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Abstract
The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex public health challenge. Evidence of the genetic links between these phenotypes is emerging, but little is currently known about the genomic regions and biological functions that are involved. To address this, we performed Local Analysis of [co]Variant Association (LAVA) using large-scale (N=9,725-933,970) genome-wide association studies (GWASs) results for three IR-related conditions (type 2 diabetes mellitus, obesity, and metabolic syndrome) and nine neuropsychiatric disorders. Subsequently, positional and expression quantitative trait locus (eQTL)-based gene mapping and downstream functional genomic analyses were performed on the significant loci. Patterns of negative and positive local genetic correlations (|rg|=0.21-1, pFDR<0.05) were identified at 109 unique genomic regions across all phenotype pairs. Local correlations emerged even in the absence of global genetic correlations between IR-related conditions and Alzheimer’s disease, bipolar disorder, and Tourette’s syndrome. Genes mapped to the correlated regions showed enrichment in biological pathways integral to immune-inflammatory function, vesicle trafficking, insulin signalling, oxygen transport, and lipid metabolism. Colocalisation analyses further prioritised 10 genetically correlated regions for likely harbouring shared causal variants, displaying high deleterious or regulatory potential. These variants were found within or in close proximity to genes, such as SLC39A8 and HLA-DRB1, that can be targeted by supplements and already known drugs, including omega-3/6 fatty acids, immunomodulatory, antihypertensive, and cholesterol-lowering drugs. Overall, our findings underscore the complex genetic landscape of IR-neuropsychiatric multimorbidity, advocating for an integrated disease model and offering novel insights for research and treatment strategies in this domain.
Highlights
Local genetic correlations found even in the absence of global correlations.
Both positive and negative local correlations found for IR-neuropsychiatric pairs.
Enrichment for immune, and insulin signalling pathways, among others.
Pinpointed shared likely causal variants within 10 genomic regions.
Identified therapeutic targets, e.g., SLC39A8 and HLA-DRB1, for drug repurposing.
Background: For rheumatoid arthritis (RA), the treat-to-target concept suggests attaining remission or at least low disease activity (LDA) after 12 weeks.
Objectives: This German, prospective, multicenter, non-interventional study aimed to determine the proportion of patients with RA who achieved their treat-to-target aim after 12 and 24 weeks of etanercept (ETN) treatment in a real-life setting, as opposed to patients achieving their therapeutic target at a later timepoint (week 36 or 52).
Methods: A total of 824 adults with a confirmed diagnosis of RA without prior ETN treatment were included. Remission and LDA were defined as DAS28 < 2.6 and DAS28 ≤ 3.2, respectively.
Results: The proportion of patients achieving remission was 24% at week 12 and 31% at week 24. The proportion of patients achieving LDA was 39% at week 12 and 45% at week 24. The proportion of patients achieving remission or LDA further increased beyond week 24 up to week 52. Improvement in pain and reduction in concomitant glucocorticoid treatment were observed. Improvements in patient-reported outcomes were also seen in patients who did not reach remission or LDA. No new safety signals were detected.
Conclusions: A considerable proportion of patients with RA attained the target of remission or LDA after 12 weeks of ETN treatment. Even beyond that timepoint, the proportion of patients achieving treatment targets continued to increase up to week 52.
Trial Registration
ClinicalTrials.gov Identifier: NCT02486302.
Plain Language Summary
Physicians measure response to treatment of rheumatoid arthritis using a disease activity score (DAS28). People with a DAS28 of less than 2.6 have very few to no symptoms (also called remission). People with a DAS28 of 3.2 or less, called low disease activity, may experience mild symptoms. When people do not respond to treatment after 12 weeks, it is usually recommended to prescribe a different treatment. Researchers do not know how many people who do not respond after 12 weeks would respond if treatment were continued. A total of 824 German people with rheumatoid arthritis who received a drug called etanercept for up to 52 weeks took part in this study. Researchers wanted to know how many people had remission or low disease activity after 12 weeks and 24 weeks of treatment.
After 12 weeks, 24 in 100 people had remission; this increased to 31 in 100 people after 24 weeks. Thirty-nine in 100 people had low disease activity after 12 weeks; this increased to 45 in 100 people after 24 weeks. The number of people with remission or low disease activity increased with longer treatment (up to 52 weeks). People needed less additional treatment with a type of drug called glucocorticoids. The people in this study experienced side effects that were similar to those reported by people who took etanercept in previous studies.
The researchers concluded that a considerable proportion of people responded to treatment with etanercept after 12 weeks. This proportion increased when treatment was continued for longer than 12 weeks.
Porous tantalum trabecular metal biomaterial has a similar structure to trabecular bone, and was recently added to titanium dental implants as a surface enhancement. The purpose of this prospective pilot study was to describe 5-year survival results and crestal bone level changes around immediately-provisionalized Trabecular Metal Dental Implants. Eligible patients were adults in need of ≥1 implants in the posterior jaw. A non-occluding single acrylic provisional crown was in place for up to 14 days before final restoration. Clinical evaluations with radiographs were conducted at each follow-up visit (1 month, 3 months, 6 months, and 1 to 5 years). The primary endpoint was implant survival, characterized using the Kaplan-Meier method. The secondary endpoint was changes in crestal bone level, evaluated using a paired t-test to compare mean crestal bone levels between the baseline, 6-month, and annual follow-up values. In total, 30 patients (37 implants) were treated. Mean patient age was 45.5 years, and 63% were female. There was one implant failure; cumulative survival at 5 years was 97.2%. After the initial bone loss of 0.40 mm in the first 6 months, there were no statistically significant changes in crestal bone level over time up to 5 years of follow-up.
Objective: Liver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients.
Design: This international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation.
Results: After screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (AUC 0.8). L-SWE cut-off at ≥20 kPa combined with MELD ≥10 could stratify the risk of mortality and first/further decompensation in ACLD patients. The 2-year mortality and decompensation rates were 36.9% and 61.8%, respectively, in the 305 (18.3%) high-risk patients (with L-SWE ≥20 kPa and MELD ≥10), while in the 944 (56.6%) low-risk patients, these were 1.1% and 3.5%, respectively. Importantly, this M10LS20 algorithm was validated by TE-based LSM and in an additional cohort of 119 patients with valid point shear SWE-LSM.
Conclusion: The M10LS20 algorithm allows risk stratification of patients with ACLD. Patients with L-SWE ≥20 kPa and MELD ≥10 should be followed closely and receive intensified care, while patients with low risk may be managed at longer intervals.
Rationale: Studies have suggested mental health improvements following the use of the psychotropic plant concoction ayahuasca in non-clinical and clinical samples.
Objectives: The present observational study assessed depressive symptomatology in 20 clinically depressed patients (symptom score > 13 on the Beck’s Depression Inventory) before attendance of an ayahuasca ceremony and 1 month and 1 year after. Secondary measures included ratings of altered states of consciousness and ego dissolution during the ayahuasca ceremony as well as global measures of mindfulness, satisfaction with life, depression, anxiety, and stress.
Results: Twenty participants completed baseline and 1-day follow-up, 19 completed measures at 1-month follow-up, and 17 completed measures at 1-year follow-up. BDI scores reduced from baseline (M = 22.7) to all post-ceremony measures (Ms 11.45, 12.89, and 8.88, for 1-day, 1-month, and 1-year follow-up, respectively). After 1 day, 12/20 participants were in remission (BDI < 13). Remission rates after 1 month and 1 year were 13/19 and 12/17, respectively. Three participants remained mildly depressed (BDI 14–19) at the 1-month and 1-year follow-up. Two participants did not respond and remained at a moderate/severe level of depression at 1-year follow-up. Reductions on the secondary mental health measures and increases in mindfulness and satisfaction with life were found up to 1 year post-ceremony. Improvements in clinical depression and mental health correlated with levels of experienced ego dissolution and oceanic boundlessness during the ceremony up to 1 month after the ceremony. Engagement in additional mental health treatments or use of another psychedelic during study participation may have contributed to improved mental health ratings at 1-year follow-up.
Conclusion: Ayahuasca produces long-term mental health improvements in clinically depressed patients, which highlights its therapeutic potential.
Rapidity-odd directed flow measurements at midrapidity are presented for Λ, Λ¯, K±, K0s and ϕ at sNN−−−−√= 7.7, 11.5, 14.5, 19.6, 27, 39, 62.4 and 200 GeV in Au+Au collisions recorded by the STAR detector at the Relativistic Heavy Ion Collider. These measurements greatly expand the scope of data available to constrain models with differing prescriptions for the equation of state of quantum chromodynamics. Results show good sensitivity for testing a picture where flow is assumed to be imposed before hadron formation and the observed particles are assumed to form via coalescence of constituent quarks. The pattern of departure from a coalescence-inspired sum-rule can be a valuable new tool for probing the collision dynamics.
Surface temperature is a fundamental parameter of Earth’s climate. Its evolution through time is commonly reconstructed using the oxygen isotope and the clumped isotope compositions of carbonate archives. However, reaction kinetics involved in the precipitation of carbonates can introduce inaccuracies in the derived temperatures. Here, we show that dual clumped isotope analyses, i.e., simultaneous ∆47 and ∆48 measurements on the single carbonate phase, can identify the origin and quantify the extent of these kinetic biases. Our results verify theoretical predictions and evidence that the isotopic disequilibrium commonly observed in speleothems and scleractinian coral skeletons is inherited from the dissolved inorganic carbon pool of their parent solutions. Further, we show that dual clumped isotope thermometry can achieve reliable palaeotemperature reconstructions, devoid of kinetic bias. Analysis of a belemnite rostrum implies that it precipitated near isotopic equilibrium and confirms the warmer-than-present temperatures during the Early Cretaceous at southern high latitudes.
We report the triton (t) production in Au+Au collisions at sNN−−−√ = 7.7 -- 200 GeV measured at mid-rapidity (|y|< 0.5) by the STAR experiment from the first phase of the beam energy scan at the Relativistic Heavy Ion Collider (RHIC). The nuclear compound yield ratio (Nt×Np/N2d), which is predicted to be sensitive to the local density fluctuation of neutrons, monotonically decreases with increasing charged-particle multiplicity (dNch/dη) and exhibits a scaling behavior. The multiplicity dependence of the yield ratios are compared with calculations from coalescence and thermal models. Relative to the coalescence baseline, enhancements of the yield ratios are observed in the 0%-10% most central collisions at 19.6 and 27 GeV with a significance of 2.3σ and 3.4σ, respectively, with a combined significance of 4.1σ. The measured significance of these enhancements decreases with smaller pT acceptance. The enhancements are not observed in peripheral collisions and model calculations without critical fluctuation. Important implications on the QCD phase structure and the production mechanism of light nuclei in heavy-ion collisions are discussed.