Serotonin Transporter (SLC6A4) and FK506-Binding Protein 5 (FKBP5) Genotype and Methylation Relationships with Response to Meditation in Veterans with PTSD.

Meditation-based interventions are novel and effective non-pharmacologic treatments for veterans with PTSD. We examined relationships between treatment response, early life trauma exposure, DNA polymorphisms, and methylation in the serotonin transporter (SLC6A4) and FK506-binding protein 5 (FKBP5) genes. DNA samples and clinical outcomes were examined in 72 veterans with PTSD who received meditation-based therapy in two separate studies of mindfulness-based stress reduction (MBSR) and Transcendental Meditation (TM). The PTSD Checklist was administered to assess symptoms at baseline and after 9 weeks of meditation intervention. We examined the SLC6A4 promoter (5HTTLPR_L/S insertion/deletion + rs25531_A/G) polymorphisms according to previously defined gene expression groups, and the FKBP5 variant rs1360780 previously associated with PTSD disease risk. Methylation for CpG sites of SLC6A4 (28 sites) and FKBP5 (45 sites) genes was quantified in DNA samples collected before and after treatment. The 5HTTLPR LALA high expression genotype was associated with greater symptom improvement in participants exposed to early life trauma (p = 0.015). Separately, pre to post-treatment change of DNA methylation in a group of nine FKBP5 CpG sites was associated with greater symptom improvement (OR = 2.8, 95% CI 1.1-7.1, p = 0.027). These findings build on a wealth of existing knowledge regarding epigenetic and genetic relationships with PTSD disease risk to highlight the potential importance of SLC6A4 and FKBP5 for treatment mechanisms and as biomarkers of symptom improvement.

Extreme Phenotype Sampling and Next Generation Sequencing to Identify Genetic Variants Associated with Tacrolimus in African American Kidney Transplant Recipients.

African American (AA) kidney transplant recipients (KTRs) have poor outcomes, which may in-part be due to tacrolimus (TAC) sub-optimal immunosuppression. We previously determined the common genetic regulators of TAC pharmacokinetics in AAs which were CYP3A5 *3, *6, and *7. To identify low-frequency variants that impact TAC pharmacokinetics, we used extreme phenotype sampling and compared individuals with extreme high (n=58) and low (n=60) TAC troughs (N=515 AA KTRs). Targeted next generation sequencing was conducted in these two groups. Median TAC troughs in the high group were 7.7 ng/ml compared with 6.3 ng/ml in the low group, despite lower daily doses of 5 versus 12mg, respectively. Of 34,542 identified variants across 99 genes, 1,406 variants were suggestively associated with TAC troughs in univariate models (p-value <0.05), however none were significant after multiple testing correction. We suggest future studies investigate additional sources of TAC pharmacokinetic variability such as drug-drug-gene interactions and pharmacomicrobiome.

Disrupted Structural Brain Networks and Structural-Functional Decoupling in First-Episode Drug-Naïve Adolescent Major Depressive Disorder.

PURPOSE: Major depressive disorder (MDD) tends to emerge during adolescence, but the neurobiology of adolescent MDD is still poorly understood. This study aimed to explore the topological organization of white matter structural networks and the relationship between structural and functional connectivity in adolescent MDD. METHODS: Structural and functional magnetic resonance imaging data were acquired from 94 first-episode drug-naïve adolescent MDD patients and 78 healthy adolescents. Whole brain structural and functional brain networks were constructed for each subject. Then, the topological organization of structural brain networks and the coupling strength between structural and functional connectivity were analyzed. RESULTS: Compared with controls, adolescent MDD patients showed disrupted small-world, rich-club, and modular organizations. Nodal centralities in the medial part of bilateral superior frontal gyrus, bilateral hippocampus, right superior occipital gyrus, right angular gyrus, bilateral precuneus, left caudate nucleus, bilateral putamen, right superior temporal gyrus, and right temporal pole part of superior temporal gyrus were significantly lower in adolescent MDD patients compared with controls. The coupling strength between structural and functional connectivity was significantly lower in adolescent MDD patients compared with controls. DISCUSSION: Our findings suggest widespread disruption of structural brain networks and structural-functional decoupling in adolescent MDD, potentially leading to reduced network communication capacity.

Gene-based association tests in family samples using GWAS summary statistics.

Genome-wide association studies (GWAS) have led to rapid growth in detecting genetic variants associated with various phenotypes. Owing to a great number of publicly accessible GWAS summary statistics, and the difficulty in obtaining individual-level genotype data, many existing gene-based association tests have been adapted to require only GWAS summary statistics rather than individual-level data. However, these association tests are restricted to unrelated individuals and thus do not apply to family samples directly. Moreover, due to its flexibility and effectiveness, the linear mixed model has been increasingly utilized in GWAS to handle correlated data, such as family samples. However, it remains unknown how to perform gene-based association tests in family samples using the GWAS summary statistics estimated from the linear mixed model. In this study, we show that, when family size is negligible compared to the total sample size, the diagonal block structure of the kinship matrix makes it possible to approximate the correlation matrix of marginal Z scores by linkage disequilibrium matrix. Based on this result, current methods utilizing summary statistics for unrelated individuals can be directly applied to family data without any modifications. Our simulation results demonstrate that this proposed strategy controls the type 1 error rate well in various situations. Finally, we exemplify the usefulness of the proposed approach with a dental caries GWAS data set.

Disrupted small-world white matter networks in patients with major depression and recent suicide plans or attempts.

Suicide is a major concern for health, and depression is an established proximal risk factor for suicide. This study aimed to investigate white matter features associated with suicide. We constructed white matter structural networks by deterministic tractography via diffusion tensor imaging in 51 healthy controls, 47 depressed patients without suicide plans or attempts and 56 depressed patients with suicide plans or attempts. Then, graph theory analysis was used to measure global and nodal network properties. We found that local efficiency was decreased and path length was increased in suicidal depressed patients compared to healthy controls and non-suicidal depressed patients; moreover, the clustering coefficient was decreased in depressed patients compared to healthy controls; and the global efficiency and normalized characteristic path length was increased in suicidal depressed patients compared to healthy controls. Similarly, compared with those in non-suicidal depressed patients, nodal efficiency in the thalamus, caudate, medial orbitofrontal cortex, hippocampus, olfactory cortex, supplementary motor area and Rolandic operculum was decreased. In summary, compared with those of non-suicidal depressed patients, the structural connectome of suicidal depressed patients exhibited weakened integration and segregation and decreased nodal efficiency in the fronto-limbic-basal ganglia-thalamic circuitry. These alterations in the structural networks of depressed suicidal brains provide insights into the underlying neurobiology of brain features associated with suicide.

Transcriptional Patterns of Brain Structural Covariance Network Abnormalities Associated With Suicidal Thoughts and Behaviors in Major Depressive Disorder.

BACKGROUND: Although brain structural covariance network (SCN) abnormalities have been associated with suicidal thoughts and behaviors (STBs) in individuals with major depressive disorder (MDD), previous studies have reported inconsistent findings based on small sample sizes, and underlying transcriptional patterns remain poorly understood. METHODS: Using a multicenter magnetic resonance imaging dataset including 218 MDD patients with STBs, 230 MDD patients without STBs, and 263 healthy control participants, we established individualized SCNs based on regional morphometric measures and assessed network topological metrics using graph theoretical analysis. Machine learning methods were applied to explore and compare the diagnostic value of morphometric and topological features in identifying MDD and STBs at the individual level. Brainwide relationships between STBs-related connectomic alterations and gene expression were examined using partial least squares regression. RESULTS: Group comparisons revealed that SCN topological deficits associated with STBs were identified in the prefrontal, anterior cingulate, and lateral temporal cortices. Combining morphometric and topological features allowed for individual-level characterization of MDD and STBs. Topological features made a greater contribution to distinguishing between patients with and without STBs. STBs-related connectomic alterations were spatially correlated with the expression of genes enriched for cellular metabolism and synaptic signaling. CONCLUSIONS: These findings revealed robust brain structural deficits at the network level, highlighting the importance of SCN topological measures in characterizing individual suicidality and demonstrating its linkage to molecular function and cell types, providing novel insights into the neurobiological underpinnings and potential markers for prediction and prevention of suicide.

Abnormal intrinsic brain functional network dynamics in first-episode drug-naïve adolescent major depressive disorder.

BACKGROUND: Alterations in brain functional connectivity (FC) have been frequently reported in adolescent major depressive disorder (MDD). However, there are few studies of dynamic FC analysis, which can provide information about fluctuations in neural activity related to cognition and behavior. The goal of the present study was therefore to investigate the dynamic aspects of FC in adolescent MDD patients. METHODS: Resting-state functional magnetic resonance imaging data were acquired from 94 adolescents with MDD and 78 healthy controls. Independent component analysis, a sliding-window approach, and graph-theory methods were used to investigate the potential differences in dynamic FC properties between the adolescent MDD patients and controls. RESULTS: Three main FC states were identified, State 1 which was predominant, and State 2 and State 3 which occurred less frequently. Adolescent MDD patients spent significantly more time in the weakly-connected and relatively highly-modularized State 1, spent significantly less time in the strongly-connected and low-modularized State 2, and had significantly higher variability of both global and local efficiency, compared to the controls. Classification of patients with adolescent MDD was most readily performed based on State 1 which exhibited disrupted intra- and inter-network FC involving multiple functional networks. CONCLUSIONS: Our study suggests local segregation and global integration impairments and segregation-integration imbalance of functional networks in adolescent MDD patients from the perspectives of dynamic FC. These findings may provide new insights into the neurobiology of adolescent MDD.

Effects of inflammation, childhood adversity, and psychiatric symptoms on brain morphometrical phenotypes in bipolar II depression.

BACKGROUND: The neuroanatomical alteration in bipolar II depression (BDII-D) and its associations with inflammation, childhood adversity, and psychiatric symptoms are currently unclear. We hypothesize that neuroanatomical deficits will be related to higher inflammation, greater childhood adversity, and worse psychiatric symptoms in BDII-D. METHODS: Voxel- and surface-based morphometry was performed using the CAT toolbox in 150 BDII-D patients and 155 healthy controls (HCs). Partial Pearson correlations followed by multiple comparison correction was used to indicate significant relationships between neuroanatomy and inflammation, childhood adversity, and psychiatric symptoms. RESULTS: Compared with HCs, the BDII-D group demonstrated significantly smaller gray matter volumes (GMVs) in frontostriatal and fronto-cerebellar area, insula, rectus, and temporal gyrus, while significantly thinner cortices were found in frontal and temporal areas. In BDII-D, smaller GMV in the right middle frontal gyrus (MFG) was correlated with greater sexual abuse (r = -0.348, q < 0.001) while larger GMV in the right orbital MFG was correlated with greater physical neglect (r = 0.254, q = 0.03). Higher WBC count (r = -0.227, q = 0.015) and IL-6 levels (r = -0.266, q = 0.015) was associated with smaller GMVs in fronto-cerebellar area in BDII-D. Greater positive symptoms was correlated with larger GMVs of the left middle temporal pole (r = 0.245, q = 0.03). CONCLUSIONS: Neuroanatomical alterations in frontostriatal and fronto-cerebellar area, insula, rectus, temporal gyrus volumes, and frontal-temporal thickness may reflect a core pathophysiological mechanism of BDII-D, which are related to inflammation, trauma, and psychiatric symptoms in BDII-D.

Heterogeneity in familial clustering of metabolic syndrome components in the multiethnic GENNID study.

OBJECTIVE: Metabolic syndrome (MetS) is defined by clustering of cardiometabolic components, which may be present in different combinations. The authors evaluated clustering in individuals and extended families within and across ancestry groups. METHODS: The prevalence of different combinations of MetS components (high fasting glucose, low high-density lipoprotein cholesterol, high triglycerides, high blood pressure, and abdominal obesity) was estimated in 1651 individuals (340 families) self-reporting as European American (EA), Hispanic/Mexican American (MA), African American (AA), and Japanese American (JA). Odds ratios were estimated using logistic regression with generalized estimating equations comparing individual MetS components, number, and combinations of components for each ancestry group versus EA. RESULTS: Clustering of all five components (Combination #16) was more prevalent in EA (29.9%) and MA (25.2%) individuals than in AA (18.7%) and JA (15.5%) individuals. Compared with EA individuals, AA individuals were 64% and 66% less likely to have high triglycerides and low high-density lipoprotein cholesterol, whereas JA individuals were 85% and 56% less likely to have abdominal obesity and high blood pressure, respectively. Compared with EA individuals, the odds of having two, four, or five components were at least 77% lower in JA individuals, whereas the odds of having three, four, or five components were at least 3.79 times greater in MA individuals. CONCLUSIONS: Understanding heterogeneity in MetS clustering may identify factors important in reducing health disparities.

Transcriptomics reveals a core transcriptional network of K-type cytoplasmic male sterility microspore abortion in wheat (Triticum aestivum L.).

BACKGROUND: Cytoplasmic male sterility (CMS) plays a crucial role in hybrid production. K-type CMS, a cytoplasmic male sterile line of wheat with the cytoplasms of Aegilops kotschyi, is widely used due to its excellent characteristics of agronomic performance, easy maintenance and easy restoration. However, the mechanism of its pollen abortion is not yet clear. RESULTS: In this study, wheat K-type CMS MS(KOTS)-90-110 (MS line) and it's fertile near-isogenic line MR (KOTS)-90-110 (MR line) were investigated. Cytological analysis indicated that the anthers of MS line microspore nucleus failed to divide normally into two sperm nucleus and lacked starch in mature pollen grains, and the key abortive period was the uninucleate stage to dinuclear stage. Then, we compared the transcriptome of MS line and MR line anthers at these two stages. 11,360 and 5182 differentially expressed genes (DEGs) were identified between the MS and MR lines in the early uninucleate and binucleate stages, respectively. Based on GO enrichment and KEGG pathways analysis, it was evident that significant transcriptomic differences were "plant hormone signal transduction", "MAPK signaling pathway" and "spliceosome". We identified 17 and 10 DEGs associated with the IAA and ABA signal transduction pathways, respectively. DEGs related to IAA signal transduction pathway were downregulated in the early uninucleate stage of MS line. The expression level of DEGs related to ABA pathway was significantly upregulated in MS line at the binucleate stage compared to MR line. The determination of plant hormone content and qRT-PCR further confirmed that hormone imbalance in MS lines. Meanwhile, 1 and 2 DEGs involved in ABA and Ethylene metabolism were also identified in the MAPK cascade pathway, respectively; the significant up regulation of spliceosome related genes in MS line may be another important factor leading to pollen abortion. CONCLUSIONS: We proposed a transcriptome-mediated pollen abortion network for K-type CMS in wheat. The main idea is hormone imbalance may be the primary factor, MAPK cascade pathway and alternative splicing (AS) may also play important regulatory roles in this process. These findings provided intriguing insights for the molecular mechanism of microspore abortion in K-type CMS, and also give useful clues to identify the crucial genes of CMS in wheat.

Altered single-subject gray matter structural networks in first-episode drug-naïve adolescent major depressive disorder.

Although previous studies have demonstrated regional gray matter (GM) structural abnormalities in adolescents with major depressive disorder (MDD), how the topological organization of GM networks is affected in these patients is still unclear. Structural magnetic resonance imaging data were acquired from 100 first-episode drug-naïve adolescent MDD patients and 80 healthy controls (HCs). Whole-brain GM structural network was constructed for each subject, and a graph theory analysis was used to calculate the topological metrics of GM networks. Adolescent MDD patients showed significantly lower cluster coefficient and local efficiency compared to HCs. Compared to controls, adolescent MDD patients showed higher nodal centralities in the bilateral cuneus, left lingual gyrus, and right middle occipital gyrus and lower nodal centralities in the bilateral dorsolateral superior frontal gyrus, bilateral middle frontal gyrus, right anterior cingulate and paracingulate gyri, bilateral hippocampus, bilateral amygdala, bilateral caudate nucleus, and bilateral thalamus. Nodal centralities of the hippocampus were negatively associated with symptom severity and illness duration. Our findings suggest disrupted topological organization of GM structural networks in adolescent MDD patients. Impaired local segregation and abnormal nodal centralities in the prefrontal-subcortical-limbic areas and visual cortex regions may play important roles in the neurobiology of adolescent-onset MDD.

Distinct gray matter abnormalities in children/adolescents and adults with history of childhood maltreatment.

Gray matter (GM) abnormalities have been reported in both adults and children/adolescents with histories of childhood maltreatment (CM). A comparison of effects in youth and adulthood may be informative regarding life-span effects of CM. Voxel-wise meta-analyses of whole-brain voxel-based morphometry studies were conducted in all datasets and age-based subgroups respectively, followed by a quantitative comparison of the subgroups. Thirty VBM studies (31 datasets) were included. The pooled meta-analysis revealed increased GM in left supplementary motor area, and reduced GM in bilateral cingulate/paracingulate gyri, left occipital lobe, and right middle frontal gyrus in maltreated individuals compared to the controls. Maltreatment-exposed youth showed less GM in the cerebellum, and greater GM in bilateral middle cingulate/paracingulate gyri and bilateral visual cortex than maltreated adults. Opposite GM alterations in bilateral middle cingulate/paracingulate gyri were found in maltreatment-exposed adults (decreased) and children/adolescents (increased). Our findings demonstrate different patterns of GM changes in youth closer to maltreatment events than those seen later in life, suggesting detrimental effects of CM on the developmental trajectory of brain structure.

Analysis of Veno-Venous Extracorporeal Membrane Oxygenation for COVID-19 Compared to Non-COVID Etiologies.

OBJECTIVE: This study analyzed the characteristics and outcomes of veno-venous (V-V) extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS) due to COVID-19 versus non-COVID causes at US academic centers. BACKGROUND DATA: V-V ECMO support has been utilized for COVID-19 patients with ARDS since the beginning of the pandemic. Mortality for ECMO in COVID-19 has been reported to be high but similar to reported mortality for ECMO support for non-COVID causes of respiratory failure. METHODS: Using ICD-10 codes, data of patients who underwent V-V ECMO for COVID-19 ARDS were compared with patients who underwent V-V ECMO for non-COVID causes between April 2020 and December 2022. The primary outcome was in-hospital mortality. Secondary outcome measures included length of stay and direct cost. Multivariate logistic regression modeling was performed to analyze differences in mortality between COVID and non-COVID groups, adjusting for other important risk factors (age, sex, and race/ethnicity). RESULTS: We identified and compared 6382 patients who underwent V-V ECMO for non-COVID causes to 6040 patients who underwent V-V ECMO for COVID-19. There was a significantly higher proportion of patients aged ≥ 65 years who underwent V-V ECMO in the non-COVID group compared with the COVID group (19.8% vs. 3.7%, respectively, P <0.001). Compared with patients who underwent V-V ECMO for non-COVID causes, patients who underwent V-V ECMO for COVID had increased in-hospital mortality (47.6% vs. 34.5%, P <0.001), length of stay (46.5±41.1 days vs. 40.6±46.1, P <0.001), and direct hospitalization cost ($207,022±$208,842 vs. $198,508±205,510, P =0.02). Compared with the non-COVID group, the adjusted odds ratio (OR) for in-hospital mortality in the COVID group was 2.03 (95% CI: 1.87-2.20, P <0.001). In-hospital mortality for V-V ECMO in COVID-19 improved during the study time period (50.3% in 2020, 48.6% in 2021, and 37.3% in 2022). However, there was a precipitous drop in the ECMO case volume for COVID starting in quarter 2 of 2022. CONCLUSIONS: In this nationwide analysis, COVID-19 patients with ARDS requiring V-V ECMO support had increased mortality compared with patients who underwent V-V ECMO for non-COVID etiologies.

Altered brain activity in patients with end-stage renal disease: A meta-analysis of resting-state functional imaging.

INTRODUCTION: Previous studies have revealed abnormal resting-state brain activity in patients with end-stage renal disease (ESRD); however, the results are inconsistent. Thus, we conducted a coordinate-based meta-analysis of whole-brain resting-state functional neuroimaging studies in ESRD to identify the most consistent neural activity alterations in ESRD patients and explore their relation to serological indicators. METHODS: A comprehensive literature search strategy was applied to select pertinent studies up to December 2022 in PubMed, Web of Science, and Embase databases. Voxel-wise meta-analysis was conducted via the latest meta-analytic algorithm, seed-based d mapping with permutation of subject images software. Meta-regression analyses were also conducted to explore the potential effect of clinical variables on resting-state neural activity. RESULTS: Eleven studies comprising 304 patients with ESRD and 296 healthy controls (HCs) were included. Compared with HCs, ESRD patients showed decreased brain activity in the default mode network (DMN) regions, including the bilateral anterior cingulate cortex/medial prefrontal cortex, bilateral midcingulate cortex/posterior cingulate cortex, bilateral precuneus, and right angular gyrus. The neural activities in the bilateral midcingulate cortex, bilateral midcingulate cortex/posterior cingulate cortex, and right angular gyrus were significantly associated with serological indexes including hemoglobin, urea, and creatinine levels. CONCLUSION: The present study provides a quantitative overview of brain activity alterations in patients with ESRD, and the results confirm the essential role of the DMN in ESRD patients, which may be the potential neural basis of their cognitive deficits. Additionally, some serological indicators may be used as predictive markers for progressive impairment of brain function.

Integrating multiple traits for improving polygenic risk prediction in disease and pharmacogenomics GWAS.

Polygenic risk score (PRS) has been recently developed for predicting complex traits and drug responses. It remains unknown whether multi-trait PRS (mtPRS) methods, by integrating information from multiple genetically correlated traits, can improve prediction accuracy and power for PRS analysis compared with single-trait PRS (stPRS) methods. In this paper, we first review commonly used mtPRS methods and find that they do not directly model the underlying genetic correlations among traits, which has been shown to be useful in guiding multi-trait association analysis in the literature. To overcome this limitation, we propose a mtPRS-PCA method to combine PRSs from multiple traits with weights obtained from performing principal component analysis (PCA) on the genetic correlation matrix. To accommodate various genetic architectures covering different effect directions, signal sparseness and across-trait correlation structures, we further propose an omnibus mtPRS method (mtPRS-O) by combining P values from mtPRS-PCA, mtPRS-ML (mtPRS based on machine learning) and stPRSs using Cauchy Combination Test. Our extensive simulation studies show that mtPRS-PCA outperforms other mtPRS methods in both disease and pharmacogenomics (PGx) genome-wide association studies (GWAS) contexts when traits are similarly correlated, with dense signal effects and in similar effect directions, and mtPRS-O is consistently superior to most other methods due to its robustness under various genetic architectures. We further apply mtPRS-PCA, mtPRS-O and other methods to PGx GWAS data from a randomized clinical trial in the cardiovascular domain and demonstrate performance improvement of mtPRS-PCA in both prediction accuracy and patient stratification as well as the robustness of mtPRS-O in PRS association test.

Gray matter alterations in adolescent major depressive disorder and adolescent bipolar disorder.

BACKGROUND: Gray matter volume (GMV) alterations in several emotion-related brain areas are implicated in mood disorders, but findings have been inconsistent in adolescents with major depressive disorder (MDD) or bipolar disorder (BD). METHODS: We conducted a comprehensive meta-analysis of 35 region-of-interest (ROI) and 18 whole-brain voxel-based morphometry (VBM) MRI studies in adolescent MDD and adolescent BD, and indirectly compared the results in the two groups. The effects of age, sex, and other demographic and clinical scale scores were explored using meta-regression analysis. RESULTS: In the ROI meta-analysis, right putamen volume was decreased in adolescents with MDD, while bilateral amygdala volume was decreased in adolescents with BD compared to healthy controls (HC). In the whole-brain VBM meta-analysis, GMV was increased in right middle frontal gyrus and decreased in left caudate in adolescents with MDD compared to HC, while in adolescents with BD, GMV was increased in left superior frontal gyrus and decreased in limbic regions compared with HC. MDD vs BD comparison revealed volume alteration in the prefrontal-limbic system. LIMITATION: Different clinical features limit the comparability of the samples, and small sample size and insufficient clinical details precluded subgroup analysis or meta-regression analyses of these variables. CONCLUSIONS: Distinct patterns of GMV alterations in adolescent MDD and adolescent BD could help to differentiate these two populations and provide potential diagnostic biomarkers.

Higher number of tacrolimus dose adjustments in kidney transplant recipients who are extensive and intermediate CYP3A5 metabolizers.

Kidney transplant recipients carrying the CYP3A5*1 allele have lower tacrolimus troughs, and higher dose requirements compared to those with the CYP3A5*3/*3 genotype. However, data on the effect of CYP3A5 alleles on post-transplant tacrolimus management are lacking. The effect of CYP3A5 metabolism phenotypes on the number of tacrolimus dose adjustments and troughs in the first 6 months post-transplant was evaluated in 78 recipients (64% Caucasians). Time to first therapeutic concentration, percentage of time in therapeutic range (TTR), and estimated glomerular filtration rate (eGFR) were also evaluated. Fifty-five kidney transplant recipients were CYP3A5 poor metabolizers (PM), 17 were intermediate metabolizers (IM), and 6 were extensive metabolizers (EM). Compared to PMs, EMs/IMs had significantly more dose adjustments (6.1 vs. 8.1, p = .015). Overall, 33.82% of trough measurements resulted in a dose change. There was no difference in the number of tacrolimus trough measurements between PMs and EM/IMs. The total daily tacrolimus dose requirements were higher in EMs and IMs compared to PMs (<.001). TTR was ∼50% in the PMs and EMs/IMs groups. CYP3A5 EM/IM metabolizers have more tacrolimus dose changes and higher dose requirements which increases clinical management complexity. Larger studies are needed to assess the cost and benefits of including genotyping data to improve clinical management.

Large-scale brain functional network abnormalities in social anxiety disorder.

BACKGROUND: Although aberrant brain regional responses are reported in social anxiety disorder (SAD), little is known about resting-state functional connectivity at the macroscale network level. This study aims to identify functional network abnormalities using a multivariate data-driven method in a relatively large and homogenous sample of SAD patients, and assess their potential diagnostic value. METHODS: Forty-six SAD patients and 52 demographically-matched healthy controls (HC) were recruited to undergo clinical evaluation and resting-state functional MRI scanning. We used group independent component analysis to characterize the functional architecture of brain resting-state networks (RSNs) and investigate between-group differences in intra-/inter-network functional network connectivity (FNC). Furtherly, we explored the associations of FNC abnormalities with clinical characteristics, and assessed their ability to discriminate SAD from HC using support vector machine analyses. RESULTS: SAD patients showed widespread intra-network FNC abnormalities in the default mode network, the subcortical network and the perceptual system (i.e. sensorimotor, auditory and visual networks), and large-scale inter-network FNC abnormalities among those high-order and primary RSNs. Some aberrant FNC signatures were correlated to disease severity and duration, suggesting pathophysiological relevance. Furthermore, intrinsic FNC anomalies allowed individual classification of SAD v. HC with significant accuracy, indicating potential diagnostic efficacy. CONCLUSIONS: SAD patients show distinct patterns of functional synchronization abnormalities both within and across large-scale RSNs, reflecting or causing a network imbalance of bottom-up response and top-down regulation in cognitive, emotional and sensory domains. Therefore, this could offer insights into the neurofunctional substrates of SAD.

Omentin-1 promotes mitochondrial biogenesis via PGC1α-AMPK pathway in chondrocytes.

OBJECTIVE: Omentin-1 is a newly discovered metabolic regulatory adipokine. Studies have shown that omentin-1 possesses pleiotropic effects in different types of cells. This study aims to investigate the regulation by omentin-1 on mitochondrial biogenesis in chondrocytes. METHODOLOGY: C-28/I2 chondrocytes were treated with omentin-1 (150 and 300 ng/ml) for 24 h. The expression of mitochondrial regulators, markers and the DNA copy was assessed. The mitochondrial morphology was observed by electron microscopy. The mitochondrial respiratory rate and ATP production in chondrocytes were measured by cell lysates. RESULTS: Omentin-1 treatment up-regulated PGC-1α, NRF-1 and mitochondrial transcription factor A (TFAM) in cultured chondrocytes, indicating that omentin-1 could be involved in the regulation of mitochondrial function. Omentin-1 promoted mtDNA/nDNA and four mitochondrial genes (Tomm20, Tomm40, Timm9 and Atp5c1), mRNA transcripts as well as two mitochondrial protein expressions (SDHB and MTCO1). At a cellular level, omentin-1 enhanced the mitochondrial respiratory rate and ATP production. Mechanistically, we proved that omentin-1 increased AMPKα activation, and the blockage of AMPKα by its inhibitor compound C abolished the inductive effect of omentin-1 on PGC1α expression and mtDNA/nDNA ratio, indicating that the effect of omentin-1 is dependent on AMPKα activation. CONCLUSION: Omentin-1 is a positive regulator of mitochondrial biogenesis in chondrocytes, and its action is dependent on the AMPK-PGC1α pathway. This study, therefore, implies that omentin-1 has the potential to remedy chondrocyte damage in the prevention and treatment of osteoarthritis.

MOVER-R and Penalized MOVER-R Confidence Intervals for the Ratio of Two Quantities.

Developing a confidence interval for the ratio of two quantities is an important task in statistics because of its omnipresence in real world applications. For such a problem, the MOVER-R (method of variance recovery for the ratio) technique, which is based on the recovery of variance estimates from confidence limits of the numerator and the denominator separately, was proposed as a useful and efficient approach. However, this method implicitly assumes that the confidence interval for the denominator never includes zero, which might be violated in practice. In this article, we first use a new framework to derive the MOVER-R confidence interval, which does not require the above assumption and covers the whole parameter space. We find that MOVER-R can produce an unbounded confidence interval, just like the well-known Fieller method. To overcome this issue, we further propose the penalized MOVER-R. We prove that the new method differs from MOVER-R only at the second order. It, however, always gives a bounded and analytic confidence interval. Through simulation studies and a real data application, we show that the penalized MOVER-R generally provides a better confidence interval than MOVER-R in terms of controlling the coverage probability and the median width.