Real-world reported adverse events related to systemic immunomodulating therapy in patients with atopic dermatitis: Results from the TREAT NL (TREatment of ATopic eczema, the Netherlands) registry.

BACKGROUND: Evidence on the (long-term) safety of systemic immunomodulating therapies in atopic dermatitis (AD) generated by real-world data is sparse. OBJECTIVES: To describe real-world reported adverse drug reactions (AEs) related to systemic immunomodulating therapy in patients with AD and to compare the incidence rates of AEs with the Summaries of Product Characteristics (SmPCs). METHODS: We conducted an observational prospective multi-centre cohort study, using the TREAT NL registry. All severe AEs, AEs of special interest and serious AEs in adult and paediatric patients on systemic immunomodulating treatment (ciclosporin, methotrexate, azathioprine, mycophenolic acid, dupilumab, tralokinumab, baricitinib and upadacitinib) were assessed. Incidences rates of all (potentially) drug-related AEs were standardized in patient years and compared to the cumulative incidences in the associated SmPCs. RESULTS: We collected 422 patient years of safety data from 266 patients, of whom 129 (48.5%) reported a total of 224 (potentially) drug-related AEs. Compared to dupilumab's SmPC, higher incidence rates were found for four AEs (reported ≥5 times): eosinophilia, blepharitis, dry eyes and head and neck erythema (i.e. dupilumab facial redness). A higher incidence rate of fatigue was found in patients on oral methotrexate in our cohort compared to the SmPC. Two new drug-related AEs (reported ≥5 times) were found in patients on dupilumab, including non-infectious conjunctivitis and meibomian gland dysfunction. CONCLUSIONS: Real-world reported AEs captured in AD patient registries can add information on the estimated incidence of AEs and benefit clinical decision aids. Future studies using data derived from the TREAT NL registry combined with data from other registries within the TREAT Registry Taskforce will provide more information on (rare) AEs associated with immunomodulating therapy in AD patients.

Intercellular transmission of pathogenic proteins in ALS: Exploring the pathogenic wave.

In patients with amyotrophic lateral sclerosis (ALS), disease symptoms and pathology typically spread in a predictable spatiotemporal pattern beginning at a focal site of onset and progressing along defined neuroanatomical tracts. Like other neurodegenerative diseases, ALS is characterized by the presence of protein aggregates in postmortem patient tissue. Cytoplasmic, ubiquitin-positive aggregates of TDP-43 are observed in approximately 97% of sporadic and familial ALS patients, while SOD1 inclusions are likely specific to cases of SOD1-ALS. Additionally, the most common subtype of familial ALS, caused by a hexanucleotide repeat expansion in the first intron of the C9orf72 gene (C9-ALS), is further characterized by the presence of aggregated dipeptide repeat proteins (DPRs). As we will describe, cell-to-cell propagation of these pathological proteins tightly correlates with the contiguous spread of disease. While TDP-43 and SOD1 are capable of seeding protein misfolding and aggregation in a prion-like manner, C9orf72 DPRs appear to induce (and transmit) a 'disease state' more generally. Multiple mechanisms of intercellular transport have been described for all of these proteins, including anterograde and retrograde axonal transport, extracellular vesicle secretion, and macropinocytosis. In addition to neuron-to-neuron transmission, transmission of pathological proteins occurs between neurons and glia. Given that the spread of ALS disease pathology corresponds with the spread of symptoms in patients, the various mechanisms by which ALS-associated protein aggregates propagate through the central nervous system should be closely examined.

Anti-thrombotics and major adverse cardiovascular events in anti-phospholipid syndrome: a cross-sectional study using the 2016-2018 National Inpatient Sample database.

OBJECTIVE: This study assessed the relationship between anti-thrombotics and major adverse cardiovascular events (MACE) in patients with anti-phospholipid syndrome (APS). METHOD: We included 13 947 subjects with APS from the National (Nationwide) Inpatient Sample (NIS) database for 2016-2018, and collected relevant covariates and demographic data using ICD-10 codes. Our two primary outcomes were MACE and death. We performed multivariate logistic regression analysis to assess the impact of various anti-thrombotic regimens on MACE/death in our primary cohort and high-risk subgroups. RESULTS: Patients on anti-coagulants had significantly reduced odds of MACE [odds ratio (OR) 0.68, 95% confidence interval (CI) 0.62-0.76, p < 0.001] as well as each of its subcomponents. Those not on any anti-coagulants had significantly increased odds of MACE (OR 1.47, 95% CI 1.24-1.72, p < 0.001). No significant association was found between anti-platelet use and the odds of MACE (p > 0.05). Patients on anti-coagulants were the only class that appeared to have a mortality benefit with reduced odds for death (OR 0.64, 95% CI 0.49-0.84, p = 0.001). In the subgroups at higher risk for MACE (those with atrial fibrillation and thrombocytopenia), full anti-coagulation therapy was also the only anti-thrombotic class that significantly affected the odds of MACE, with a protective effect on MACE, but had no mortality benefit. CONCLUSION: Patients with APS are most likely to benefit from anti-coagulant therapy in reducing MACE. Furthermore, anti-platelets alone or in combination with anti-coagulants are probably not beneficial in MACE reduction and may even increase risk.

Pesticides as a potential independent childhood leukemia risk factor and as a potential confounder for electromagnetic fields exposure.

BACKGROUND: Both pesticides and high magnetic fields are suspected to be childhood leukemia risk factors. Pesticides are utilized at commercial plant nurseries, which sometimes occupy the areas underneath high-voltage powerlines. OBJECTIVES: To evaluate whether potential pesticide exposures (intended use, chemical class, active ingredient) utilized at plant nurseries act as an independent childhood leukemia risk factor or as a confounder for proximity to, or magnetic fields exposure from, high-voltage powerlines. METHODS: We conducted a state-wide records-based case-control study for California with 5788 childhood leukemia cases and 5788 controls that examined specific pesticide use, magnetic field exposures and distances to both powerlines and plant nurseries. Exposure assessment incorporated geographic information systems, aerial satellite images, and other historical information. RESULTS: Childhood leukemia risk was potentially elevated for several active pesticide ingredients: permethrin (odds ratio (OR) 1.49, 95% confidence interval (CI) (0.83-2.67), chlorpyrifos (OR 1.29, 95% CI 0.89-1.87), dimethoate (OR 1.79, 95% CI 0.85-3.76), mancozeb (OR 1.41, 95% CI 0.85-2.33), oxyfluorfen (OR 1.41, 95% CI 0.75-2.66), oryzalin (OR 1.60, 95% CI 0.97-2.63), and pendimethalin (OR 1.82, 95% CI 0.81-2.25). Rodenticide (OR 1.42, 95% CI 0.78-2.56) and molluscicide (OR 1.22, 95% CI 0.82-1.81) exposure also presented potentially elevated childhood leukemia risks. Childhood leukemia associations with calculated fields or powerline proximity did not materially change after adjusting for pesticide exposure. Childhood leukemia risks with powerline proximity remained similar when pesticide exposures were excluded. DISCUSSION: Pesticide exposure may be an independent childhood leukemia risk factor. Childhood leukemia risks for powerline proximity and magnetic fields exposure were not explained by pesticide exposure.

Patient-reported outcomes before treatment for localized prostate cancer: are there differences among countries? Data from the True North Global Registry.

INTRODUCTION: Similar Patient-Reported Outcomes (PROs) at diagnosis for localized prostate cancer among countries may indicate that different treatments are recommended to the same profile of patients, regardless the context characteristics (health systems, medical schools, culture, preferences…). The aim of this study was to assess such comparison. METHODS: We analyzed the EPIC-26 results before the primary treatment of men diagnosed of localized prostate cancer from January 2017 onwards (revised data available up to September 2019), from a multicenter prospective international cohort including seven regions: Australia/New Zealand, Canada, Central Europe (Austria / Czech Republic / Germany), United Kingdom, Italy, Spain, and the United States. The EPIC-26 domain scores and pattern of three selected items were compared across regions (with Central Europe as reference). All comparisons were made stratifying by treatment: radical prostatectomy, external radiotherapy, brachytherapy, and active surveillance. RESULTS: The sample included a total of 13,483 men with clinically localized or locally advanced prostate cancer. PROs showed different domain patterns before treatment across countries. The sexual domain was the most impaired, and the one with the highest dispersion within countries and with the greatest medians' differences across countries. The urinary incontinence domain, together with the bowel and hormonal domains, presented the highest scores (better outcomes) for all treatment groups, and homogeneity across regions. CONCLUSIONS: Patients with localized or locally advanced prostate cancer undergoing radical prostatectomy, EBRT, brachytherapy, or active surveillance presented mainly negligible or small differences in the EPIC-26 domains before treatment across countries. The results on urinary incontinence or bowel domains, in which almost all patients presented the best possible score, may downplay the baseline data role for evaluating treatments' effects. However, the heterogeneity within countries and the magnitude of the differences found across countries in other domains, especially sexual, support the need of implementing the PRO measurement from diagnosis.

Motor cortex excitability in chronic low back pain.

Chronic pain is associated with dysfunctional cortical excitability. Research has identified altered intracortical motor cortex excitability in Chronic Lower Back Pain (CLBP). However, research identifying the specific intracortical changes underlying CLBP has been met with inconsistent findings. In the present case-control study, we examined intracortical excitability of the primary motor cortex using transcranial magnetic stimulation (TMS) in individuals with CLBP. Twenty participants with CLBP (Mage = 54.45 years, SDage = 15.89 years) and 18 age- and gender-matched, pain-free controls (M = 53.83, SD = 16.72) were included in this study. TMS was applied to the hand motor area of the right hemisphere and motor evoked potentials (MEPs) were recorded from the first dorsal interosseous muscle of the contralateral hand. Resting motor threshold (rMT) and MEP amplitude were measured using single-pulse stimulation. Short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were assessed using paired-pulse stimulation. Individuals with CLBP had significantly higher rMT (decreased corticospinal excitability) and lower ICF compared to controls. No significant differences were found in MEP amplitude and SICI. These findings add to the growing body of evidence that CLBP is associated with deficits in intracortical modulation involving glutamatergic mechanisms.

Commercial outdoor plant nurseries as a confounder for electromagnetic fields and childhood leukemia risk.

BACKGROUND: Close residential proximity to powerlines and high magnetic fields exposure may be associated with elevated childhood leukemia risks as reported by prior studies and pooled analyses. Magnetic fields exposure from high-voltage powerlines is associated with proximity to these powerlines and consequently with any factor varying with distance. Areas underneath powerlines in California may be sites for commercial plant nurseries that can use pesticides, a potential childhood leukemia risk factor. OBJECTIVES: Assess if potential pesticide exposure from commercial plant nurseries is a confounder or interacts with proximity or magnetic fields exposure from high-voltage powerlines to increase childhood leukemia risk. METHODS: A comprehensive childhood leukemia record-based case-control study with 5788 cases and 5788 controls (born and diagnosed in California, 1986-2008) was conducted. Pesticide, powerline, and magnetic field exposure assessment utilized models that incorporated geographical information systems, aerial satellite images, site visits and other historical information. RESULTS: The relationship for calculated fields with childhood leukemia (odds ratio (OR) 1.51, 95% confidence interval (CI) 0.70-3.23) slightly attenuated when controlling for nursery proximity (OR 1.43, 95% CI 0.65-3.16) or restricting analysis to subjects living far (>300 m) from nurseries (OR 1.43, 95% CI 0.79-2.60). A similar association pattern was observed between distance to high-voltage powerlines and childhood leukemia. The association between nursery proximity and childhood leukemia was unchanged or only slightly attenuated when controlling for calculated fields or powerline distance; ORs remained above 2 when excluding subjects with high calculated fields or close powerline proximity (OR 2.16, 95% CI 0.82-5.67 and OR 2.15, 95% CI 0.82-5.64, respectively). The observed relationships were robust to different time periods, reference categories, and cut points. DISCUSSION: Close residential proximity to nurseries is suggested as an independent childhood leukemia risk factor. Our results do not support plant nurseries as an explanation for observed childhood leukemia risks for powerline proximity and magnetic fields exposure, although small numbers of subjects concurrently exposed to high magnetic fields, close powerline proximity and plant nurseries limited our ability to fully assess potential confounding.

Model selection of chaotic systems from data with hidden variables using sparse data assimilation.

Many natural systems exhibit chaotic behavior, including the weather, hydrology, neuroscience, and population dynamics. Although many chaotic systems can be described by relatively simple dynamical equations, characterizing these systems can be challenging due to sensitivity to initial conditions and difficulties in differentiating chaotic behavior from noise. Ideally, one wishes to find a parsimonious set of equations that describe a dynamical system. However, model selection is more challenging when only a subset of the variables are experimentally accessible. Manifold learning methods using time-delay embeddings can successfully reconstruct the underlying structure of the system from data with hidden variables, but not the equations. Recent work in sparse-optimization based model selection has enabled model discovery given a library of possible terms, but regression-based methods require measurements of all state variables. We present a method combining variational annealing-a technique previously used for parameter estimation in chaotic systems with hidden variables-with sparse-optimization methods to perform model identification for chaotic systems with unmeasured variables. We applied the method to ground-truth time-series simulated from the classic Lorenz system and experimental data from an electrical circuit with Lorenz-system like behavior. In both cases, we successfully recover the expected equations with two measured and one hidden variable. Application to simulated data from the Colpitts oscillator demonstrates successful model selection of terms within nonlinear functions. We discuss the robustness of our method to varying noise.

To mask or not to mask mosaicism? The impact of reporting embryo mosaicism on reproductive potential.

PURPOSE: To evaluate euploidy rates and probability of having at least one euploid embryo for transfer per cycle when mosaicism is reported compared to when it is masked. METHODS: Women age 18-46 years who underwent PGT-A with next generation sequencing of blastocyst biopsies were analyzed. When reported, mosaic embryos were classified as low-level, 20-40% mosaic, or high-level, 41-80% mosaic. When masked, low-level mosaics were categorized as euploid and high-level mosaics were considered aneuploid. Comparative analyses were performed with χ2 tests and t-tests. RESULTS: A total of 22,504 PGT-A biopsy cycles from 18,401 patients were included. These cycles were from 293 different clinics with a mean of 1.22 cycles per patient. The majority of cycles (94.8%) reported mosaicism, and only 5.2% cycles were masked. The euploidy rate was significantly lower when mosaicism was reported versus masked (38.7% v 47.4%, p < 0.0001), which remained significant for age 40 years old and younger. The mosaic reporting cohort was less likely to have at least one euploid embryo for transfer (68.8%) compared to the masked cohort (75.7%) (p < 0.0001); however, this was no longer significant after stratification by age. CONCLUSION: Mosaicism reporting shows an overall expected reduction in euploidy rate. In turn, the probability of having a euploid embryo to transfer depends on clinic transfer practices and patient preference. If mosaic embryos are not transferred, we observe a reduction in probability of having an embryo for transfer. Although the magnitude of these differences is small, our data show that mosaic reporting may contribute to embryo attrition rate.

IVIg increases interleukin-11 levels, which in turn contribute to increased platelets, VWF and FVIII in mice and humans.

The mechanisms of action of intravenous immunoglobulins (IVIg) in autoimmune diseases are not fully understood. The fixed duration of efficacy and noncumulative effects of IVIg in immune thrombocytopenia (ITP) and acquired von Willebrand disease (AVWD) suggest other mechanisms besides immunological ones. Additionally to the peripheral destruction of platelets in ITP, their medullary hypoproduction emerged as a new paradigm with rescue of thrombopoietin receptor agonists (TPO-RA). In an ITP mouse model, interleukin (IL)-11 blood levels increase following IVIg. IL-11 stimulates the production of platelets and other haemostasis factors; recombinant IL-11 (rIL-11) is thus used as a growth factor in post-chemotherapy thrombocytopenia. We therefore hypothesized that IVIg induces IL-11 over-production, which increases platelets, VWF and factor VIII (FVIII) levels in humans and mice. First, in an ITP mouse model, we show that IVIg or rIL-11 induces a rapid increase (72 h) in platelets, FVIII and VWF levels, whereas anti-IL-11 antibody greatly decreased this effect. Secondly, we quantify for the first time in patients with ITP, AVWD, inflammatory myopathies or Guillain-Barré syndrome the dramatic IL-11 increase following IVIg, regardless of the disease. As observed in mice, platelets, VWF and FVIII levels increased following IVIg. The late evolution (4 weeks) of post-IVIg IL-11 levels overlapped with those of VWF and platelets. These data may explain thrombotic events following IVIg and open perspectives to monitor post-IVIg IL-11/thrombopoietin ratios, and to assess rIL-11 use with or without TPO-RA as megakaryopoiesis co-stimulating factors to overcome the relative hypoproduction of platelets or VWF in corresponding autoimmune diseases, besides immunosuppressant.

Recent Progress in Electrochemical pH-Sensing Materials and Configurations for Biomedical Applications.

pH-sensing materials and configurations are rapidly evolving toward exciting new applications, especially those in biomedical applications. In this review, we highlight rapid progress in electrochemical pH sensors over the past decade (2008-2018) with an emphasis on key considerations, such as materials selection, system configurations, and testing protocols. In addition to recent progress in optical pH sensors, our main focus in this review is on electromechanical pH sensors due to their significant advances, especially in biomedical applications. We summarize developments of electrochemical pH sensors that by virtue of their optimized material chemistries (from metal oxides to polymers) and geometrical features (from thin films to quantum dots) enable their adoption in biomedical applications. We further present an overview of necessary sensing standards and protocols. Standards ensure the establishment of consistent protocols, facilitating collective understanding of results and building on the current state. Furthermore, they enable objective benchmarking of various pH-sensing reports, materials, and systems, which is critical for the overall progression and development of the field. Additionally, we list critical issues in recent literary reporting and suggest various methods for objective benchmarking. pH regulation in the human body and state-of-the-art pH sensors (from ex vivo to in vivo) are compared for suitability in biomedical applications. We conclude our review by (i) identifying challenges that need to be overcome in electrochemical pH sensing and (ii) providing an outlook on future research along with insights, in which the integration of various pH sensors with advanced electronics can provide a new platform for the development of novel technologies for disease diagnostics and prevention.

The role of dwelling type when estimating the effect of magnetic fields on childhood leukemia in the California Power Line Study (CAPS).

PURPOSE: The type of dwelling where a child lives is an important factor when considering residential exposure to environmental agents. In this paper, we explore its role when estimating the potential effects of magnetic fields (MF) on leukemia using data from the California Power Line Study (CAPS). In this context, dwelling type could be a risk factor, a proxy for other risk factors, a cause of MF exposure, a confounder, an effect-measure modifier, or some combination. METHODS: We obtained information on type of dwelling at birth on over 2,000 subjects. Using multivariable-adjusted logistic regression, we assessed whether dwelling type was a risk factor for childhood leukemia, which covariates and MF exposures were associated with dwelling type, and whether dwelling type was a potential confounder or an effect-measure modifier in the MF-leukemia relationship under the assumption of no-uncontrolled confounding. RESULTS: A majority of children lived in single-family homes or duplexes (70%). Dwelling type was associated with race/ethnicity and socioeconomic status but not with childhood leukemia risk, after other adjustments, and did not alter the MF-leukemia relationship upon adjustment as a potential confounder. Stratification revealed potential effect-measure modification by dwelling type on the multiplicative scale. CONCLUSION: Dwelling type does not appear to play a significant role in the MF-leukemia relationship in the CAPS dataset as a leukemia risk factor or confounder. Future research should explore the role of dwelling as an effect-measure modifier of the MF-leukemia association.

Atmospheric Warming Drives Growth in Arctic Sea Ice: A Key Role for Snow.

A number of feedbacks regulate the response of Arctic sea ice to local atmospheric warming. Using a realistic coupled ocean-sea ice model and its adjoint, we isolate a mechanism by which significant ice growth at the end of the melt season may occur as a lagged response to Arctic atmospheric warming. A series of perturbation simulations informed by adjoint model-derived sensitivity patterns reveal the enhanced ice growth to be accompanied by a reduction of snow thickness on the ice pack. Detailed analysis of ocean-ice-snow heat budgets confirms the essential role of the reduced snow thickness for persistence and delayed overshoot of ice growth. The underlying mechanism is a snow-melt-conductivity feedback, wherein atmosphere-driven snow melt leads to a larger conductive ocean heat loss through the overlying ice layer. Our results highlight the need for accurate observations of snow thickness to constrain climate models and to initialize sea ice forecasts.

Cooperative improvement in growth rate, red-colour score and astaxanthin level of white-leg shrimp by Bacillus strains originating from shrimp gut.

AIMS: We investigated the potential cooperative effects of carotenoid-producing Bacillus aquimaris SH6 and nonpigmented Bacillus subtilis SH23 on white-leg shrimp growth and health. METHODS AND RESULTS: SH6, SH23 and a combination of both spores (1 × 106  CFU per g pellet) were administered in shrimp. The growth rate (2·36% day-1 ), red-colour score (25) and astaxanthin concentration (3·5 µg g-1 shrimp) were maximum in two-spore-administered shrimp. Immune-related Rho mRNA expression level and phenoloxidase and superoxidase dismutase activities were higher in two-spore-administered shrimp than in control shrimp, with Rho mRNA expression level being 55-fold higher in two-spore-administered shrimp than in SH6-administered shrimp and phenoloxidase activity being 1·2-fold higher in two-spore-administered shrimp than in SH23-administered shrimp. Although live SH6 count was 2·7-fold lower, SH6 germination level was 3·5-fold higher in the combination group than in SH6 group. CONCLUSIONS: When both SH6 and SH23 spores were administered, SH6 spore germination was enhanced and cooperative improvement was seen in growth, astaxanthin level and red-colour score of white-leg shrimp; however, immune-related parameters were induced in a noncooperative manner. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report showing the cooperative probiotic activities of Bacillus strains and their possible mechanisms in a shrimp model.

Wavelength scaling of terahertz pulse energies delivered by two-color air plasmas.

We address the long-standing problem of anomalous growth observed in the terahertz (THz) energy yield from air plasmas created by two-color laser pulses, as the fundamental wavelength λ0 is increased. Using two distinct optical parametric amplifiers (OPAs), we report THz energies scaling like λ0α with large exponents 5.6≤α≤14.3, which departs from the growth in λ02 expected from photocurrent theory. By means of comprehensive 3D simulations, we demonstrate that the changes in the laser beam size, pulse duration, and phase-matching conditions in the second-harmonic generation process when tuning the OPA's carrier wavelength can lead to these high scaling powers. The value of the phase angle between the two colors reached at the exit of the doubling crystal turns out to be crucial and even explains non-monotonic behaviors in the measurements.

Measuring implementation in global mental health: validation of a pragmatic implementation science measure in eastern Ukraine using an experimental vignette design.

BACKGROUND: There is mounting evidence supporting the effectiveness of task-shifted mental health interventions in low- and middle-income countries (LMIC). However, there has been limited systematic scale-up or sustainability of these programs, indicating a need to study implementation. One barrier to progress is a lack of locally relevant and valid implementation measures. We adapted an existing brief dissemination and implementation (D&I) measure which includes scales for acceptability, appropriateness, feasibility and accessibility for local use and studied its validity and reliability among a sample of consumers in Ukraine. METHODS: Local qualitative data informed adaptation of the measure and development of vignettes to test the reliability and validity. Participants were veterans and internally displaced persons (IDPs) recruited as part of a separate validity study of adapted mental health instruments. We examined internal consistency reliability, test-retest reliability, and construct and criterion validity for each scale on the measure. We randomly assigned half the participants to respond to a vignette depicting existing local psychiatric services which we knew were not well regarded, while the other half was randomized to a vignette describing a potentially more well-implemented mental health service. Criterion validity was assessed by comparing scores on each scale by vignette and by overall summary ratings of the programs described in the vignettes. RESULTS: N = 169 participated in the qualitative study and N = 153 participated in the validity study. Qualitative findings suggested the addition of several items to the measure and indicated the importance of addressing professionalism/competency of providers in both the scales and the vignettes. Internal consistency reliabilities ranged from α = 0.85 for feasibility to α = 0.91 for appropriateness. Test-rest reliabilities were acceptable to good for all scales (rho: 0.61-0.79). All scales demonstrated substantial and significant differences in average scores by vignette assignment (ORs: 2.21-5.6) and overall ratings (ORs: 5.1-14.47), supporting criterion validity. CONCLUSIONS: This study represents an innovative mixed-methods approach to testing an implementation science measure in contexts outside the United States. Results support the reliability and validity of most scales for consumers in Ukraine. Challenges included large amounts of missing data due to participants' difficulties responding to questions about a hypothetical program.

Occurrence of Melibiose-Containing Glycosphingolipids in a Sample of a Sponge-Coral Association (Desmapsamma anchorata/Carijoa riisei).

In our research on biologically active compounds from Vietnamese marine invertebrates, rare melibiose-containing glycosphingolipids were found in a sample of a sponge-coral association (Desmapsamma anchorata/Carijoa riisei). Melibiosylceramides were analyzed as constituents of some multi-component RP-HPLC fractions, and the structures of 14 new (1b, 3b, 4a-4c, 6a-6c, 8b, 9a, 9b, 10b, 11a, 11b) and five known (2b, 5a-5c, 7b) natural compounds were elucidated using NMR, mass spectrometry, optical rotation, and chemical transformations. These α-d-Galp-(1→6)-ß-d-Glcp-(1 ↔ 1)-ceramides (presumably sponge-derived compounds) were shown to contain phytosphingosine-type n-t17:0 (1), (6E)-n-t17:1 (2), i-t17:0 (3), n-t18:0 (4), (6E)-n-t18:1 (5), i-t18:0 (6), (6E)-i-t18:1 (7), i-t19:0 (8), (6E)-i-t19:1 (9), ai-t19:0 (10), and (6E)-ai-t19:1 (11) backbones N-acylated with saturated straight-chain (2R)-2-hydroxy C21 (a), C22 (b), and C23 (c) acids. Characteristic trends in the fragmentations of the terminal parts of tetraacetylated normal-chain and iso- and anteiso-branched sphingoid bases were observed using GC/MS. The total sum of melibiosylceramides and compound 5b caused a reduction in colony formation of human melanoma cells.

European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity (EASO) clinical practice recommendations for the management of non-alcoholic fatty liver disease: evaluation of their application in people with Type 2 diabetes.

AIMS: To evaluate the application of the recently proposed recommendations by the European Association for the Study of the Liver, European Association for the Study of Diabetes and European Association for the Study of Obesity for the diagnosis, treatment and follow-up of non-alcoholic fatty liver disease in people with Type 2 diabetes. METHODS: A total of 179 people with Type 2 diabetes were included in this study. Liver fat content (assessed using proton magnetic resonance spectroscopy), fatty liver index score, non-alcoholic fatty liver disease fibrosis score, and SteatoTest and FibroTest scores were determined. RESULTS: According to proton magnetic resonance spectroscopy, 68.7% of participants had steatosis (liver fat content >5.5%). The application of the guidelines using several combinations (fatty liver index + non-alcoholic fatty liver disease fibrosis scores, Steatotest + FibroTest scores, proton magnetic resonance spectroscopy + non-alcoholic fatty liver disease fibrosis score, proton magnetic resonance spectroscopy + FibroTest) resulted in a referral to a liver clinic for 33.5-84.9% people with Type 2 diabetes. CONCLUSIONS: The application of these new algorithms for the diagnosis, and follow-up of non-alcoholic fatty liver disease would lead to an excessive number of people with Type 2 diabetes being referred to a liver clinic. We suggest that new clinical and/or biological biomarkers of steatosis and fibrosis be specifically validated in people with Type 2 diabetes.

Connecting the dots between breast cancer, obesity and alcohol consumption in middle-aged women: ecological and case control studies.

BACKGROUND: Breast cancer (BC) incidence in Australian women aged 45 to 64 years ('middle-aged') has tripled in the past 50 years, along with increasing alcohol consumption and obesity in middle-age women. Alcohol and obesity have been individually associated with BC but little is known about how these factors might interact. Chronic psychological stress has been associated with, but not causally linked to, BC. Here, alcohol could represent the 'missing link' - reflecting self-medication. Using an exploratory cross-sectional design, we investigated inter-correlations of alcohol intake and overweight/obesity and their association with BC incidence in middle-aged women. We also explored the role of stress and various lifestyle factors in these relationships. METHODS: We analysed population data on BC incidence, alcohol consumption, overweight/obesity, and psychological stress. A case control study was conducted using an online survey. Cases (n = 80) were diagnosed with BC and controls (n = 235) were women in the same age range with no BC history. Participants reported lifestyle data (including alcohol consumption, weight history) over consecutive 10-year life periods. Data were analysed using a range of bivariate and multivariate techniques including correlation matrices, multivariate binomial regressions and multilevel logistic regression. RESULTS: Ecological inter-correlations were found between BC and alcohol consumption and between BC and obesity but not between other variables in the matrix. Strong pairwise correlations were found between stress and alcohol and between stress and obesity. BMI tended to be higher in cases relative to controls across reported life history. Alcohol consumption was not associated with case-control status. Few correlations were found between lifestyle factors and stress, although smoking and alcohol consumption were correlated in some periods. Obesity occurring during the ages of 31 to 40 years emerged as an independent predictor of BC (OR 3.5 95% CI: 1.3-9.4). CONCLUSIONS: This study provides ecological evidence correlating obesity and alcohol consumption with BC incidence. Case-control findings suggest lifetime BMI may be important with particular risk associated with obesity prior to 40 years of age. Stress was ecologically linked to alcohol and obesity but not to BC incidence and was differentially correlated with alcohol and smoking among cases and controls. Our findings support prevention efforts targeting weight in women below 40 years of age and, potentially, lifelong alcohol consumption to reduce BC risk in middle-aged women.

Six New Polyhydroxysteroidal Glycosides, Anthenosides S1 - S6, from the Starfish Anthenea sibogae.

Six new polyhydroxysteroidal glycosides, anthenosides S1  - S6 (1 - 6), along with a mixture of two previously known related glycosides, 7 and 8, were isolated from the methanolic extract of the starfish Anthenea sibogae. The structures of 1 - 6 were established by NMR and HR-ESI-MS techniques as well as by chemical transformations. All new compounds have a 5α-cholest-8(14)-ene-3α,6ß,7ß,16α-tetrahydroxysteroidal nucleus and differ from majority of starfish glycosides in positions of carbohydrate moieties at C(7) and C(16) (1 - 4, 6) or only at C(16) (5). The 4-O-methyl-ß-d-glucopyranose residue (2) and Δ24 -cholestane side chain (3) have not been found earlier in the starfish steroidal glycosides. The mixture of 7 and 8 slightly inhibited the proliferation of human breast cancer T-47D cells and decreased the colony size in the colony formation assay.