Quantile regression in the field of liver transplantation: A case study-based tutorial.

We present a tutorial on quantile regression, an underutilized yet valuable class of multivariable linear regression models that allows researchers to understand more fully the conditional distribution of response as compared to models based on conditional means. Quantile regression models are flexible, have attractive interpretations, and are implemented in most statistical software packages. Our focus is on an intuitive understanding of quantile regression models, particularly as compared with more familiar regression methods such as conditional mean models as estimated using ordinary least squares (OLS).

Psychiatric diagnoses are common after liver transplantation and are associated with increased health care utilization and patient financial burden.

Psychiatric disorders after liver transplantation (LT) are associated with worse patient and graft outcomes, which may be amplified by inadequate treatment. We aimed to characterize the burden of psychiatric disorders, treatment patterns, and associated financial burden among liver transplantation recipients (LTRs). IQVIA PharMetrics (R) Plus for Academics-a large health plan claims database representative of the commercially insured US population-was used to identify psychiatric diagnoses among adult LTRs and assess treatment.

Financial burden following adult liver transplantation is common and associated with adverse recipient outcomes.

The financial impact of liver transplantation has been underexplored. We aimed to identify associations between high financial burden (≥10% annual income spent on out-of-pocket medical costs) and work productivity, financial distress (coping behaviors in response to the financial burden), and financial toxicity (health-related quality of life, HRQOL) among adult recipients of liver transplant. Between June 2021 and May 2022, we surveyed 207 adult recipients of liver transplant across 5 US transplant centers.

The financial burden after liver transplantation is significant among commercially insured adults: A large US National Cohort.

Liver transplantation (LT) is lifesaving for patients with cirrhosis; however, the resultant financial burden to patients has not been well characterized. We aimed to provide a nationally representative portrayal of patient financial burden after LT. Adult recipients of LT from 2006 to 2021 were identified using IQVIA PharMetrics® Plus for Academics-a large nationally representative claims database of commercially insured Americans.

Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine.

Niemann-Pick type C (NPC) disease is a lysosomal storage disease (LSD) characterized by the buildup of endo-lysosomal cholesterol and glycosphingolipids due to loss of function mutations in the NPC1 and NPC2 genes. NPC patients can present with a broad phenotypic spectrum, with differences at the age of onset, rate of progression, severity, organs involved, effects on the central nervous system, and even response to pharmacological treatments. This article reviews the phenotypic variation of NPC and discusses its possible causes, such as the remaining function of the defective protein, modifier genes, sex, environmental cues, and splicing factors, among others.

A paradigm for fostering patient-centered research in liver disease: The liver transplant patient-engagement program.

Background: Many federal funding and regulatory agencies require patient engagement to conduct patient-centered research and drug development. We developed a liver transplantation patient-engagement program, which can serve as a model for bringing the patient perspective to digestive diseases research.

Methods: Six liver transplantation patient-engagement program advisors completed training in patient engagement; participated in several virtual sessions; and completed postsession surveys.

Active coping, resilience, post-traumatic growth, and psychiatric symptoms among early and late liver transplant survivors.

Understanding survivorship experiences at different stages postliver transplantation (poat-LT) is essential to improving care. Patient-reported concepts including coping, resilience, post-traumatic growth (PTG), and anxiety/depression, have been implicated as important predictors of quality of life and health behaviors after LT. We aimed to descriptively characterize these concepts at different post-LT survivorship stages.

Statins for Smith-Lemli-Opitz syndrome.

Background: Smith-Lemli-Opitz syndrome (SLOS) is a multiple congenital malformations syndrome caused by defective cholesterol biosynthesis. Affected individuals show cholesterol deficiency and accumulation of various precursor molecules, mainly 7-dehydrocholesterol and 8-dehydrocholesterol. There is currently no cure for SLOS, with cholesterol supplementation being primarily a biochemical therapy of limited evidence.

AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease.

Neuronal ceroid lipofuscinosis type 7 (CLN7) disease is a lysosomal storage disease caused by mutations in the facilitator superfamily domain containing 8 (MFSD8) gene, which encodes a membrane-bound lysosomal protein, MFSD8. To test the effectiveness and safety of adeno-associated viral (AAV) gene therapy, an in vitro study demonstrated that AAV2/MFSD8 dose dependently rescued lysosomal function in fibroblasts from a CLN7 patient. An in vivo efficacy study using intrathecal administration of AAV9/MFSD8 to Mfsd8- /- mice at P7-P10 or P120 with high or low dose led to clear age- and dose-dependent effects.

Effects of a 33-ion sequential beam galactic cosmic ray analog on male mouse behavior and evaluation of CDDO-EA as a radiation countermeasure.

In long-term spaceflight, astronauts will face unique cognitive loads and social challenges which will be complicated by communication delays with Earth. It is important to understand the central nervous system (CNS) effects of deep spaceflight and the associated unavoidable exposure to galactic cosmic radiation (GCR). Rodent studies show single- or simple-particle combination exposure alters CNS endpoints, including hippocampal-dependent behavior.

Lung transplantation: how we do it.

Lung transplantation is considered the gold standard for patients with chronic end-stage pulmonary disease. However, due to the complexity of management and relatively lower median survival as compared to other solid organs, many programs across the world have been slow to adopt the same. In our institution, we started lung transplantation in September 1990.

Ex vivo lung perfusion: how we do it.

Lung transplantation is an established treatment for patients with end-stage lung disease. However, a shortage of donors, low lung utilization among potential donors, and waitlist mortality continue to be challenges. In the last decade, ex vivo lung perfusion (EVLP) has expanded the donor pool by allowing prolonged evaluation of marginal donor lungs and allowing reparative therapies for lungs, which are otherwise considered not transplantable.

Translational Control of Immune Evasion in Cancer.

Mechanisms that control translation play important roles in tumor progression and metastasis. Emerging evidence has revealed that dysregulated translation also impacts immune evasion in response to cellular or oncogenic stress. Here, we summarize current knowledge regarding the translational control of immune checkpoints and implications for cancer immunotherapies.

ANGPTL8 has both endocrine and autocrine effects on substrate utilization.

The angiopoietin-like protein ANGPTL8 (A8) is one of 3 ANGPTLs (A8, A3, A4) that coordinate changes in triglyceride (TG) delivery to tissues by inhibiting lipoprotein lipase (LPL), an enzyme that hydrolyzes TG. Previously we showed that A8, which is expressed in liver and adipose tissue, is required to redirect dietary TG from oxidative to storage tissues following food intake. Here we show that A8 from liver and adipose tissue have different roles in this process.

Polymerase-mediated ultramutagenesis in mice produces diverse cancers with high mutational load.

Mutations underlie all cancers, and their identification and study are the foundation of cancer biology. We describe what we believe to be a novel approach to mutagenesis and cancer studies based on the DNA polymerase ε (POLE) ultramutator phenotype recently described in human cancers, in which a single amino acid substitution (most commonly P286R) in the proofreading domain results in error-prone DNA replication. We engineered a conditional PoleP286R allele in mice.

Intracellular lipid metabolism impairs β cell compensation during diet-induced obesity.

The compensatory proliferation of insulin-producing β cells is critical to maintaining glucose homeostasis at the early stage of type 2 diabetes. Failure of β cells to proliferate results in hyperglycemia and insulin dependence in patients. To understand the effect of the interplay between β cell compensation and lipid metabolism upon obesity and peripheral insulin resistance, we eliminated LDL receptor-related protein 1 (LRP1), a pleiotropic mediator of cholesterol, insulin, energy metabolism, and other cellular processes, in β cells.

Leptin action in pubertal development: recent advances and unanswered questions.

In recent years we have witnessed a considerable advance in the understanding of the processes involved in pubertal development. This is partially due to the discovery of the kisspeptin system and its fundamental role in the control of reproductive physiology. In addition, the suspected relationship between increasing rates of childhood obesity and the apparent reduction in the age of puberty onset in girls has generated a growing interest in identifying the mechanisms by which nutrition may influence reproductive maturation.

Molecular correlates of emotional learning using genetically selected rat lines.

The genetic contributions to active avoidance learning in rodents have been well established, yet the molecular basis for genetically selected line differences remains poorly understood. To identify candidate genes influencing this active avoidance paradigm, we utilized the bidirectionally selected Syracuse high- and low-avoidance (SHA and SLA) rat lines that markedly differ in their two-way active avoidance behavior. Rats were phenotyped, rested to allow recovery from testing stress and then hippocampi were dissected for gene expression profiling (Affymetrix U34A chips; approximately 7000 known genes), comparing SLA to SHA.

MerMade: an oligodeoxyribonucleotide synthesizer for high throughput oligonucleotide production in dual 96-well plates.

We have designed and constructed a machine that synthesizes two standard 96-well plates of oligonucleotides in a single run using standard phosphoramidite chemistry. The machine is capable of making a combination of standard, degenerate, or modified oligos in a single plate. The run time is typically 17 hr for two plates of 20-mers and a reaction scale of 40 nM.