Evidence suggests that chronic subclinical inflammation plays an important role in the pathogenesis of type 2 diabetes (T2DM). Circulating levels of interleukin (IL)-18 appear to be associated with a ...number of micro- and macrovascular comorbidities of obesity and T2DM. This study was designed to investigate whether inhibition of IL-18 had any therapeutic benefit in the treatment of T2DM. Preliminary efficacy, safety and tolerability, pharmacokinetics, and pharmacodynamics of the anti-IL-18 monoclonal antibody, GSK1070806, were assessed.
This was a multicentre, randomized, single-blind (sponsor-unblinded), placebo-controlled, parallel-group, phase IIa trial. Obese patients of either sex, aged 18-70 years, with poorly controlled T2DM on metformin monotherapy were recruited. Patients received two doses, of placebo (n = 12), GSK1070806 0.25 mg/kg (n = 13) or GSK1070806 5 mg/kg (n = 12). The primary end-point was the change from baseline in fasting plasma glucose and weighted mean glucose area under the curve (AUC)(0-4 hours) postmixed meal test on Days 29, 57, and 85.
Thirty-seven patients were randomized to one of the three treatment arms. There were no statistically significant effects of GSK1070806 doses on fasting plasma glucose levels, or weighted mean glucose AUC(0-4 hours) compared with placebo.
GSK1070806 was well tolerated, and inhibition of IL-18 did not lead to any improvements in glucose control. However, because of study limitations, smaller, potentially clinically meaningful effects of IL-18 inhibition cannot be excluded.
ClinicalTrials.gov NCT01648153.
As autism has gained increased attention in the past few decades, autistic advocates have adopted the phrase “Nothing about us without us,” illustrating the idea that autistic people should be ...centered in all conversations regarding autism. However, in a large portion of autism research, autistic people are still not meaningfully engaged throughout the research process, leading to continued stigma in research through biased methods. Thus, stigma about autism influences not only the content of autism research, but the ways in which neurotypical people conduct research alongside (or without) autistic people, ultimately resulting in less valid conclusions or research that actively harms the autistic community. One way to address this stigma is through involving autistic individuals as equal partners in the research process, such as by including autistic co-interviewers in qualitative studies of autistic people. In this perspectives piece, we will highlight the benefits of participatory research practices within qualitative research. Furthermore, we will outline methods for conducting co-interviews with autistic research partners and share insights from our experiences implementing this practice. We hope this piece provides researchers the practical resources and inspiration to continue working toward decreasing the stigma surrounding autism in research spaces.
Photoinduced charge transfer in van der Waals heterostructures occurs on the 100 fs timescale despite weak interlayer coupling and momentum mismatch. However, little is understood about the ...microscopic mechanism behind this ultrafast process and the role of the lattice in mediating it. Here, using femtosecond electron diffraction, we directly visualize lattice dynamics in photoexcited heterostructures of WSe
/WS
monolayers. Following the selective excitation of WSe
, we measure the concurrent heating of both WSe
and WS
on a picosecond timescale-an observation that is not explained by phonon transport across the interface. Using first-principles calculations, we identify a fast channel involving an electronic state hybridized across the heterostructure, enabling phonon-assisted interlayer transfer of photoexcited electrons. Phonons are emitted in both layers on the femtosecond timescale via this channel, consistent with the simultaneous lattice heating observed experimentally. Taken together, our work indicates strong electron-phonon coupling via layer-hybridized electronic states-a novel route to control energy transport across atomic junctions.
Individuals vary in their immune genotype, inbreeding coefficient f, immune responses, survival to adulthood, and adult longevity. However, whether immune genes predict survival or longevity, whether ...such relationships are mediated through immune responses, and how f affects immune genotype remain unclear. We use a wild song sparrow (Melospiza melodia) population in which survival to adulthood, adult longevity, and f were measured precisely, and in which immune responses have previously been assessed. We investigate four toll‐like receptor (TLR) and the major histocompatibility complex (MHC) class IIB exon 2 genes. We test whether immune genes predict fitness (survival to adulthood or adult longevity); whether immune genes predict immune response; whether immune response predicts fitness and whether fitness, immune responses, or immune genotypes are correlated with f. We find that survival to adulthood is not associated with immune gene variation, but adult longevity is decreased by high MHC allele diversity (especially in birds that were relatively outbred), and by the presence of a specific MHC supertype. Immune responses were affected by specific immune genotypes. Survival to adulthood and adult longevity were not predicted by immune response, implying caution in the use of immune response as a predictor for fitness. We also found no relationship between f and immune genotype. This finding indicates that immune gene associations with longevity and immune response are not artefacts of f, and suggests that pathogen‐mediated selection at functional loci can slow the loss of genetic variation arising from genetic drift and small population size.
As part of the United Arab Emirates Unified Aerosol Experiment (UAE2), the size distribution and chemistry of dust particles were measured for the months of August and September 2004 at an Arabian ...Gulf coastal site impacted by dust from several sources within southwest Asia. The characteristics of common mode dust (0.8 < dp < 10 μm) were examined using an aerodynamic particle sizer (APS), a DRUM cascade impactor, and AERONET Sun/sky retrievals. While size properties from these distinct methods do correlate, accurate dust measurement is still an outstanding challenge. But when instruments are applied consistently in the correct context, the dynamics of dust particle size can be accurately studied. Here, observations are used to study the stability of dust size and chemistry characteristics. We found that dust particle size, chemistry, and morphology appear to be fairly static from individual sources, confirming preliminary hypotheses based on large‐scale observations of Saharan dust. Thus, our data provide experimental evidence that on regional scales, common mode dust is not functionally impacted by production wind speed, but rather influenced by soil properties such as geomorphology or roughness length. Similarly, we found transport processes from the mesoscale to near synoptic scale do not significantly impact common mode dust size either. When combined with other APS observations around the world, the dust coarse mode is found to be fairly robust with a volume median diameter on the order of ∼3.5 μm ± 30%. Finally, evidence for a strong submicron dust mode, suggested in previous studies, was inconclusive.
Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene, and loss of function mutations are common and appear to be important in the pathogenesis of endometrial carcinomas. Loss of PTEN ...causes deregulated phosphatidylinositol-3 kinase/serine-threonine kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell cycle progression. Temsirolimus, an ester derivative of rapamycin that inhibits mTOR, was evaluated in this setting.
Sequential phase II studies evaluated single-agent activity of temsirolimus in women with recurrent or metastatic chemotherapy-naive or chemotherapy-treated endometrial cancer. Temsirolimus 25 mg intravenously was administered weekly in 4-week cycles.
In the chemotherapy-naive group, 33 patients received a median of four cycles (range, one to 23 cycles). Of the 29 patients evaluable for response, four (14%) had an independently confirmed partial response and 20 (69%) had stable disease as best response, with a median duration of 5.1 months (range, 3.7 to 18.4 months) and 9.7 months (range, 2.1 to 14.6 months). Only five patients (18%) had progressive disease. In the chemotherapy-treated group, 27 patients received a median of three cycles (range, one to six cycles). Of the 25 patients evaluable for response, one (4%) had an independently confirmed partial response, and 12 patients (48%) had stable disease, with a median duration of 4.3 months (range, 3.6 to 4.9 months) and 3.7 months (range, 2.4 to 23.2 months). PTEN loss (immunohistochemistry and mutational analysis) and molecular markers of PI3K/Akt/mTOR pathway did not correlate with the clinical outcome.
mTOR inhibition with temsirolimus has encouraging single-agent activity in endometrial cancer which is higher in chemotherapy-naive patients than in chemotherapy-treated patients and is independent of PTEN status. The difference in activity according to prior therapy should be factored into future clinical trial designs.
Nostalgia, a sentimental longing for one's past, can serve as a resource for individuals coping with discomforting experiences. The experience of bereavement poses psychological and physical risks. ...In a longitudinal study, we examined whether dispositional nostalgia predicted reductions in distress associated with the death of a loved one. Undergraduate students (N = 133) provided information regarding their loss (time elapsed since loss, expectedness) and levels of initial grief, nostalgia, and distress (hyperarousal, intrusion, avoidance) at three time points over a one-month period (Times 2 and 3 occurred one week and one month after the initial session, respectively). Individuals experiencing higher nostalgia reported a decrease in intrusive thoughts across time, whereas those experiencing lower nostalgia reported no change in intrusive thoughts across time. Hyperarousal (physical symptoms, negative feelings) decreased across time among individuals with higher initial grief who experienced greater nostalgia, but increased across time among those with higher initial grief who experienced lesser nostalgia. No changes occurred in avoidance. Nostalgia can palliate bereavement.
To define the prevalence of poor sleep patterns in the US Hispanic/Latino population, identify sociodemographic and psychosocial predictors of short and long sleep duration, and the association ...between sleep and cardiometabolic outcomes.
Cross-sectional analysis.
Community-based study.
Adults age 18-74 y free of sleep disorders (n = 11,860) from the Hispanic Community Health Study/Study of Latinos baseline examination (2008-2011).
N/A.
The mean self-reported sleep duration was 8.0 h per night with 18.6% sleeping less than 7 h and 20.1% sleeping more than 9 h in age- and sex-adjusted analyses. Short sleep was most common in individuals of Puerto Rican heritage (25.6%) and the Other Hispanic group (27.4%). Full-time employment, low level of education, and depressive symptoms were independent predictors of short sleep, whereas unemployment, low household income, low level of education, and being born in the mainland US were independent predictors of long sleep. After accounting for sociodemographic differences, short sleep remained significantly associated with obesity with an odds ratio of 1.29 95% confidence interval 1.12-1.49 but not with diabetes, hypertension, or heart disease. In contrast, long sleep was not associated with any of these conditions.
Sleep duration is highly variable among US Hispanic/Latinos, varying by Hispanic/Latino heritage as well as socioeconomic status. These differences may have health consequences given associations between sleep duration and cardiometabolic disease, particularly obesity.
Although satellite retrievals and data assimilation have progressed to where there is a good skill for monitoring maritime Aerosol Optical Depth (AOD), there remains uncertainty in achieving further ...degrees of freedom, such as distinguishing fine and coarse mode dominated species in maritime environments (e.g., coarse mode sea salt and dust versus fine mode terrestrial anthropogenic emissions, biomass burning, and maritime secondary production). For the years 2016 through 2019, we performed an analysis of 550 nm total AOD550, fine mode AOD (FAOD550; also known as FM AOD in the literature), coarse mode AOD (CAOD550), and fine mode fraction (η550) between Moderate Resolution Spectral Imaging Radiometer (MODIS) V6.1 MOD/MYD04 dark target aerosol retrievals and the International Cooperative for Aerosol Prediction (ICAP) core four multi-model consensus (C4C) of analyses/short term forecasts that assimilate total MODIS AOD550. Differences were adjudicated by the global shipboard Maritime Aerosol Network (MAN) and selected island AERONET sun photometer observations with the application of the spectral deconvolution algorithm (SDA). Through a series of conditional and regional analyses, we found divergence included regions of terrestrial influence and latitudinal dependencies in the remote oceans. Notably, MODIS and the C4C and its members, while having good correlations overall, have a persistent +0.04 to +0.02 biases relative to MAN and AERONET for typical AOD550 values (84th% < 0.28), with the C4C underestimating significant events thereafter. Second, high biases in AOD550 are largely associated with the attribution of the fine mode in satellites and models alike. Thus, both MODIS and C4C members are systematically overestimating AOD550 and FAOD550 but perform better in characterizing the CAOD550. Third, for MODIS, findings are consistent with previous reports of a high bias in the retrieved Ångström Exponent, and we diagnosed both the optical model and cloud masking as likely causal factors for the AOD550 and FAOD550 high bias, whereas for the C4C, it is likely from secondary overproduction and perhaps numerical diffusion. Fourth, while there is no wind-speed-dependent bias for surface winds <12 m s−1, the C4C and MODIS AOD550s also overestimate CAOD550 and FAOD550, respectively, for wind speeds above 12 m/s. Finally, sampling bias inherent in MAN, as well as other circumstantial evidence, suggests biases in MODIS are likely MODIS and the C4C products have their own strengths and challenges for a given climate application and discuss needed research. even larger than what was diagnosed here. We conclude with a discussion on how
Context.--The original guideline, "Validating Whole Slide Imaging for Diagnostic Purposes in Pathology," was published in 2013 and included 12 guideline statements. The College of American ...Pathologists convened an expert panel to update the guideline following standards established by the National Academies of Medicine for developing trustworthy clinical practice guidelines. Objective.--To assess evidence published since the release of the original guideline and provide updated recommendations for validating whole slide imaging (WSI) systems used for diagnostic purposes. Design.--An expert panel performed a systematic review of the literature. Frozen sections, anatomic pathology specimens (biopsies, curettings, and resections), and hematopathology cases were included. Cytology cases were excluded. Using the Grading of Recommendations Assessment, Development, and Evaluation approach, the panel reassessed and updated the original guideline recommendations. Results.--Three strong recommendations and 9 good practice statements are offered to assist laboratories with validating WSI digital pathology systems. Conclusions.--Systematic review of literature following release of the 2013 guideline reaffirms the use of a validation set of at least 60 cases, establishing intraobserver diagnostic concordance between WSI and glass slides and the use of a 2-week washout period between modalities. Although all discordances between WSI and glass slide diagnoses discovered during validation need to be reconciled, laboratories should be particularly concerned if their overall WSI-glass slide concordance is less than 95%.
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