronaria or Sulla). WSM1592 was isolated from a nodule recovered from H. coronarium roots located in Ottava, bordering Sassari, Sardinia in 1995. WSM1592 is highly effective at fixing nitrogen with H. coronarium, and is currently the commercial Sulla inoculant strain in Australia. Here we describe the features of R. sullae strain WSM1592, together with genome sequence information and its annotation. The 7,530,820 bp high-quality permanent draft genome is arranged into 118 scaffolds of 118 contigs containing 7.453 protein-coding genes and 73 RNA-only encoding genes. This rhizobial genome is sequenced as part of the DOE Joint Genome Institute 2010 Genomic Encyclopedia for Bacteria and Archaea-Root Nodule Bacteria (GEBA-RNB) project.


Effects of intralaryngeal carbon dioxide and acetazolamide on the laryngeal chemoreflex.
Sudden infant death syndrome is the leading cause of death in infants in the United States. The laryngeal chemoreflex (LCR) is thought to contribute to its pathogenesis. In adult animals, increasing levels of intralaryngeal CO2 result in a decrease in ventilatory activity. Intravenous acetazolamide (AZ) abolishes this response. The purpose of this study was to determine the effects of intralaryngeal CO2 and AZ on the LCR and respiratory physiology of piglets under normoxic and hypoxic conditions. We applied 0% or 10% CO2 in a randomized order to the larynx of 26 piglets. Intubation via tracheotomy prevented inhalation of the gas mixtures. Laryngeal stimulation was performed under normoxic conditions (PaO2 of >70 mm Hg) in 15 animals and under hypoxic conditions (PaO2 of 50 to 65 mm Hg) in 11 animals both with and without intravenous AZ (5 mg/kg). Respiratory and cardiovascular response data were recorded. Ten percent intralaryngeal CO2 has no significant effect on mean baseline respiratory rate, systemic PaCO2 or PaO2 levels, or apnea duration (p > .05). The use of AZ (versus no AZ) resulted in significantly higher baseline respiratory rates (64 versus 51 breaths per minute; p = .016), a decreased baseline systemic PaCO2 level (38.8 versus 45.9 mm Hg; p < .001), a higher baseline PaO2 level (97.9 versus 82.8 mm Hg; p < .001), shorter mean apnea durations (15.5 versus 24.8 seconds; p = .001), a higher lowest O2 saturation level after the stimulus (78.0% versus 68.4%; p = .003), and fewer profound apneas (10 of 90 versus 41 of 90 trials; p < .001). We conclude that 10% intralaryngeal CO2 does not decrease ventilatory activity in piglets and has no significant effect on the LCR. Acetazolamide, however, appears to have a protective effect against the LCR, resulting in shorter and less severe apneas. The protective effect of AZ against the LCR appears to be related to its ability to stimulate the respiratory drive and increase oxygenation at baseline.


Insulin-receptor interactions. Possible involvement of metals.
Addition of Zn2+ or Cu2+ ions to plasma membrane preparations or to purified insulin receptors from rat liver resulted in an increase of specific insulin binding; no effect was observed with the addition of Fe3+, Ca2+ or Na+. Dialysis of membrane preparations, or of purified receptors, against chelating agents such as zincon (2-carboxy-2'-hydroxy-5'-sulfoformazyl-benzene) or 1,10-phenantroline resulted in a decrease in specific binding of insulin. With the readdition of Zn2+ or Cu2+ to the medium an increase in specific binding was observed, and values much higher than those of the original preparations were obtained; the addition of Ca2+, Fe3+ or Na+ to dialyzed preparations did not cause any effect on the specific binding. Dialysis of purified receptors against chelating agents resulted in a decrease in the content of Zn2+ and Cu2+. Zincon has been found to be a competitive inhibitor of insulin interfering with the specific binding to the receptor, and noncompetitive with the nonspecific binding. These results suggest the possible involvement of a metal ion present in the receptor in the formation of the insulin-receptor complex.


Projected loss of a salamander diversity hotspot as a consequence of projected global climate change.
Significant shifts in climate are considered a threat to plants and animals with significant physiological limitations and limited dispersal abilities. The southern Appalachian Mountains are a global hotspot for plethodontid salamander diversity. Plethodontids are lungless ectotherms, so their ecology is strongly governed by temperature and precipitation. Many plethodontid species in southern Appalachia exist in high elevation habitats that may be at or near their thermal maxima, and may also have limited dispersal abilities across warmer valley bottoms. We used a maximum-entropy approach (program Maxent) to model the suitable climatic habitat of 41 plethodontid salamander species inhabiting the Appalachian Highlands region (33 individual species and eight species included within two species complexes). We evaluated the relative change in suitable climatic habitat for these species in the Appalachian Highlands from the current climate to the years 2020, 2050, and 2080, using both the HADCM3 and the CGCM3 models, each under low and high CO(2) scenarios, and using two-model thresholds levels (relative suitability thresholds for determining suitable/unsuitable range), for a total of 8 scenarios per species. While models differed slightly, every scenario projected significant declines in suitable habitat within the Appalachian Highlands as early as 2020. Species with more southern ranges and with smaller ranges had larger projected habitat loss. Despite significant differences in projected precipitation changes to the region, projections did not differ significantly between global circulation models. CO(2) emissions scenario and model threshold had small effects on projected habitat loss by 2020, but did not affect longer-term projections. Results of this study indicate that choice of model threshold and CO(2) emissions scenario affect short-term projected shifts in climatic distributions of species; however, these factors and choice of global circulation model have relatively small affects on what is significant projected loss of habitat for many salamander species that currently occupy the Appalachian Highlands.


Rational Design of Polynuclear Organometallic Assemblies from a Simple Heteromultifunctional Ligand.
In modern coordination chemistry, supramolecular coordination complexes take advantage of ligand design to control the shapes and sizes of such architectures. Here we describe how to utilize starting building blocks and a multifunctional ligand to rationally design and synthesize different types of discrete assemblies. Using a hydroxamate ligand featuring two pair of chelating sites together with half-sandwich iridium and rhodium fragments, we were able to construct a series multinuclear organometallic macrocycles and cages through stepwise coordination-driven self-assembly. Experimental observations, supported by computational work, show that selective coordination modes were ascribed to the significant electronic density differences of the two chelating sites, (O,O') and (N,N'). The results underline the advantages of the discrimination between soft and hard binding sites, and suggest that hydroxamic acids can be used as a versatile class of facile multifunctional scaffold for the construction of novel two-dimensional and three-dimensional architectures.


Influence of individual and combined health behaviors on total and cause-specific mortality in men and women: the United Kingdom health and lifestyle survey.
Physical activity, diet, smoking, and alcohol consumption have been shown to be related to mortality. We examined prospectively the individual and combined influence of these risk factors on total and cause-specific mortality. The prospective cohort study included 4886 individuals at least 18 years old from a United Kingdom-wide population in 1984 to 1985. A health behavior score was calculated, allocating 1 point for each poor behavior: smoking; fruits and vegetables consumed less than 3 times daily; less than 2 hours physical activity per week; and weekly consumption of more than 14 units of alcohol (in women) and more than 21 units (in men) (range of points, 0-4). We examined the relationship between health behaviors and mortality using Cox models and compared it with the mortality risk associated with aging. During a mean follow-up period of 20 years, 1080 participants died, 431 from cardiovascular diseases, 318 from cancer, and 331 from other causes. Adjusted hazard ratios and 95% confidence intervals (CIs) for total mortality associated with 1, 2, 3, and 4 poor health behaviors compared with those with none were 1.85 (95% CI, 1.28-2.68), 2.23 (95% CI, 1.55-3.20), 2.76 (95% CI, 1.91-3.99), and 3.49 (95% CI, 2.31-5.26), respectively (P value for trend, <.001). The effect of combined health behaviors was strongest for other deaths and weakest for cancer mortality. Those with 4 compared with those with no poor health behaviors had an all-cause mortality risk equivalent to being 12 years older. The combined effect of poor health behaviors on mortality was substantial, indicating that modest, but sustained, improvements to diet and lifestyle could have significant public health benefits.


Polychromatic reflectance and transmittance of a slab with a randomly rough boundary.
We investigated four different approximation models for describing the polychromatic reflectance and transmittance of a slab with a randomly rough boundary while taking into account the coherent and the incoherent scattering of the rough boundary. Comparisons with experiments (an etched-silicon wafer) show that approximation models that apply a two-scale roughness to the randomly rough boundary and that take into account the coherent and the incoherent scattering yield better agreement and extend the range of validity of the approximation to shorter wavelengths.


[Mother's ability of childcare and children malnutrition].
To identify and measure the risk of malnutrition associated to determining indicators of mother's ability of childcare: familial structure, education level, work, maternal physical and mental health. A case-control study was performed. Cases (101 children whose weight/age was below 5th percentile) and controls (200 children whose weight/age was above 25th percentile) were selected using anthropometric surveys during three vaccination campaigns in 1996 and 1997. Data was collected by interviewing the children's mothers at home. To detect the net effect of each factor studied, multivariate hierarchical analyses were carried out. The factors investigated and possible control variables were grouped in blocks, arranged according to order they affected the child's nutritional status. In order to identify the control variables a p<0.20 (univariate analyses) was assumed and to identify associations between a given factor and malnutrition a p<0.05 was assumed. Malnutrition risk factors identified are: (a) adverse familial structure, indicated by single parenting (OR=2.2; 95%CI, 1.1-4.5); (b) hospitalization of the mother during pregnancy (OR=3.5; 95%CI, 1.6-7.7); (c) mother's poor mental health, determined by the presence of 3 to 4 symptoms of depression included in the SRQ-20 (OR=3.1; 95%CI, 0.9-10.3); and (d) family stress factors, suggestive signs of alcoholism in at least one family member (OR=2.1; 95%CI, 1.2-3.9). In addition to these factors, child's age at the time the mother resumed/started working was also independently associated to malnutrition. However, it produced mixed effects: for children aged 4 to 12 months, the mothers' resuming work resulted in a protection factor whereas their resuming later tended to increase the risk of malnutrition. It was evidenced that the factors that define the mother's ability of child care affect the child's nutritional status.


A novel p38 alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model.
An accumulating body of evidence is consistent with the hypothesis that excessive or prolonged increases in proinflammatory cytokine production by activated glia is a contributor to the progression of pathophysiology that is causally linked to synaptic dysfunction and hippocampal behavior deficits in neurodegenerative diseases such as Alzheimer's disease (AD). This raises the opportunity for the development of new classes of potentially disease-modifying therapeutics. A logical candidate CNS target is p38 alpha MAPK, a well-established drug discovery molecular target for altering proinflammatory cytokine cascades in peripheral tissue disorders. Activated p38 MAPK is seen in human AD brain tissue and in AD-relevant animal models, and cell culture studies strongly implicate p38 MAPK in the increased production of proinflammatory cytokines by glia activated with human amyloid-beta (A beta) and other disease-relevant stressors. However, the vast majority of small molecule drugs do not have sufficient penetrance of the blood-brain barrier to allow their use as in vivo research tools or as therapeutics for neurodegenerative disorders. The goal of this study was to test the hypothesis that brain p38 alpha MAPK is a potential in vivo target for orally bioavailable, small molecules capable of suppressing excessive cytokine production by activated glia back towards homeostasis, allowing an improvement in neurologic outcomes. A novel synthetic small molecule based on a molecular scaffold used previously was designed, synthesized, and subjected to analyses to demonstrate its potential in vivo bioavailability, metabolic stability, safety and brain uptake. Testing for in vivo efficacy used an AD-relevant mouse model. A novel, CNS-penetrant, non-toxic, orally bioavailable, small molecule inhibitor of p38 alpha MAPK (MW01-2-069A-SRM) was developed. Oral administration of the compound at a low dose (2.5 mg/kg) resulted in attenuation of excessive proinflammatory cytokine production in the hippocampus back towards normal in the animal model. Animals with attenuated cytokine production had reductions in synaptic dysfunction and hippocampus-dependent behavioral deficits. The p38 alpha MAPK pathway is quantitatively important in the A beta-induced production of proinflammatory cytokines in hippocampus, and brain p38 alpha MAPK is a viable molecular target for future development of potential disease-modifying therapeutics in AD and related neurodegenerative disorders.


Immunological monitoring of newly diagnosed CML patients treated with bosutinib or imatinib first-line.
Changes in the immune system induced by tyrosine kinase inhibitors (TKI) have been shown to positively correlate with therapy responses in chronic myeloid leukemia (CML). However, only a few longitudinal studies exist and no randomized comparisons between two TKIs have been reported. Therefore, we prospectively analyzed the immune system of newly diagnosed CML patients treated with imatinib (n = 20) or bosutinib (n = 13), that participated in the randomized BFORE trial (NCT02130557). Comprehensive immunophenotyping, plasma protein profiling, and functional assays to determine activation levels of T and NK cells were performed at diagnosis, 3, and 12 months after therapy start. All results were correlated with clinical parameters such as Sokal risk and BCR-ABL load measured according to IS%. At diagnosis, low Sokal risk CML patients had a higher frequency of cytotoxic cells (CD8 + T and NK cells), increased cytotoxic potential of NK cells and lower frequency of naïve and central memory CD4 + T cells. Further, soluble plasma protein profile divided patients into two distinct clusters with different disease burden at diagnosis. During treatment, BCR-ABL IS% correlated with immunological parameters such as plasma proteins, together with different memory subsets of CD4+ and CD8 + T cells. Interestingly, the proportion and cytotoxic potential of NK cells together with several soluble proteins increased during imatinib treatment. In contrast, no major immunological changes were observed during bosutinib treatment. In conclusion, imatinib and bosutinib were shown to have differential effects on the immune system in this randomized clinical trial. Increased number and function of NK cells were especially observed during imatinib therapy.


Nonlocal discrete regularization on weighted graphs: a framework for image and manifold processing.
We introduce a nonlocal discrete regularization framework on weighted graphs of the arbitrary topologies for image and manifold processing. The approach considers the problem as a variational one, which consists of minimizing a weighted sum of two energy terms: a regularization one that uses a discrete weighted p-Dirichlet energy and an approximation one. This is the discrete analogue of recent continuous Euclidean nonlocal regularization functionals. The proposed formulation leads to a family of simple and fast nonlinear processing methods based on the weighted p-Laplace operator, parameterized by the degree p of regularity, the graph structure and the graph weight function. These discrete processing methods provide a graph-based version of recently proposed semi-local or nonlocal processing methods used in image and mesh processing, such as the bilateral filter, the TV digital filter or the nonlocal means filter. It works with equal ease on regular 2-D and 3-D images, manifolds or any data. We illustrate the abilities of the approach by applying it to various types of images, meshes, manifolds, and data represented as graphs.


The growing human footprint on coastal and open-ocean biogeochemistry.
Climate change, rising atmospheric carbon dioxide, excess nutrient inputs, and pollution in its many forms are fundamentally altering the chemistry of the ocean, often on a global scale and, in some cases, at rates greatly exceeding those in the historical and recent geological record. Major observed trends include a shift in the acid-base chemistry of seawater, reduced subsurface oxygen both in near-shore coastal water and in the open ocean, rising coastal nitrogen levels, and widespread increase in mercury and persistent organic pollutants. Most of these perturbations, tied either directly or indirectly to human fossil fuel combustion, fertilizer use, and industrial activity, are projected to grow in coming decades, resulting in increasing negative impacts on ocean biota and marine resources.


Caspases in virus-infected cells contribute to recognition by CD8+ T lymphocytes.
CD8(+) cytotoxic T lymphocytes recognize infected cells in which MHC class I molecules present pathogen-derived peptides that have been processed mainly by proteasomes. Many infections induce a set of proteases, the caspases involved in apoptosis or inflammation. In this study, we report that processing and presentation of a short vaccinia virus-encoded Ag can take place also by a nonproteasomal pathway, which was blocked in infected cells with chemical inhibitors of caspases. By cleaving at noncanonical sites, at least two caspases generated antigenic peptides recognized by T lymphocytes. The sites and the peptidic products were partially overlapping but different to those used and produced by proteasomes in vitro. Antigenic natural peptides produced in infected cells by either pathway were quantitatively and qualitatively similar. Finally, coexpression of the natural vaccinia virus protein B13, which is an inhibitor of caspases and apoptosis, impaired Ag presentation by the caspase pathway in infected cells. These data support the hypothesis that numerous cellular proteolytic systems, including those induced during infection, such as caspases involved in apoptosis or in inflammation, contribute to the repertoire of presented peptides, thereby facilitating immunosurveillance.


The predictive power of diagnostic tests and the effect of prevalence of illness.
There is a great interest in the potential usefulness of biomedical tests in psychiatry, but basic statistical principles required for critical evaluation of their value remain poorly integrated into clinical thinking. We developed a useful scheme for organizing clinical test data so as to permit simple calculations of the sensitivity, specificity, and predictive power of medical tests. Some loss of predictive power is inherent in moving from artificial populations used for test development into more typical clinical settings, where prevalence is usually substantially lower.


Hox and a newly identified E2F co-repress cell death in Caenorhabditis elegans.
The development of an organism depends on individual cells receiving and executing their specific fates, although how this process is regulated remains largely unknown. Here, we identify a mechanism by which a specific cell fate, apoptosis, is determined through the cooperative efforts of Hox and E2F proteins. E2F transcription factors are critical, conserved regulators of the cell cycle and apoptosis. However, little is known about the two most recently discovered mammalian E2Fs-E2F7 and E2F8. In the nematode Caenorhabditis elegans, we identify a novel E2F7/8 homolog, EFL-3, and show that EFL-3 functions cooperatively with LIN-39, providing the first example in which these two major developmental pathways-E2F and Hox-are able to directly regulate the same target gene. Our studies demonstrate that LIN-39 and EFL-3 function in a cell type-specific context to regulate transcription of the egl-1 BH3-only cell death gene and to determine cell fate during development.


Testosterone Therapy and Its Monitoring in Adolescent Boys with Hypogonadism: Results of an International Survey from the I-DSD Registry.
It is unclear whether testosterone replacement therapy (TRT) in adolescent boys, affected by a range of endocrine diseases that may be associated with hypogonadism, is particularly common. The aim of this study was to assess the contemporary practice of TRT in boys included in the I-DSD Registry. All participating centres in the I-DSD Registry that had boys between 10 and 18 years of age and with a condition that could be associated with hypogonadism were invited to provide further information in 2019. Information on 162 boys was collected from 15 centres that had a median (range) number of 6 boys per centre (1.35). Of these, 30 (19%) from 9 centres were receiving TRT and the median (range) age at the start was 12.6 years (10.8-16.2), with 6 boys (20%) starting at <12 years. Median (range) age of boys not on TRT was 11.7 years (10.7-17.7), and 69 out of 132 (52%) were <12 years. TRT had been initiated in 20 of 71 (28%) boys with a disorder of gonadal development, 3 of 14 (21%) with a disorder of androgen synthesis, and all 7 (100%) boys with hypogonadotropic hypogonadism. The remainder who did not have TRT included 15 boys with partial androgen insensitivity, 52 with non-specific XY DSD, and 3 with persistent Müllerian duct syndrome. Before starting TRT, liver function and blood count were checked in 19 (68%) and 18 boys (64%), respectively, a bone age assessment was performed in 23 (82%) and bone mineral density assessment in 12 boys (43%). This snapshot of contemporary practice reveals that TRT in boys included in the I-DSD Registry is not very common, whilst the variation in starting and monitoring therapy is quite marked. Standardisation of practice may lead to more effective assessment of treatment outcomes.


Promoting children's learning and development in conflict-affected countries: Testing change process in the Democratic Republic of the Congo.
Improving children's learning and development in conflict-affected countries is critically important for breaking the intergenerational transmission of violence and poverty. Yet there is currently a stunning lack of rigorous evidence as to whether and how programs to improve learning and development in conflict-affected countries actually work to bolster children's academic learning and socioemotional development. This study tests a theory of change derived from the fields of developmental psychopathology and social ecology about how a school-based universal socioemotional learning program, the International Rescue Committee's Learning to Read in a Healing Classroom (LRHC), impacts children's learning and development. The study was implemented in three conflict-affected provinces of the Democratic Republic of the Congo and employed a cluster-randomized waitlist control design to estimate impact. Using multilevel structural equation modeling techniques, we found support for the central pathways in the LRHC theory of change. Specifically, we found that LRHC differentially impacted dimensions of the quality of the school and classroom environment at the end of the first year of the intervention, and that in turn these dimensions of quality were differentially associated with child academic and socioemotional outcomes. Future implications and directions are discussed.


Cryo-EM structure of the human concentrative nucleoside transporter CNT3.
Concentrative nucleoside transporters (CNTs), members of the solute carrier (SLC) 28 transporter family, facilitate the salvage of nucleosides and therapeutic nucleoside derivatives across the plasma membrane. Despite decades of investigation, the structures of human CNTs remain unknown. We determined the cryogenic electron microscopy (cryo-EM) structure of human CNT (hCNT) 3 at an overall resolution of 3.6 Å. As with its bacterial homologs, hCNT3 presents a trimeric architecture with additional N-terminal transmembrane helices to stabilize the conserved central domains. The conserved binding sites for the substrate and sodium ions unravel the selective nucleoside transport and distinct coupling mechanism. Structural comparison of hCNT3 with bacterial homologs indicates that hCNT3 is stabilized in an inward-facing conformation. This study provides the molecular determinants for the transport mechanism of hCNTs and potentially facilitates the design of nucleoside drugs.


Foxa1 and Foxa2 regulate bile duct development in mice.
The forkhead box proteins A1 and A2 (Foxa1 and Foxa2) are transcription factors with critical roles in establishing the developmental competence of the foregut endoderm and in initiating liver specification. Using conditional gene ablation during a later phase of liver development, we show here that deletion of both Foxa1 and Foxa2 (Foxa1/2) in the embryonic liver caused hyperplasia of the biliary tree. Abnormal bile duct formation in Foxa1/2-deficient liver was due, at least in part, to activation of IL-6 expression, a proliferative signal for cholangiocytes. The glucocorticoid receptor is a negative regulator of IL-6 transcription; in the absence of Foxa1/2, the glucocorticoid receptor failed to bind to the IL-6 promoter, causing enhanced IL-6 expression. Thus, after liver specification, Foxa1/2 are required for normal bile duct development through prevention of excess cholangiocyte proliferation. Our data suggest that Foxa1/2 function as terminators of bile duct expansion in the adult liver through inhibition of IL-6 expression.


Enhanced Fowler-Nordheim tunneling effect in nanocrystallite Si based LED with interfacial Si nano-pyramids.
The premier observation on the enhanced light emission from such a metal-SiO(x)-Si light emitting diode (MOSLED) with Si nano-pyramids at SiO(x)/Si interface is demonstrated at low biases. The Si nano-pyramids exhibits capability in providing the roughness of the SiO(x)/Si interface, and improving the Fowler-Nordheim (F-N) tunneling mechanism based carrier injection through the novel SiO(x)/nano-Si-pyramid/Si structure. HRTEM analysis reveals a precisely controllable size and concentration of the crystallized interfacial Si nano-pyramids at 10nm(height)x10nm(width) and within the range of 10(8)-10(11) cm(-2), respectively. With these Si nano-pyramids at a surface density of up to 1012/cm(2), the F-N tunneling threshold can be reduce from 7 MV/cm to 1.4 MV/cm. The correlation between surface density of the interfacial Si nano-pyramids and the threshold F-N tunneling field has been elucidated. Such a turn-on reduction essentially provides a less damaged SiO(x)/Si interface as the required bias for the electroluminescence of the MOSLED is greatly decreased, which thus suppresses the generation of structural damage related radiant defects under a lower biased condition and leads to a more stable near-infrared electroluminescence with a narrowing linewidth and an operating lifetime lengthened to >3 hours. An output EL power of nearly 150 nW under a biased voltage of 75 V and current density of 32 mA/cm(2) is reported for the first time.


Attenuation of autoimmune responses to oxidative specific epitopes, but not nitroso-adducts, is associated with a better clinical outcome in Myalgic Encephalomyelitis/chronic fatigue syndrome.
There is evidence that inflammatory, oxidative and nitrosative stress (IO&NS) pathways participate in the pathophysiology of a subgroup of patients with Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Increased IgM-related autoimmune responses to oxidative specific epitopes (OSEs), including malondialdehyde (MDA), oleic acid and phosphatidyl inositol (Pi), and nitroso-(NO)-adducts, including NO-tryptophan (NOW), NO-arginine and NO-cysteinyl, are frequently observed in ME/CFS. Autoimmune responses in ME/CFS may be driven by increased bacterial translocation as measured by IgM and IgA responses to LPS of gram negative bacteria. The aim of this study is to examine whether IgM responses to OSEs and NO-adducts are related to a better outcome as measured by the Fibromyalgia and Fatigue Rating Scale (FF). 76 ME/CFS patients with initially abnormal autoimmune responses were treated with care-as-usual, including nutraceuticals with anti-IO&NS effects (NAIOS), such as L-carnitine, coenzyme Q10, taurine + lipoic acid, with or without curcumine + quercitine or N-acetyl-cysteine, zinc + glutamine. We found that use of these NAIOS was associated with highly significant reductions in initially increased IgM-mediated autoimmune responses to OSEs and NO-adducts. A greater reduction in autoimmune responses to OSEs during intake of these NAIOS was associated with a lower FF score. Reductions in IgM responses to oleic acid, MDA and Pi, but not in any of the NO-adducts, were associated with reductions in severity of illness. These associations remained significant after adjusting for possible effects of increased bacterial translocation (leaky gut). Our results show that autoimmune responses to OSEs are involved in the pathophysiology of ME/CFS and that these pathways are a new drug target in a subgroup of ME/CFS patients. Although hypernitrosylation and nitrosative stress play a role in ME/CFS, reductions in these pathways are not associated with lowered severity of illness. Randomized controlled trials with NAIOS should be carried out in the subgroup of ME/CFS patients with initially increased autoimmune responses to OSEs.


Moral concepts set decision strategies to abstract values.
Persons have different value preferences. Neuroimaging studies where value-based decisions in actual conflict situations were investigated suggest an important role of prefrontal and cingulate brain regions. General preferences, however, reflect a superordinate moral concept independent of actual situations as proposed in psychological and socioeconomic research. Here, the specific brain response would be influenced by abstract value systems and moral concepts. The neurobiological mechanisms underlying such responses are largely unknown. Using functional magnetic resonance imaging (fMRI) with a forced-choice paradigm on word pairs representing abstract values, we show that the brain handles such decisions depending on the person's superordinate moral concept. Persons with a predominant collectivistic (altruistic) value system applied a "balancing and weighing" strategy, recruiting brain regions of rostral inferior and intraparietal, and midcingulate and frontal cortex. Conversely, subjects with mainly individualistic (egocentric) value preferences applied a "fight-and-flight" strategy by recruiting the left amygdala. Finally, if subjects experience a value conflict when rejecting an alternative congruent to their own predominant value preference, comparable brain regions are activated as found in actual moral dilemma situations, i.e., midcingulate and dorsolateral prefrontal cortex. Our results demonstrate that superordinate moral concepts influence the strategy and the neural mechanisms in decision processes, independent of actual situations, showing that decisions are based on general neural principles. These findings provide a novel perspective to future sociological and economic research as well as to the analysis of social relations by focusing on abstract value systems as triggers of specific brain responses.


Effects of Turmeric and Curcumin Dietary Supplementation on Human Gut Microbiota: A Double-Blind, Randomized, Placebo-Controlled Pilot Study.
Curcuma longa (common name: turmeric) and one of its biologically active constituents, curcumin, have received increased clinical attention. Insufficient data exist on the effects of curcumin and turmeric on the gut microbiota and such studies in humans are lacking. Turmeric tablets with extract of piperine (Bioperine) (n = 6), curcumin with Bioperine tablets (n = 5), or placebo tablets (n = 3) were provided to healthy human subjects and subsequent changes in the gut microbiota were determined by 16S rDNA sequencing. The number of taxa detected ranged from 172 to 325 bacterial species. The placebo group displayed an overall reduction in species by 15%, whereas turmeric-treated subjects displayed a modest 7% increase in observed species posttreatment. Subjects taking curcumin displayed an average increase of 69% in detected species. The gut microbiota response to treatment was highly personalized, thus leading to responders and nonresponders displaying response concordance. These "responsive" subjects defined a signature involving uniform increases in most Clostridium spp., Bacteroides spp., Citrobacter spp., Cronobacter spp., Enterobacter spp., Enterococcus spp., Klebsiella spp., Parabacteroides spp., and Pseudomonas spp. Common to these subjects was the reduced relative abundance of several Blautia spp. and most Ruminococcus spp. All participants' microbiota displayed significant variation over time and individualized response to treatment. Among the responsive participants, both turmeric and curcumin altered the gut microbiota in a highly similar manner, suggesting that curcumin may drive the majority of observed changes observed in turmeric-treated subjects.


Primary biliary cholangitis development after hepatitis C virus eradication with direct acting antivirals: a case report and review of the literature.
We report the case of an 84-year-old man with asymptomatic chronic hepatitis C virus (HCV) infection treated with direct antiviral agents. At the end of the antiviral therapy laboratory tests showed an abrupt increase in cholestasis parameters and aminotransferases, associated with anti-mitochondria antibodies positivity. Therefore, primary biliary cholangitis (PBC) was diagnosed. The patient was treated with ursodeoxycholic acid achieving a good biochemical response. This is the second case described in literature of PBC onset after HCV eradication with an interferon-free antiviral regimen. In both cases an autoimmune damage of cholangiocytes secondary to the immunological derangement caused by virus clearance may be hypothesized. Indeed, according to the hygiene hypothesis, when two different triggers act simultaneously on the immune system they tend to be mutually inhibitory, and an immune tolerance develops; when one of these triggers disappears (as HCV in this case), the immune system may mount a response against self-antigens, causing autoimmune disorders such as PBC.


Predictors of long-term clinical outcomes in adult patients after lumbar total disc replacement: development and validation of a prediction model.
Long-term outcomes of single-level lumbar arthroplasty are understood to be very good, with the most recent Investigational Device Exemption (IDE) trial showing a < 5% reoperation rate at the close of the 7-year study. This post hoc analysis was conducted to determine whether specific patients from the activL IDE data set had better outcomes than the mean good outcome of the IDE trial, as well as to identify contributing factors that could be optimized in real-world use. Univariable and multivariable logistic regression models were developed using the randomized patient set (n = 283) from the activL trial and used to identify predictive factors and to derive risk equations. The models were internally validated using the randomized patient set and externally validated using the nonrandomized patient set (n = 52) from the activL trial. Predictive power was assessed using area under the receiver operating characteristic curve analysis. Two factors were significantly associated with achievement of better than the mean outcomes at 7 years. Randomization to receive the activL device was positively associated with better than the mean visual analog scale (VAS)-back pain and Oswestry Disability Index (ODI) scores, whereas preoperative narcotics use was negatively associated with better than the mean ODI score. Preoperative narcotics use was also negatively associated with return to unrestricted full-time work. Other preoperative factors associated with positive outcomes included unrestricted full-time work, working manual labor after index back injury, and decreasing disc height. Older age, greater VAS-leg pain score, greater ODI score, female sex, and working manual labor before back injury were identified as preoperative factors associated with negative outcomes. Preoperative BMI, VAS-back pain score, back pain duration ≥ 1 year, SF-36 physical component summary score, and recreational activity had no effect on outcomes. Lumbar total disc replacement for symptomatic single-level lumbar degenerative disc disease is a well-established option for improving long-term patient outcomes. Discontinuing narcotics use may further improve patient outcomes, as this analysis identified associations between no preoperative narcotics use and better ODI score relative to the mean score of the activL trial at 7 years and increased likelihood of return to work within 7 years. Other preoperative factors that may further improve outcomes included unrestricted full-time work, working manual labor despite back injury, sedentary work status before back injury, and randomization to receive the activL device. Tailoring patient care before total disc replacement may further improve patient outcomes.


Diffusion of reactive metabolites out of hepatocytes: studies with bromobenzene.
We have developed a simple experimental technique which allows the determination of the relative rates of intracellular inactivation of chemically reactive metabolites and their diffusion out of isolated rat hepatocytes. By using bromobenzene as a model compound we have demonstrated that bromobenzene-3, 4-oxide generated within hepatocytes is sufficiently stable to leave the endoplasmic reticulum in which it is formed, traverse the cytoplasm and cross the cell membrane to the external environment. The addition of varying amounts of protein, which serves as an external sink to trap the epoxide as a covalently bound adduct, permits the calculation of the relative rates at which the epoxide is inactivated within the cells and diffuses out of the cells. As much as 35% of bromobenzene-3,4-oxide is capable of leaving hepatocytes and being trapped as a covalently bound adduct to glutathione (GSH)-transferase B. The extensive diffusion of bromobenzene-3,4-oxide may play an important role in the intercellular toxicity of this compound within the liver and perhaps may contribute to extrahepatic toxicity. The addition of GSH-transferase B to isolated hepatocyte suspensions caused a decrease in the formation of the 3,4-dihydrodiol, p-bromophenol and o- and p-bromophenol glucuronides, an increase in the formation of bromobenzene GSH conjugates, but did not affect intracellular covalent binding. Kinetic analyses of the data revealed that, in the absence of GSH-transferase B, nearly all of the bromobenzene GSH conjugates are formed within hepatocytes as the epoxide is formed, whereas rearrangement of bromobenzene-3,4-oxide to p-bromophenol and hydration to bromobenzene-3,4-dihydrodiol occurs almost exclusively outside the hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)


Prostate Cancer, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.
The NCCN Guidelines for Prostate Cancer include recommendations regarding diagnosis, risk stratification and workup, treatment options for localized disease, and management of recurrent and advanced disease for clinicians who treat patients with prostate cancer. The portions of the guidelines included herein focus on the roles of germline and somatic genetic testing, risk stratification with nomograms and tumor multigene molecular testing, androgen deprivation therapy, secondary hormonal therapy, chemotherapy, and immunotherapy in patients with prostate cancer.


The chemokine monocyte chemoattractant protein-1 induces functional responses through dimerization of its receptor CCR2.
Cytokines interact with hematopoietin superfamily receptors and stimulate receptor dimerization. We demonstrate that chemoattractant cytokines (chemokines) also trigger biological responses through receptor dimerization. Functional responses are induced after pairwise crosslinking of chemokine receptors by bivalent agonistic antichemokine receptor mAb, but not by their Fab fragments. Monocyte chemoattractant protein (MCP)-1-triggered receptor dimerization was studied in human embryonic kidney (HEK)-293 cells cotransfected with genes coding for the CCR2b receptor tagged with YSK or Myc sequences. After MCP-1 stimulation, immunoprecipitation with Myc-specific antibodies revealed YSK-tagged receptors in immunoblotting. Receptor dimerization also was validated by chemical crosslinking in both HEK-293 cells and the human monocytic cell line Mono Mac 1. Finally, we constructed a loss-of-function CCR2bY139F mutant that acted as a dominant negative, blocking signaling through the CCR2 wild-type receptor. This study provides functional support for a model in which the MCP-1 receptor is activated by ligand-induced homodimerization, allowing discussion of the similarities between bacterial and leukocyte chemotaxis.


Understanding the Strategies to Overcome Phosphorus-Deficiency and Aluminum-Toxicity by Ryegrass Endophytic and Rhizosphere Phosphobacteria.
Phosphobacteria, secreting organic acids and phosphatases, usually favor plant performance in acidic soils by increasing phosphorus (P) availability and aluminum (Al) complexing. However, it is not well-known how P-deficiency and Al-toxicity affect the phosphobacteria physiology. Since P and Al problems often co-occur in acidic soils, we have therefore proposed the evaluation of the single and combined effects of P-deficiency and Al-toxicity on growth, organic acids secretion, malate dehydrogenase (mdh) gene expression, and phosphatase activity of five Al-tolerant phosphobacteria previously isolated from ryegrass. These phosphobacteria were identified as Klebsiella sp. RC3, Stenotrophomona sp. RC5, Klebsiella sp. RCJ4, Serratia sp. RCJ6, and Enterobacter sp. RJAL6. The strains were cultivated in mineral media modified to obtain (i) high P in absence of Al-toxicity, (ii) high P in presence of Al-toxicity, (iii) low P in absence of Al-toxicity, and (iv) low P in presence of Al-toxicity. High and low P were obtained by adding KH2PO4 at final concentration of 1.4 and 0.05 mM, respectively. To avoid Al precipitation, AlCl3 × 6H2O was previously complexed to citric acid (sole carbon source) in concentrations of 10 mM. The secreted organic acids were identified and quantified by HPLC, relative mdh gene expression was determined by qRT-PCR and phosphatase activity was colorimetrically determined using p-nitrophenyl phosphate as substrate. Our results revealed that although a higher secretion of all organic acids was achieved under P-deficiency, the patterns of organic acids secretion were variable and dependent on treatment and strain. The organic acid secretion is exacerbated when Al was added into media, particularly in the form of malic and citric acid. The mdh gene expression was significantly up-regulated by the strains RC3, RC5, and RCJ6 under P-deficiency and Al-toxicity. In general, Al-tolerant phosphobacteria under P deficiency increased both acid and alkaline phosphatase activity with respect to the control, which was deepened when Al was present. The knowledge of this bacterial behavior in vitro is important to understand and predict the behavior of phosphobacteria in vivo. This knowledge is essential to generate smart and efficient biofertilizers, based in Al-tolerant phosphobacteria which could be expansively used in acidic soils.


Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Scandinavian Breast Group 9401 study.
Chemotherapy drug distribution varies greatly among individual patients. Therefore, we developed an individualised fluorouracil, epirubicin, cyclophosphamide (FEC) regimen to improve outcomes in patients with high-risk early breast cancer. We then did a randomised trial to compare this individually tailored FEC regimen with conventional adjuvant chemotherapy followed by consolidation with high-dose chemotherapy with stem-cell support. 525 women younger than 60 years of age with high-risk primary breast cancer were randomised after surgery to receive nine cycles of tailored FEC to haematological equitoxicity with granulocyte colony-stimulating factor (G-CSF) support (n=251), or three cycles of FEC at standard doses followed by high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin (CTCb), and peripheral-blood stem-cell or bone-marrow support (n=274). Both groups received locoregional radiation therapy and tamoxifen for 5 years. The primary outcome measure was relapse-free survival, and analysis was by intention to treat. At a median follow-up of 34.3 months, there were 81 breast-cancer relapses in the tailored FEC group versus 113 in the CTCb group (double triangular method p=0.04). 60 deaths occurred in the tailored FEC group and 82 in the CTCb group (log-rank p=0.12). Patients in the CTCb group experienced more grade 3 or 4 acute toxicity compared with the tailored FEC group (p<0.0001). Two treatment-related deaths (0.7%) occurred in the CTCb group. Six patients in the tailored FEC group developed acute myeloid leukaemia and three developed myelodysplastic syndrome. Tailored FEC with G-CSF support resulted in a significantly improved relapse-free survival and fewer grade 3 and 4 toxicities compared with marrow-supported high-dose chemotherapy with CTCb as adjuvant therapy of women with high-risk primary breast cancer.


Efficient control of arm movements in advanced age.
The present study addresses the influence of aging on the ability to regulate mechanical effects arising during arm movements due to the multi-joint structure of the arm. Two mechanical factors were considered, interaction torque (IT) and inertial resistance (IR). Regulation of these two factors can be demanding in terms of the timing and magnitude of the required muscle torque (MT), specifically during fast movements. We hypothesized that aging exacerbates the challenge regarding the regulation of these effects with muscular control due to declines in the motor system. This hypothesis was tested by comparing performance of a cyclic line-drawing task in two age groups, young and older adults. Only two joints, the shoulder and elbow, participated in motion. Four orientations of the lines were used to provide variations in the requirements for regulation of IT and IR. Cyclic frequency was manipulated to emphasize the dependence of the mechanical factors on movement speed. Various characteristics of fingertip motion showed that there were no age-related deteriorations in accuracy of line drawing. However, older adults were systematically slower, particularly in the directions of high IR. A detailed analysis of the magnitude of MT and the contribution of this torque to production of net torque at each joint demonstrated that older adults modified joint control and decreased the demands for MT by skillful exploitation of IT in a way specific for each particular line orientation. The results point to a tendency in older adults to decrease the production of muscle force. Nevertheless, older adults also demonstrated an ability to partially compensate for declines in the force production by developing sophisticated strategies of joint control that exploit the multi-joint mechanical structure of the arm. This ability suggests that the internal representation of inter-segmental dynamics and the capability to use it for movement control does not decay with age. The study emphasizes the importance of analysis of joint motion and control characteristics for the investigation of arm movements and for comparison of these movements between different subject populations.


Exploitation of Castration-Resistant Prostate Cancer Transcription Factor Dependencies by the Novel BET Inhibitor ABBV-075.
Competitive inhibitors of acetyl-lysine binding to the bromodomains of the BET (bromodomain and extra terminal) family are being developed for the treatment of solid and hematologic malignancies. The function of BET family member BRD4 at enhancers/superenhancers has been shown to sustain signal-dependent or pathogenic gene expression programs. Here, the hypothesis was tested that the transcription factor drivers of castration-resistant prostate cancer (CRPC) clinical progression, including the androgen receptor (AR), are critically dependent on BRD4 and thus represent a sensitive solid tumor indication for the BET inhibitor ABBV-075. DHT-stimulated transcription of AR target genes was inhibited by ABBV-075 without significant effect on AR protein expression. Furthermore, ABBV-075 disrupted DHT-stimulated recruitment of BET family member BRD4 to gene-regulatory regions cooccupied by AR, including the well-established PSA and TMPRSS2 enhancers. Persistent BET inhibition disrupted the composition and function of AR-occupied enhancers as measured by a reduction in AR and H3K27Ac ChIP signal and inhibition of enhancer RNA transcription. ABBV-075 displayed potent antiproliferative activity in multiple models of resistance to second-generation antiandrogens and inhibited the activity of the AR splice variant AR-V7 and ligand-binding domain gain-of-function mutations, F877L and L702H. ABBV-075 was also a potent inhibitor of MYC and the TMPRSS2-ETS fusion protein, important parallel transcription factor drivers of CRPC. The ability of BET family inhibitor ABBV-075 to inhibit transcription activation downstream of the initiating events of transcription factors like AR and TMPRSS2:ETS fusion proteins provides a promising therapeutic option for CRPC patients who have developed resistance to second-generation antiandrogens. Mol Cancer Res; 15(1); 35-44. ©2016 AACR.


Natural history of knee cartilage defects and factors affecting change.
Knee cartilage defects may play an important role in early osteoarthritis, but little is known about their natural history. Knee cartilage defect score (range, 0-4), cartilage volume, and bone surface area were determined using T1-weighted fat-saturated magnetic resonance imaging in 325 subjects (mean age, 45 years) at baseline and 2 years later. Thirty-three percent of the subjects had a worsening (>or=1-point increase) and 37% of the subjects had an improvement (>or=1-point decrease) in cartilage defect score in any knee compartment during 2.3 years. A worsening in cartilage defect score was significantly associated with female sex (odds ratio [OR], 3.09 and 3.64 in the medial and lateral tibiofemoral compartments) and baseline factors, including age (OR, 1.05 per year in the medial tibiofemoral compartment), body mass index (OR, 1.08 in the lateral tibiofemoral compartment), tibiofemoral osteophytes (OR, 6.22 and 6.04 per grade), tibial bone area (OR, 1.24 and 2.07 per square centimeter), and cartilage volume (OR, 2.91 and 1.71 per milliliter in the medial tibiofemoral and patellar compartments). An improvement in cartilage defect score had similar but reversed associations with these factors (except for sex), including a decrease in body mass index (OR, 1.23 in the medial tibiofemoral compartment). Knee cartilage defects are variable, and changes are associated with female sex, age, and body mass index. Increases are associated with baseline cartilage volume, bone size, and osteophytes, suggesting a role for these in the pathogenesis of cartilage defects. Interventions such as weight loss may improve knee cartilage defects.


Altered distribution and function of natural killer cells in murine and human Niemann-Pick disease type C1.
Niemann-Pick type C (NPC) is a neurodegenerative lysosomal storage disorder caused by defects in the lysosomal proteins NPC1 or NPC2. NPC cells are characterized by reduced lysosomal calcium levels and impaired sphingosine transport from lysosomes. Natural killer (NK) cells kill virally infected/transformed cells via degranulation of lysosome-related organelles. Their trafficking from lymphoid tissues into the circulation is dependent on sphingosine-1-phosphate (S1P) gradients, sensed by S1P receptor 5 (S1P5). We hypothesized that NK-cell function and trafficking could be affected in NPC disease due to the combined effects of the lysosomal calcium defect and sphingosine storage. In an NPC1 mouse model, we found the frequency of NK cells was altered and phenocopied S1P5-deficient mice, consistent with defects in S1P levels. NK cells from NPC1 mice also had a defect in cytotoxicity due to a failure in degranulation of cytotoxic granules, which was associated with reduced lysosomal calcium levels. Affected NPC1 patients and NPC1 heterozygote carriers had reduced NK-cell numbers in their blood and showed similar phenotypic and developmental changes to those observed in the NPC1 mouse. These findings highlight the effects of lysosomal storage on the peripheral immune system.


Histone H4 lysine 20 methylation: key player in epigenetic regulation of genomic integrity.
Maintenance of genomic integrity is essential to ensure normal organismal development and to prevent diseases such as cancer. Nuclear DNA is packaged into chromatin, and thus genome maintenance can be influenced by distinct chromatin environments. In particular, post-translational modifications of histones have emerged as key regulators of genomic integrity. Intense research during the past few years has revealed histone H4 lysine 20 methylation (H4K20me) as critically important for the biological processes that ensure genome integrity, such as DNA damage repair, DNA replication and chromatin compaction. The distinct H4K20 methylation states are mediated by SET8/PR-Set7 that catalyses monomethylation of H4K20, whereas SUV4-20H1 and SUV4-20H2 enzymes mediate further H4K20 methylation to H4K20me2 and H4K20me3. Disruption of these H4K20-specific histone methyltransferases leads to genomic instability, demonstrating the important functions of H4K20 methylation in genome maintenance. In this review, we explain molecular mechanisms underlying these defects and discuss novel ideas for furthering our understanding of genome maintenance in higher eukaryotes.


Mortality of Testicular Cancer in East and West Germany 20 Years after Reunification: A Gap Not Closed Yet.
The decline of testicular cancer mortality in East Germany began in the 1980s, about 10 years later than that recorded in West Germany. We aimed at providing up-to-date time trends of testicular cancer mortality rates in Germany. Mortality data from East Germany (1971-2010) and West Germany (1954-2010) were provided by the Federal Bureau of Statistics. We estimated age-specific and age-standardized mortality rates using the World Standard Population. Despite the declining trend in the 2000s, the mortality rates of testicular cancer remained higher in East than in West Germany. These rates were 5.5 and 2.6 per million person-years in 2010, respectively. Age-specific mortality trends by period and birth cohort showed that the mortality decline was larger among younger (15-44 years) than elderly men. The mortality of testicular cancer is still higher in East than West Germany. Despite very similar densities of hospital beds, urologists and oncologist per million male population in both parts of Germany, we hypothesized that a paucity of centers of expertise for treating testicular cancers in the East could account for this particular pattern.


Effect of carbohydrate feeding on the bone metabolic response to running.
Bone resorption is increased after running, with no change in bone formation. Feeding during exercise might attenuate this increase, preventing associated problems for bone. This study investigated the immediate and short-term bone metabolic responses to carbohydrate (CHO) feeding during treadmill running. Ten men completed two 7-day trials, once being fed CHO (8% glucose immediately before, every 20 min during, and immediately after exercise at a rate of 0.7 g CHO · kg body mass(-1) · h(-1)) and once being fed placebo (PBO). On day 4 of each trial, participants completed a 120-min treadmill run at 70% of maximal oxygen consumption (V̇o2 max). Blood was taken at baseline (BASE), immediately after exercise (EE), after 60 (R1) and 120 (R2) min of recovery, and on three follow-up days (FU1-FU3). Markers of bone resorption [COOH-terminal telopeptide region of collagen type 1 (β-CTX)] and formation [NH2-terminal propeptides of procollagen type 1 (P1NP)] were measured, along with osteocalcin (OC), parathyroid hormone (PTH), albumin-adjusted calcium (ACa), phosphate, glucagon-like peptide-2 (GLP-2), interleukin-6 (IL-6), insulin, cortisol, leptin, and osteoprotogerin (OPG). Area under the curve was calculated in terms of the immediate (BASE, EE, R1, and R2) and short-term (BASE, FU1, FU2, and FU3) responses to exercise. β-CTX, P1NP, and IL-6 responses to exercise were significantly lower in the immediate postexercise period with CHO feeding compared with PBO (β-CTX: P = 0.028; P1NP: P = 0.021; IL-6: P = 0.036), although there was no difference in the short-term response (β-CTX: P = 0.856; P1NP: P = 0.721; IL-6: P = 0.327). No other variable was significantly affected by CHO feeding during exercise. We conclude that CHO feeding during exercise attenuated the β-CTX and P1NP responses in the hours but not days following exercise, indicating an acute effect of CHO feeding on bone turnover.


Dynamic causal modeling of spatiotemporal integration of phonological and semantic processes: an electroencephalographic study.
Integration of phonological and lexicosemantic processes is essential for visual word recognition. Here we used dynamic causal modeling of event-related potentials, combined with group source reconstruction, to estimate how those processes translate into context-dependent modulation of effective connectivity within the temporal-frontal language network. Fifteen healthy human subjects performed a phoneme detection task in pseudo-words and a semantic categorization task in words. Cortical current densities revealed the sequential activation of temporal regions, from the occipital-temporal junction toward the anterior temporal lobe, before reaching the inferior frontal gyrus. A difference of activation between phonology and semantics was identified in the anterior temporal lobe within the 240-300 ms peristimulus time window. Dynamic causal modeling indicated this increase of activation of the anterior temporal lobe in the semantic condition as a consequence of an increase of forward connectivity from the posterior inferior temporal lobe to the anterior temporal lobe. In addition, fast activation of the inferior frontal region, which allowed a feedback control of frontal regions on the superior temporal and posterior inferior temporal cortices, was found to be likely. Our results precisely describe spatiotemporal network mechanisms occurring during integration of phonological and semantic processes. In particular, they support the hypothesis of multiple pathways within the temporal lobe for language processing, where frontal regions would exert a top-down control on temporal regions in the recruitment of the anterior temporal lobe for semantic processing.


Enzymatic production and in situ separation of natural β-ionone from β-carotene.
A biotechnological process concept for generation and in situ separation of natural β-ionone from β-carotene is presented. The process employs carotenoid cleavage dioxygenases (CCDs), a plant-derived iron-containing nonheme enzyme family requiring only dissolved oxygen as cosubstrate and no additional cofactors. Organophilic pervaporation was found to be very well suited for continuous in situ separation of β-ionone. Its application led to a highly pure product despite the complexity of the reaction solution containing cell homogenates. Among three different pervaporation membrane types tested, a polyoctylmethylsiloxane active layer on a porous polyetherimide support led to the best results. A laboratory-scale demonstration plant was set up, and a highly pure aqueous-ethanolic solution of β-ionone was produced from β-carotene. The described process permits generation of high-value flavor and fragrance compounds bearing the desired label "natural" according to US and European food and safety regulations and demonstrates the potential of CCD enzymes for selective oxidative cleavage of carotenoids.


Cane toads (Rhinella marina) rely on water access, not drought tolerance, to invade xeric Australian environments.
The invasion of habitats with novel environmental challenges may require physiological tolerances not seen in conspecifics from the native range. We used a combination of field and laboratory-based experiments to assess physiological tolerance to limited water access at four sites distributed across the historical invasion path of cane toads (Rhinella marina) in Australia that, from east to west, alternated between mesic and seasonally xeric habitats. Toads from all locations were well hydrated at the time of capture. However, experimental dehydration caused greater mass loss, higher plasma osmolality, and inhibition of lytic ability in toads from xeric compared to mesic locations. These results suggest somewhat surprisingly that toads from xeric environments are physiologically more vulnerable to water loss. In contrast, bactericidal ability was not sensitive to hydric state and was greater in toads from eastern (long-colonized) areas. Similar patterns in lytic ability in hydrated toads and agglutination ability in wild toads suggest that toads along the invasion front face a tradeoff between enhanced dispersal ability and physiological responses to dehydration. The ability of this invasive species to spread into drier environments may be underpinned by a combination of phenotypic plasticity and evolved (heritable) traits.


Healthcare delivery for paediatric and adolescent diabetes in low resource settings: Type 1 diabetes clinics in Uganda.
The management of type 1 diabetes (T1DM) includes setting up organised follow-up clinics. A programme for establishing such clinics in Uganda commenced in 2009. The clinics were established along the chronic care model and were integrated into the health structure of other chronic diseases. Web-based electronic medical records were utilised to establish a centralised registry. All children with diabetes below 18 years of age were encouraged to enrol into the programme by attending the nearest established T1DM clinic. At the commencement of the programme, there were 178 patients with T1DM receiving care in various health facilities but without organised follow-up T1DM clinics. These patients were subsequently enrolled into the programme and as of June 30, 2018, the programme had a total of 32 clinics with 1187 children; 3 with neonatal diabetes. Challenges encountered included difficulties in timely diagnosis, failure to provide adequate care in the remote rural areas and failure to achieve pre-defined glycated haemoglobin (HbA1c) goals. Despite these challenges, this observational study demonstrates that healthcare delivery for T1DM organised along the chronic care model and supported by web-based electronic medical records is achievable and provides care that is sustainable. Addressing the encountered challenges should result in improved outcomes for T1DM.


Pd2Au36(SR)24 cluster: structure studies.
The location of the Pd atoms in Pd2Au36(SC2H4Ph)24, is studied both experimentally and theoretically. X-ray photoelectron spectroscopy (XPS) indicates oxidized Pd atoms. Palladium K-edge extended X-ray absorption fine-structure (EXAFS) data clearly show Pd-S bonds, which is supported by far infrared spectroscopy and by comparing theoretical EXAFS spectra in R space and circular dichroism spectra of the staple, surface and core doped structures with experimental spectra.


Mandarin-Speaking Children's Speech Recognition: Developmental Changes in the Influences of Semantic Context and F0 Contours.
The goal of this developmental speech perception study was to assess whether and how age group modulated the influences of high-level semantic context and low-level fundamental frequency (F0) contours on the recognition of Mandarin speech by elementary and middle-school-aged children in quiet and interference backgrounds. The results revealed different patterns for semantic and F0 information. One the one hand, age group modulated significantly the use of F0 contours, indicating that elementary school children relied more on natural F0 contours than middle school children during Mandarin speech recognition. On the other hand, there was no significant modulation effect of age group on semantic context, indicating that children of both age groups used semantic context to assist speech recognition to a similar extent. Furthermore, the significant modulation effect of age group on the interaction between F0 contours and semantic context revealed that younger children could not make better use of semantic context in recognizing speech with flat F0 contours compared with natural F0 contours, while older children could benefit from semantic context even when natural F0 contours were altered, thus confirming the important role of F0 contours in Mandarin speech recognition by elementary school children. The developmental changes in the effects of high-level semantic and low-level F0 information on speech recognition might reflect the differences in auditory and cognitive resources associated with processing of the two types of information in speech perception.


Lexical interference effects in sentence processing: evidence from the visual world paradigm and self-organizing models.
Psycholinguistic research spanning a number of decades has produced diverging results with regard to the nature of constraint integration in online sentence processing. For example, evidence that language users anticipatorily fixate likely upcoming referents in advance of evidence in the speech signal supports rapid context integration. By contrast, evidence that language users activate representations that conflict with contextual constraints, or only indirectly satisfy them, supports nonintegration or late integration. Here we report on a self-organizing neural network framework that addresses 1 aspect of constraint integration: the integration of incoming lexical information (i.e., an incoming word) with sentence context information (i.e., from preceding words in an unfolding utterance). In 2 simulations, we show that the framework predicts both classic results concerned with lexical ambiguity resolution (Swinney, 1979; Tanenhaus, Leiman, & Seidenberg, 1979), which suggest late context integration, and results demonstrating anticipatory eye movements (e.g., Altmann & Kamide, 1999), which support rapid context integration. We also report 2 experiments using the visual world paradigm that confirm a new prediction of the framework. Listeners heard sentences like "The boy will eat the white …" while viewing visual displays with objects like a white cake (i.e., a predictable direct object of "eat"), white car (i.e., an object not predicted by "eat," but consistent with "white"), and distractors. In line with our simulation predictions, we found that while listeners fixated white cake most, they also fixated white car more than unrelated distractors in this highly constraining sentence (and visual) context.


Somatic evolution in the immune system: the need for germinal centers for efficient affinity maturation.
In the course of a humoral immune response, the average affinity of antibody for the immunizing antigen can increase in time. This process of affinity maturation is due to antigen-driven selection of higher affinity B cell clones and somatic hypermutation of the genes that code for the antibody variable region. Through the use of simulation models we show that the efficiency of affinity maturation is substantially improved if mutation and selection occur in germinal centers, specialized regions of lymphoid tissues, rather than in the body as a whole. We show that confining mutation and selection to germinal centers decouples the problem of affinity maturation from the problem of antigen elimination. In the germinal centers, stored antigen, high rates of B cell proliferation and apoptosis combine to create an environment where effective maturation occurs even after the primary response has eliminated much or all of the free antigen. Kepler and Perelson suggested that if hypermutation were turned on and off in a phasic manner, affinity maturation could be made more efficient under circumstances when affinity-improving mutations have a low probability of occurrence. We confirm this in the context of a stochastic model. However, even in the absence of phasic mutation, we show that affinity maturation is significantly improved when proliferation, mutation, and selection are restricted to germinal centers as opposed to occurring systemically.


TV-based conjugate gradient method and discrete L-curve for few-view CT reconstruction of X-ray in vivo data.
High-resolution, three-dimensional (3D) imaging of soft tissues requires the solution of two inverse problems: phase retrieval and the reconstruction of the 3D image from a tomographic stack of two-dimensional (2D) projections. The number of projections per stack should be small to accommodate fast tomography of rapid processes and to constrain X-ray radiation dose to optimal levels to either increase the duration of in vivo time-lapse series at a given goal for spatial resolution and/or the conservation of structure under X-ray irradiation. In pursuing the 3D reconstruction problem in the sense of compressive sampling theory, we propose to reduce the number of projections by applying an advanced algebraic technique subject to the minimisation of the total variation (TV) in the reconstructed slice. This problem is formulated in a Lagrangian multiplier fashion with the parameter value determined by appealing to a discrete L-curve in conjunction with a conjugate gradient method. The usefulness of this reconstruction modality is demonstrated for simulated and in vivo data, the latter acquired in parallel-beam imaging experiments using synchrotron radiation.


A review on cognitive behavorial therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS.
Benign Myalgic Encephalomyelitis (ME) / Chronic Fatigue Syndrome (CFS) is a debilitating disease which, despite numerous biological abnormalities has remained highly controversial. Notwithstanding the medical pathogenesis of ME/CFS, the (bio)psychosocial model is adopted by many governmental organizations and medical profes-sio-nals to legitimize the combination of Cognitive Behavioral Therapy (CBT) and Graded Exercise Therapy (GET) for ME/CFS. Justified by this model CBT and GET aim at eliminating presumed psychogenic and socially induced maintaining factors and reversing deconditioning, respectively. In this review we invalidate the (bio)psychosocial model for ME/CFS and demonstrate that the success claim for CBT/GET to treat ME/CFS is unjust. CBT/GET is not only hardly more effective than non-interventions or standard medical care, but many patients report that the therapy had affected them adversely, the majority of them even reporting substantial deterioration. Moreover, this review shows that exertion and thus GET most likely have a negative impact on many ME/CFS patients. Exertion induces post-exertional malaise with a decreased physical performan-ce/aerobic capacity, increased muscoskeletal pain, neurocognitive impairment, "fatigue", and weakness, and a long lasting "recovery" time. This can be explained by findings that exertion may amplify pre-existing pa-thophysiological abnormalities underpinning ME/CFS, such as inflammation, immune dysfunction, oxidative and nitrosative stress, channelopathy, defec-tive stress response mechanisms and a hypoactive hypothalamic-pituitary-adrenal axis. We conclude that it is unethical to treat patients with ME/CFS with ineffective, non-evidence-based and potentially harmful "rehabilitation therapies", such as CBT/GET.