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Efavirenz and CYP2C9 Genetic Polymorphisms Reduce CYP2C9 Activity in Healthy Participants
No full textEfavirenz's effects on cytochrome P450 2C9 (CYP2C9) activity have not been formally characterized in vivo. We conducted the first clinical drug-drug interaction (DDI) study to test the effect of chronic efavirenz dosing on CYP2C9 activity, using tolbutamide as a selective probe. Healthy participants received a single oral dose of tolbutamide (250 mg) with a single 600 mg dose of efavirenz (SD) before and after 600 mg daily efavirenz for 17 days (MD). Tolbutamide, efavirenz, and their metabolites were quantified in plasma and urine samples by LC-MS/MS method. Participants were genotyped for CYP2C9*2 and *3 and for CYP2B6*4, *9, and *18. Pharmacokinetic data were valid for 71 and 59 participants for SD- and MD groups, respectively. MD efavirenz caused more than 50% increase in median tolbutamide AUC0-∞ and C24 in all subjects, and 1.42-1.46-fold increase in the paired analysis (p < 0.0001); tolbutamide/metabolite ratios were also increased (p < 0.001), while tolbutamide's CL/F/kg, metabolite formation clearance, and metabolite Cmax were significantly reduced. CYP2C9 genetic variants were associated with reduced tolbutamide elimination compared to *1/*1 and *1/*2 (slowest, *3/*3; and intermediate, *1/*3, *2/*2, and *2/*3). The lowest percent change occurred in *2/*2 and *3/*3 genotypes, though small sample sizes limited reliable assessment of genotype-specific DDI effects. In conclusion, chronic efavirenz use inhibits CYP2C9 activity in vivo. This inhibition may increase the risk of adverse effects from narrow-therapeutic-index CYP2C9 substrates (e.g., warfarin, phenytoin, and sulfonylureas). Therefore, therapeutic drug monitoring and dose adjustments are warranted when efavirenz is co-administered with these medications
Indiana's 2024 Behavioral Health and Human Services Workforce Snapshot: Licensed Mental Health Counselor
No full textThis document is a 2024 data snapshot of actively practicing Licensed Mental Health Counselors (LMHCs) in Indiana within the Behavioral Health and Human Services workforce. It reports the total number of active LMHCs (2,395) and identifies primary practice settings, with the largest share working in private practice, followed by community mental health centers and telehealth. The document also highlights core services provided, particularly general counseling and mental health diagnosis, and identifies key populations served, with a predominant focus on adults and individuals in recovery
Qualitative Research Checklist
No full textThis worksheet combines qualitative reporting criteria into a checklist that can be utilized by authors and reviewers to ensure each element is addressed within the methods description of qualitative research
Evaluating white matter microstructure in aging and age‐related cognitive impairment: A comparison of free‐water and NODDI ISOVF diffusion models
No full textBackground:
White matter (WM) abnormalities are prevalent in aging and neurodegenerative cognitive decline. This study compares single‐shell free‐water (FW) imaging and multi‐shell NODDI Isotropic Volume Fraction (ISOVF) in assessing WM microstructure and their associations with cognitive decline.
Methods:
FW and ISOVF were quantified across 48 white matter tracts in cognitively unimpaired (CU) and impaired (MCI and AD dementia) individuals from ADNI and VMAP. Multi‐shell dMRI data (b=1000, 2000 s/mm2) were collated from 139 ADNI‐3 participants (age=75.9 ± 6.7; 56.8% female; 92.1% NHW) and 437 VMAP participants (age=65.8 ± 9.3; 57.0% female; 78.0% NHW). Memory and executive function composites were harmonized using ComBat. Covariates included age, sex, years of education, race, clinical status, and ApoE‐ε4 positivity. Analyses included linear correlations between FW and ISOVF, group comparisons, and age modeling via general linear models. Linear regression examined associations between tract‐specific metrics and cognitive composites, with bootstrapped comparisons testing differences in R2adj values between FW and ISOVF models.
Results:
FW and ISOVF showed strong correlations across key white matter tracts (Figure 1), particularly in transcallosal (TC) pathways, with the highest correlations in the calcarine sulcus TC (r=0.784), lingual gyrus TC (r=0.780), and ILF (r=0.775). Group‐wise analyses revealed significant CU vs. MCI differences in all 48 tracts, most notably in the ILF (FW: p = 1.05×10‐15) and temporoparietal SLF (ISOVF: p = 4.36×10‐14). Age effects were significant across all 96 measures, with FW explaining marginally greater variance than ISOVF. The highest R2adj values were in the ILF for FW (54.82%) and ISOVF (47.73%). FW in the lateral (42.93%) and anterior (47.84%) orbital gyri TC best explained memory variance, while FW in the ILF (51.98%) and ISOVF in the inferior parietal lobule TC (51.59%) best explained executive function. Bootstrapped comparisons identified significant R2adj differences between FW and ISOVF in 10 tracts for memory and 14 tracts for executive function, including the ILF, SLF, UF, and superior temporal gyrus TC.
Conclusion:
Both bi‐tensor FW and NODDI ISOVF showed robust associations with age and cognitive performance, varying in magnitude and tract specificity. FW and ISOVF provided largely comparable insights, highlighting their complementary value for understanding white matter health in neurodegenerative research
No significant associations between history of head injury and Alzheimer’s disease fluid biomarkers in older adults
No full textBackground:
Concussions are gaining attention as a risk factor for Alzheimer’s disease (AD). Previous reports suggest concussion, also called head injury (HI), may be associated with changes to AD biomarkers, including amyloid and tau. However, there has been little characterization of biofluid biomarkers in older adults with remote history of HI.
Objective:
We investigated whether aging participants at risk for AD with self-reported HI history would demonstrate alterations to cerebrospinal fluid (CSF) and blood plasma biomarkers of AD.
Methods:
Using two-way ANCOVAs and linear mixed effects models, we examined both baseline cross-sectional and longitudinal associations between HI history, cognition, and AD biofluid biomarkers in 100 participants with HI history compared to 2411 without HI history from the ADNI dataset.
Results:
On baseline analysis, participants with HI history had higher CSF Aβ42/40 ratios than non-HI participants. There were no other baseline differences in biomarkers between HI and non-HI participants, nor were there any main effects of HI upon longitudinal analysis. We observed consistent main effects of age and cognitive impairment that suggested a pattern of worsened AD biomarker signatures in impaired participants with increasing age.
Conclusions:
Our findings do not support an association between self-reported HI history and AD fluid biomarkers in older adults from the ADNI dataset. Further characterization of fluid biomarker trajectories both in the acute post-HI period and in participants with remote HI is needed to understand the temporal dynamics of fluid biomarkers after HI and the implications of HI for AD risk
Modeling Pressure‐Dependent Wave and Vessel Compliance in the Brain Following Middle Cerebral Artery Occlusion
No full textObjective: This study demonstrates the impact of alterations in pressure, vascular compliance, arterial pulsatility, and autoregulation on tissue perfusion following middle cerebral artery (MCA) occlusion using mathematical modeling.
Methods: Our previous mathematical model of the cerebral circulation is expanded to include vessel compliance and pulsatility of blood flow. An experimentally-obtained pressure waveform is used as an incoming boundary condition to simulate the effects of vascular compliance and pulsatility of flow on perfusion following MCA occlusion. The waveform is adjusted to model the effects of elevated mean arterial pressure.
Results: Increased distensibility reduces the amplitude of oscillations in the time-dependent pressure solutions, whereas decreased distensibility produces more variation in these pressures. Occlusion significantly alters the magnitude of flow changes when incoming pressure is varied. The addition of the pulsatile pressure boundary condition and capacitances in the arteries and veins shifts the autoregulation plateau to higher pressures.
Conclusions: This study reveals how changes in incoming pressure affect compensatory responses to ischemic stroke caused by MCA occlusion. Boundary conditions corresponding to elevated mean arterial pressures are associated with lower degrees of ischemia, an improvement that is supported by changes in autoregulation patterns following occlusion. The results also demonstrate how increases in arterial stiffness associated with aging can inhibit the ability of the vasculature to accommodate pulsatile flow by analyzing resulting patterns such as larger amplitudes of pressure and flow oscillations in the microcirculation. The study provides a foundation for modeling the relationships among vessel compliance, arterial blood pressure, and cerebrovascular conditions
The Cost and Management of Chronic Pain
No full textIUIChronic pain is a significant public health problem in the United States, affecting more than 50 million adults. It ranks among the costliest chronic health conditions due to high healthcare utilization, disability rates, and lost worker productivity. Most patients with chronic pain are managed in primary care. Yet, primary care clinicians face significant barriers when managing patients with chronic pain, as they navigate patients’ multifaceted pain histories under time constraints. Digital health technology, such as clinical decision support (CDS) systems can provide PCCs with relevant patient information through streamlined workflows to improve care, yet they are often underutilized. At the same time, there is a lack of evidence on the national incremental healthcare costs of chronic pain, making it challenging to allocate limited healthcare resources effectively. Thus, there is a significant need for evidence to guide both economic and digital health technology strategies to improve pain care for millions of adults with chronic pain.
This dissertation addresses critical gaps in the cost and CDS system management of chronic pain by: 1) estimating the incremental annual healthcare costs associated with chronic pain using nationally representative data; 2) examining how primary care clinician characteristics moderate the relationship between patient encounter characteristics and CDS system use; and (3) evaluating the effect of CDS use at a patient encounter on guideline-recommended chronic pain management. Findings from the cost analysis can help policymakers and health systems more accurately target investments in chronic pain care and assess the value of intervention strategies. Findings from studies on CDS system use provide actionable insights to inform the design, targeting, and implementation of digital health technologies that enable more efficient, evidence-based care for patients with chronic pain
A Unified Continuous Staging Framework for Alzheimer’s Disease and Lewy Body Dementia via Hierarchical Anatomical Features
No full textAlzheimer's Disease (AD) and Lewy Body Dementia (LBD) often exhibit overlapping pathologies, leading to common symptoms that make diagnosis challenging and protracted in clinical settings. While many studies achieve promising accuracy in identifying AD and LBD at earlier stages, they often focus on discrete classification rather than capturing the gradual nature of disease progression. Since dementia develops progressively, understanding the continuous trajectory of dementia is crucial, as it allows us to uncover hidden patterns in cognitive decline and provides critical insights into the underlying mechanisms of disease progression. To address this gap, we propose a novel multi-scale learning framework that leverages hierarchical anatomical features to model the continuous relationships across various neurodegenerative conditions, including Mild Cognitive Impairment, AD, and LBD. Our approach employs the proposed hierarchical graph embedding fusion technique, integrating anatomical features, cortical folding patterns, and structural connectivity at multiple scales. This integration captures both fine-grained and coarse anatomical details, enabling the identification of subtle patterns that enhance differentiation between dementia types. Additionally, our framework projects each subject onto continuous tree structures, providing intuitive visualizations of disease trajectories and offering a more interpretable way to track cognitive decline. To validate our approach, we conduct extensive experiments on our in-house dataset of 308 subjects spanning multiple groups. Our results demonstrate that the proposed tree-based model effectively represents dementia progression, achieves promising performance in intricate classification task of AD and LBD, and highlights discriminative brain regions that contribute to the differentiation between dementia types. Our code is available at https://github.com/tongchen2010/haff
Mapping the genetic landscape across 14 psychiatric disorders
No full textPsychiatric disorders display high levels of comorbidity and genetic overlap1,2, challenging current diagnostic boundaries. For disorders for which diagnostic separation has been most debated, such as schizophrenia and bipolar disorder3, genomic methods have revealed that the majority of genetic signal is shared4. While over a hundred pleiotropic loci have been identified by recent cross-disorder analyses5, the full scope of shared and disorder-specific genetic influences remains poorly defined. Here we addressed this gap by triangulating across a suite of cutting-edge statistical and functional genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders (1,056,201 cases). Using genetic association data from common variants, we identified and characterized five underlying genomic factors that explained the majority of the genetic variance of the individual disorders (around 66% on average) and were associated with 238 pleiotropic loci. The two factors defined by (1) Schizophrenia and bipolar disorders (SB factor); and (2) major depression, PTSD and anxiety (Internalizing factor) showed high levels of polygenic overlap6 and local genetic correlation and very few disorder-specific loci. The genetic signal shared across all 14 disorders was enriched for broad biological processes (for example, transcriptional regulation), while more specific pathways were shared at the level of the individual factors. The shared genetic signal across the SB factor was substantially enriched in genes expressed in excitatory neurons, whereas the Internalizing factor was associated with oligodendrocyte biology. These observations may inform a more neurobiologically valid psychiatric nosology and implicate targets for therapeutic development designed to treat commonly occurring comorbid presentations
Sepiapterin as a treatment for people living with phenylketonuria: a plain language summary of the APHENITY trial
No full textWhat is this summary about?: This plain language summary is based on an article about the APHENITY trial that was published in The Lancet journal in October 2024. The APHENITY trial was a phase 3 clinical trial to find out whether sepiapterin helped people living with phenylketonuria (PKU) and to learn more about its safety. PKU is a rare, genetic condition that causes high levels of phenylalanine (Phe) to build up in the body. High levels of Phe in the body can cause symptoms such as seizures, rashes, and problems with movement, and can also affect brain development, thinking skills, and behaviour. These symptoms can have an impact on people's health-related quality of life.
What happened in the aphenity trial?: Previous studies have shown that sepiapterin is able to decrease Phe levels in the blood. In the APHENITY trial, the researchers wanted to learn more about the efficacy and safety of sepiapterin in a large group of people living with PKU over the course of 8 weeks of treatment. The researchers wanted to: Assess the efficacy of sepiapterin by seeing whether sepiapterin decreased Phe levels in the blood compared with a placebo Assess the safety of sepiapterin by seeing how many health complaints the participants who took sepiapterin had compared with those who took the placebo The APHENITY trial was carried out in two parts: During Part 1, the participants took sepiapterin for 2 weeks to find out if it decreased their Phe levels During Part 2, the participants who benefitted from sepiapterin during Part 1 were randomly assigned to either continue taking sepiapterin or start taking a placebo for a further 6 weeks.
What were the results?: During Part 1, the researchers found that 114 out of 156 participants benefitted from sepiapterin. This was 73% or about 7 in 10 participants. During Part 2, the researchers found that the participants who took sepiapterin had reduced blood Phe levels compared with those who took the placebo. The researchers also found that compared with those who took the placebo, more of the participants who took sepiapterin reduced their blood Phe levels to within the ranges recommended by treatment guidelines. For both parts of the trial, the participants did not have any serious health complaints. So, the researchers concluded that no safety concerns were seen with sepiapterin in this trial.
What do the results of the trial mean?: These results showed that sepiapterin helped to reduce blood Phe levels in the participants, and there were no unexpected safety concerns in people living with PKU