Rational divisors in rational divisor classes

We discuss the situation where a curve C, defined over a number field K, has a known K-rational divisor class of degree 1, and consider whether this class contains an actual K-rational divisor. When C has points everywhere locally, the local to global principle of the Brauer group gives the existence of such a divisor. In this situation, we give an alternative, more down to earth, approach, which indicates how to compute this divisor in certain situations. We also discuss examples where C does not have points everywhere locally, and where no such K-rational divisor is contained in the K-rational divisor class

Identifying Diagnostic Studies in MEDLINE: Reducing the Number Needed to Read

Objectives: The search filters in PubMed have become a cornerstone in information retrieval in evidence-based practice. However, the filter for diagnostic studies is not fully satisfactory, because sensitive searches have low precision. The objective of this study was to construct and validate better search strategies to identify diagnostic articles recorded on MEDLINE with special emphasis on precision. Design: A comparative, retrospective analysis was conducted. Four medical journals were hand-searched for diagnostic studies published in 1989 and 1994. Four other journals were hand-searched for 1999. The three sets of studies identified were used as gold standards. A new search strategy was constructed and tested using the 1989-subset of studies and validated in both the 1994 and 1999 subsets. We identified candidate text words for search strategies using a word frequency analysis of the abstracts. According to the frequency of identified terms, searches were run for each term independently. The sensitivity, precision, and number needed to read (1/precision) of every candidate term were calculated. Terms with the highest sensitivity × precision product were used as free text terms in combination with the MeSH term "SENSITIVITY AND SPECIFICITY” using the Boolean operator OR. In the 1994 and 1999 subsets, we performed head-to-head comparisons of the currently available PubMed filter with the one we developed. Measurements: The sensitivity, precision and the number needed to read (1/precision) were measured for different search filters. Results: The most frequently occurring three truncated terms (diagnos*; predict* and accura*) in combination with the MeSH term "SENSITIVITY AND SPECIFICITY” produced a sensitivity of 98.1 percent (95% confidence interval: 89.9-99.9%) and a number needed to read of 8.3 (95% confidence interval: 6.7-11.3%). In direct comparisons of the new filter with the currently available one in PubMed using the 1994 and 1999 subsets, the new filter achieved better precision (12.0% versus 8.2% in 1994 and 5.0% versus 4.3% in 1999. The 95% confidence intervals for the differences range from 0.05% to 7.5% (p = 0.041) and -1.0% to 2.3% (p = 0.45), respectively). The new filter achieved slightly better sensitivities than the currently available one in both subsets, namely 98.1 and 96.1% (p = 0.32) versus 95.1 and 88.8% (p = 0.125). Conclusions: The quoted performance of the currently available filter for diagnostic studies in PubMed may be overstated. It appears that even single external validation may lead to over optimistic views of a filter's performance. Precision appears to be more unstable than sensitivity. In terms of sensitivity, our filter for diagnostic studies performed slightly better than the currently available one and it performed better with regards to precision in the 1994 subset. Additional research is required to determine whether these improvements are beneficial to searches in practic

The functional connectome of 3,4‐methyldioxymethamphetamine‐related declarative memory impairments

The chronic intake of 3,4‐methylenedioxymethamphetamine (MDMA, “ecstasy”) bears a strong risk for sustained declarative memory impairments. Although such memory deficits have been repeatedly reported, their neurofunctional origin remains elusive. Therefore, we here investigate the neuronal basis of altered declarative memory in recurrent MDMA users at the level of brain connectivity. We examined a group of 44 chronic MDMA users and 41 demographically matched controls. Declarative memory performance was assessed by the Rey Auditory Verbal Learning Test and a visual associative learning test. To uncover alterations in the whole brain connectome between groups, we employed a data‐driven multi‐voxel pattern analysis (MVPA) approach on participants' resting‐state functional magnetic resonance imaging data. Recent MDMA use was confirmed by hair analyses. MDMA users showed lower performance in delayed recall across tasks compared to well‐matched controls with moderate‐to‐strong effect sizes. MVPA revealed a large cluster located in the left postcentral gyrus of global connectivity differences between groups. Post hoc seed‐based connectivity analyses with this cluster unraveled hypoconnectivity to temporal areas belonging to the auditory network and hyperconnectivity to dorsal parietal regions belonging to the dorsal attention network in MDMA users. Seed‐based connectivity strength was associated with verbal memory performance in the whole sample as well as with MDMA intake patterns in the user group. Our findings suggest that functional underpinnings of MDMA‐related memory impairments encompass altered patterns of multimodal sensory integration within auditory processing regions to a functional heteromodal connector hub, the left postcentral gyrus. In addition, hyperconnectivity in regions of a cognitive control network might indicate compensation for degraded sensory processing

Conflict monitoring and emotional processing in 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine users – A comparative neurophysiological study

In stimulant use and addiction, conflict control processes are crucial for regulating substance use and sustaining abstinence, which can be particularly challenging in social-affective situations. Users of methamphetamine (METH, “Ice”) and 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) both experience impulse control deficits, but display different social-affective and addictive profiles. We thus aimed to compare the effects of chronic use of the substituted amphetamines METH and MDMA on conflict control processes in different social-affective contexts (i.e., anger and happiness) and investigate their underlying neurophysiological mechanisms. For this purpose, chronic but recently abstinent users of METH (n = 38) and MDMA (n = 42), as well as amphetamine-naïve healthy controls (n = 83) performed an emotional face-word Stroop paradigm, while event-related potentials (ERPs) were recorded. Instead of substance-specific differences, both MDMA and METH users showed smaller behavioral effects of cognitive-emotional conflict processing (independently of emotional valence) and selective deficits in emotional processing of anger content. Both effects were underpinned by stronger P3 ERP modulations suggesting that users of substituted amphetamines employ altered stimulus–response mapping and decision-making. Given that these processes are modulated by noradrenaline and that both MDMA and METH use may be associated with noradrenergic dysfunctions, the noradrenaline system may underlie the observed substance-related similarities. Better understanding the functional relevance of this currently still under-researched neurotransmitter and its functional changes in chronic users of substituted amphetamines is thus an important avenue for future research

White matter alterations in chronic MDMA use: Evidence from diffusion tensor imaging and neurofilament light chain blood levels.

3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") is a serotonin- and noradrenaline-releasing substance, currently among the most widely used illicit substances worldwide. In animal studies, repeated exposure to MDMA has been associated with dendritic but also axonal degeneration in the brain. However, translation of the axonal findings, specifically, to humans has been repeatedly questioned and the few existing studies investigating white matter alterations in human chronic MDMA users have yielded conflicting findings. In this study, we combined whole-brain diffusion tensor imaging and neurofilament light chain (NfL) analysis in blood to reveal potential MDMA-induced axonal neuropathology. To this end, we assessed 39 chronic MDMA users and 39 matched MDMA-naïve healthy controls. MDMA users showed increased fractional anisotropy in several white matter tracts, most prominently in the corpus callosum as well as corticospinal tracts, with these findings partly related to MDMA use intensity. However, the NfL levels of MDMA users were not significantly different from those of controls. We conclude that MDMA use is not associated with significant white matter lesions due to the absence of reduced fractional anisotropy and increased NfL levels commonly observed in conditions associated with white matter lesions, including stimulant and ketamine use disorders. Hence, the MDMA-induced axonal degradation demonstrated in animal models was not observed in this human study of chronic MDMA users

White matter alterations in chronic MDMA use: Evidence from diffusion tensor imaging and neurofilament light chain blood levels

3,4–Methylenedioxymethamphetamine (MDMA, “Ecstasy”) is a serotonin- and noradrenaline-releasing substance, currently among the most widely used illicit substances worldwide. In animal studies, repeated exposure to MDMA has been associated with dendritic but also axonal degeneration in the brain. However, translation of the axonal findings, specifically, to humans has been repeatedly questioned and the few existing studies investigating white matter alterations in human chronic MDMA users have yielded conflicting findings. In this study, we combined whole-brain diffusion tensor imaging and neurofilament light chain (NfL) analysis in blood to reveal potential MDMA-induced axonal neuropathology. To this end, we assessed 39 chronic MDMA users and 39 matched MDMA-naïve healthy controls. MDMA users showed increased fractional anisotropy in several white matter tracts, most prominently in the corpus callosum as well as corticospinal tracts, with these findings partly related to MDMA use intensity. However, the NfL levels of MDMA users were not significantly different from those of controls. We conclude that MDMA use is not associated with significant white matter lesions due to the absence of reduced fractional anisotropy and increased NfL levels commonly observed in conditions associated with white matter lesions, including stimulant and ketamine use disorders. Hence, the MDMA-induced axonal degradation demonstrated in animal models was not observed in this human study of chronic MDMA users

Chronic 3,4-Methylenedioxymethamphetamine (MDMA) Use Is Related to Glutamate and GABA Concentrations in the Striatum But Not the Anterior Cingulate Cortex

Background: 3,4-Methylenedioxymethamphetamine (MDMA) is a widely used recreational substance inducing acute release of serotonin. Previous studies in chronic MDMA users demonstrated selective adaptations in the serotonin system, which were assumed to be associated with cognitive deficits. However, serotonin functions are strongly entangled with glutamate as well as γ-aminobutyric acid (GABA) neurotransmission, and studies in MDMA-exposed rats show long-term adaptations in glutamatergic and GABAergic signaling. Methods: We used proton magnetic resonance spectroscopy (MRS) to measure the glutamate-glutamine complex (GLX) and GABA concentrations in the left striatum and medial anterior cingulate cortex (ACC) of 44 chronic but recently abstinent MDMA users and 42 MDMA-naïve healthy controls. While the Mescher-Garwood point-resolved-spectroscopy sequence (MEGA-PRESS) is best suited to quantify GABA, recent studies reported poor agreement between conventional short–echo-time PRESS and MEGA-PRESS for GLX measures. Here, we applied both sequences to assess their agreement and potential confounders underlying the diverging results. Results: Chronic MDMA users showed elevated GLX levels in the striatum but not the ACC. Regarding GABA, we found no group difference in either region, although a negative association with MDMA use frequency was observed in the striatum. Overall, GLX measures from MEGA-PRESS, with its longer echo time, appeared to be less confounded by macromolecule signal than the short–echo-time PRESS and thus provided more robust results. Conclusion: Our findings suggest that MDMA use affects not only serotonin but also striatal GLX and GABA concentrations. These insights may offer new mechanistic explanations for cognitive deficits (e.g., impaired impulse control) observed in MDMA users

Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy.

MotivationMultiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia.ResultsWe performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified.Availability and implementationDatasets and scripts for reproduction of results are available through: https://nalab.stanford.edu/multiomics-pregnancy/.Supplementary informationSupplementary data are available at Bioinformatics online

Identification of Interleukin-27 (IL-27)/IL-27 Receptor Subunit Alpha as a Critical Immune Axis for In Vivo HIV Control

Intact and broad immune cell effector functions and specific individual cytokines have been linked to HIV disease outcome, but their relative contribution to HIV control remains unclear. We asked whether the proteome of secreted cytokines and signaling factors in peripheral blood can be used to discover specific pathways critical for host viral control. A custom glass-based microarray, able to measure >600 plasma proteins involved in cell-to-cell communication, was used to measure plasma protein profiles in 96 HIV-infected, treatment-naive individuals with high (>50,000) or low (600 soluble proteins, our data highlight the importance of Th17 cells and Wnt/β-catenin signaling in HIV control and especially identify the IL-27/IL-27 receptor subunit alpha (IL-27RA) axis as a predictor of plasma viral load and proviral copy number in the peripheral blood. These data may provide important guidance to therapeutic approaches in the HIV cure agenda