Heterogeneity of major depressive disorder (MDD) illness course complicates clinical decision-making. Although efforts to use symptom profiles or biomarkers to develop clinically useful prognostic ...subtypes have had limited success, a recent report showed that machine-learning (ML) models developed from self-reports about incident episode characteristics and comorbidities among respondents with lifetime MDD in the World Health Organization World Mental Health (WMH) Surveys predicted MDD persistence, chronicity and severity with good accuracy. We report results of model validation in an independent prospective national household sample of 1056 respondents with lifetime MDD at baseline. The WMH ML models were applied to these baseline data to generate predicted outcome scores that were compared with observed scores assessed 10-12 years after baseline. ML model prediction accuracy was also compared with that of conventional logistic regression models. Area under the receiver operating characteristic curve based on ML (0.63 for high chronicity and 0.71-0.76 for the other prospective outcomes) was consistently higher than for the logistic models (0.62-0.70) despite the latter models including more predictors. A total of 34.6-38.1% of respondents with subsequent high persistence chronicity and 40.8-55.8% with the severity indicators were in the top 20% of the baseline ML-predicted risk distribution, while only 0.9% of respondents with subsequent hospitalizations and 1.5% with suicide attempts were in the lowest 20% of the ML-predicted risk distribution. These results confirm that clinically useful MDD risk-stratification models can be generated from baseline patient self-reports and that ML methods improve on conventional methods in developing such models.
Isocitrate dehydrogenase-1 (Idh1) is an important metabolic enzyme that produces NADPH by converting isocitrate to α-ketoglutarate. Idh1 is known to reduce reactive oxygen species (ROS) induced in ...cells by treatment with lipopolysaccharide (LPS) in vitro. Here, we used Idh1-deficient knockout (Idh1 KO) mice to investigate the role of Idh1 in antioxidant defense in vivo. Idh1 KO mice showed heightened susceptibility to death induced by LPS and exhibited increased serum levels of inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. The serum of LPS-injected Idh1 KO mice also contained elevated levels of AST, a marker of inflammatory liver damage. Furthermore, after LPS injection, livers of Idh1 KO mice showed histological evidence of elevated oxidative DNA damage compared with livers of wild-type (WT) mice. Idh1 KO livers showed a faster and more pronounced oxidative stress than WT livers. In line with that, Idh1 KO hepatocytes showed higher ROS levels and an increase in the NADP(+)/NADPH ratio when compared with hepatocytes isolated from WT mice. These results suggest that Idh1 has a physiological function in protecting cells from oxidative stress by regulating the intracellular NADP(+)/NADPH ratio. Our findings suggest that stimulation of Idh1 activity may be an effective therapeutic strategy for reducing oxidative stress during inflammatory responses, including the early stages of septic shock.
Nanometre- and micrometre-sized charged particles at aqueous interfaces are typically stabilized by a repulsive Coulomb interaction. If one of the phases forming the interface is a nonpolar substance ...(such as air or oil) that cannot sustain a charge, the particles will exhibit long-ranged dipolar repulsion; if the interface area is confined, mutual repulsion between the particles can induce ordering and even crystallization. However, particle ordering has also been observed in the absence of area confinement, suggesting that like-charged particles at interfaces can also experience attractive interactions. Interface deformations are known to cause capillary forces that attract neighbouring particles to each other, but a satisfying explanation for the origin of such distortions remains outstanding. Here we present quantitative measurements of attractive interactions between colloidal particles at an oil-water interface and show that the attraction can be explained by capillary forces that arise from a distortion of the interface shape that is due to electrostatic stresses caused by the particles' dipolar field. This explanation, which is consistent with all reports on interfacial particle ordering so far, also suggests that the attractive interactions might be controllable: by tuning the polarity of one of the interfacial fluids, it should be possible to adjust the electrostatic stresses of the system and hence the interparticle attractions.
Clinicians need guidance to address the heterogeneity of treatment responses of patients with major depressive disorder (MDD). While prediction schemes based on symptom clustering and biomarkers have ...so far not yielded results of sufficient strength to inform clinical decision-making, prediction schemes based on big data predictive analytic models might be more practically useful.
We review evidence suggesting that prediction equations based on symptoms and other easily-assessed clinical features found in previous research to predict MDD treatment outcomes might provide a foundation for developing predictive analytic clinical decision support models that could help clinicians select optimal (personalised) MDD treatments. These methods could also be useful in targeting patient subsamples for more expensive biomarker assessments.
Approximately two dozen baseline variables obtained from medical records or patient reports have been found repeatedly in MDD treatment trials to predict overall treatment outcomes (i.e., intervention v. control) or differential treatment outcomes (i.e., intervention A v. intervention B). Similar evidence has been found in observational studies of MDD persistence-severity. However, no treatment studies have yet attempted to develop treatment outcome equations using the full set of these predictors. Promising preliminary empirical results coupled with recent developments in statistical methodology suggest that models could be developed to provide useful clinical decision support in personalised treatment selection. These tools could also provide a strong foundation to increase statistical power in focused studies of biomarkers and MDD heterogeneity of treatment response in subsequent controlled trials.
Coordinated efforts are needed to develop a protocol for systematically collecting information about established predictors of heterogeneity of MDD treatment response in large observational treatment studies, applying and refining these models in subsequent pragmatic trials, carrying out pooled secondary analyses to extract the maximum amount of information from these coordinated studies, and using this information to focus future discovery efforts in the segment of the patient population in which continued uncertainty about treatment response exists.
Cell densities of the fecal pollution indicator genus,
Enterococcus, were determined by a rapid (3
h or less) quantitative polymerase chain reaction (QPCR) analysis method in 100
ml water samples ...collected from recreational beaches on Lake Michigan and Lake Erie during the summer of 2003. Measurements by this method were compared with counts of
Enterococcus colony-forming units (CFU) determined by Method 1600 membrane filter (MF) analysis using mEI agar. The QPCR method had an estimated 95% confidence, minimum detection limit of 27
Enterococcus cells per sample in analyses of undiluted DNA extracts and quantitative analyses of multiple lake water samples, spiked with known numbers of these organisms, gave geometric mean results that were highly consistent with the spike levels. At both beaches, the geometric means of ambient
Enterococcus concentrations in water samples, determined from multiple collection points during each sampling visit, showed approximately lognormal distributions over the study period using both QPCR and MF analyses. These geometric means ranged from 10 to 8548
cells by QPCR analysis and 1–2499 CFU by MF culture analysis in Lake Michigan
(
N
=
56
)
and from 8 to 8695
cells by QPCR and 3–1941 CFU by MF culture in Lake Erie
(
N
=
47
)
. Regression analysis of these results showed a significant positive correlation between the two methods with an overall correlation coefficient (
r) of 0.68.
Dysregulation of the gut microbiome has been implicated in the progression of non-alcoholic fatty liver disease (NAFLD) to advanced fibrosis and cirrhosis. To determine the diagnostic capacity of ...this association, we compared stool microbiomes across 163 well-characterized participants encompassing non-NAFLD controls, NAFLD-cirrhosis patients, and their first-degree relatives. Interrogation of shotgun metagenomic and untargeted metabolomic profiles by using the random forest machine learning algorithm and differential abundance analysis identified discrete metagenomic and metabolomic signatures that were similarly effective in detecting cirrhosis (diagnostic accuracy 0.91, area under curve AUC). Combining the metagenomic signature with age and serum albumin levels accurately distinguished cirrhosis in etiologically and genetically distinct cohorts from geographically separated regions. Additional inclusion of serum aspartate aminotransferase levels, which are increased in cirrhosis patients, enabled discrimination of cirrhosis from earlier stages of fibrosis. These findings demonstrate that a core set of gut microbiome species might offer universal utility as a non-invasive diagnostic test for cirrhosis.
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•Non-invasive detection of cirrhosis by using microbial species, age, and serum measures•Stool microbial and metabolite signatures independently predict NAFLD-cirrhosis•Machine-learning-based prediction of cirrhosis validated in independent cohorts
Oh et al. identify diagnostic signatures for fibrosis from stool metagenomic and metabolomic profiling that, when combined with serum AST levels, distinguishes cirrhosis in mixed fibrosis cohort. Moreover, this combination signature was validated in racially and geographically independent cohorts.
The RAS protooncogene has a central role in regulation of cell proliferation, and point mutations leading to oncogenic activation of Ras occur in a large number of human cancers. Silencing of ...tumor-suppressor genes by DNA methyltransferase 1 (Dnmt1) is essential for oncogenic cellular transformation by Ras, and Dnmt1 is overexpressed in numerous human cancers. Here we provide new evidence that the pleiotropic regulator of G protein signaling (RGS) family member RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated degradation of Dmnt1 and promoting apoptosis. Employing mouse embryonic fibroblasts from wild-type and RGS6(-/-) mice, we found that oncogenic Ras induced upregulation of RGS6, which in turn blocked Ras-induced cellular transformation. RGS6 functions to suppress cellular transformation in response to oncogenic Ras by downregulating Dnmt1 protein expression leading to inhibition of Dnmt1-mediated anti-apoptotic activity. Further experiments showed that RGS6 functions as a scaffolding protein for both Dnmt1 and Tip60 and is required for Tip60-mediated acetylation of Dnmt1 and subsequent Dnmt1 ubiquitylation and degradation. The RGS domain of RGS6, known only for its GTPase-activating protein activity toward Gα subunits, was sufficient to mediate Tip60 association with RGS6. This work demonstrates a novel signaling action for RGS6 in negative regulation of oncogene-induced transformation and provides new insights into our understanding of the mechanisms underlying Ras-induced oncogenic transformation and regulation of Dnmt1 expression. Importantly, these findings identify RGS6 as an essential cellular defender against oncogenic stress and a potential therapeutic target for developing new cancer treatments.
Homogenization estimates based on the self-consistent scheme are customarily used to describe the plastic yielding of polycrystals. Such estimates of the initial micro yield surface of a polycrystal ...depend on the morphologic and crystallographic textures, the slip system geometry, the corresponding critical resolved shear stresses and the single crystal elastic anisotropy. The usual approach relies on a rather crude description of the stress field induced by the local elastic anisotropy. This deficiency is addressed and a new concept, i.e. a “probability” yield surface is proposed. Based on a statistical description of the local fields, the latter makes use of the average and the standard deviation of the resolved shear stress on the different slip systems within a given crystalline orientation. By comparing the homogenization estimates with full-field results, it is shown that the self-consistent scheme does not present intrinsic shortcomings regarding the prediction of the micro yield stress of polycrystals with anisotropic elastic constitutive behaviour. On the contrary, it delivers realistic estimates if the local field fluctuations are taken into account in the yield criterion. The quantitative results obtained for cubic elasticity show a strong influence of the intragranular stress heterogeneity on the estimate of the micro yield stress.
Despite high curability, some testicular cancer (TC) patient groups may have increased mortality. We provide a detailed age- and histology-specific comparison of population-based relative survival of ...TC patients in Europe and the USA.
Using data from 12 European cancer registries and the USA Surveillance, Epidemiology and End Results 9 database, we report survival trends for patients diagnosed with testicular seminomas and nonseminomas between 1993–1997 and 2003–2007. Additionally, a model-based analysis was used to compare survival trends and relative excess risk (RER) of death between Europe and the USA adjusting for differences in age and histology.
In 2003–2007, the 5-year relative survival of patients with testicular seminoma was at least 98% among those aged <50 years, survival of patients with nonseminoma remained 3%–6% units lower.
Despite improvements in the relative survival of nonseminoma patients aged ≥50 years by 13%–18% units, survival remained markedly lower than the survival of seminoma patients of the same age. Model-based analyses showed increased RERs for nonseminomas, older, and European patients.
There remains little room for survival improvement among testicular seminoma patients, especially for those aged <50 years. Older TC patients remain at increased risk of death, which seems mainly attributable to the lower survival among the nonseminoma patients.
Background: Long term studies of cognitive development and colic have not differentiated between typical colic and prolonged crying. Objective: To evaluate whether colic and excessive crying that ...persists beyond 3 months is associated with adverse cognitive development. Design: Prospective cohort study. A sample of 561 women was enrolled in the second trimester of pregnancy. Colic and prolonged crying were based on crying behaviour assessed at 6 and 13 weeks. Children’s intelligence, motor abilities, and behaviour were measured at 5 years (n = 327). Known risk factors for cognitive impairment were ascertained prenatally, after birth, at 6 and 13 weeks, at 6, 9, and 13 months, and at 5 years of age. Results: Children with prolonged crying (but not those with colic only) had an adjusted mean IQ that was 9 points lower than the control group. Their performance and verbal IQ scores were 9.2 and 6.7 points lower than the control group, respectively. The prolonged crying group also had significantly poorer fine motor abilities compared with the control group. Colic had no effect on cognitive development. Conclusions: Excessive, uncontrolled crying that persists beyond 3 months of age in infants without other signs of neurological damage may be a marker for cognitive deficits during childhood. Such infants need to be examined and followed up more intensively.
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