Persistent interactive effects of developmental salinity and temperature in Atlantic killifish (Fundulus heteroclitus).

Climate change alters multiple abiotic environmental factors in aquatic environments but relatively little is known about their interacting impacts, particularly in developing organisms where these exposures have the potential to cause long-lasting effects. To explore these issues, we exposed developing killifish embryos (Fundulus heteroclitus) to 26 °C or 20 °C and 20 ppt or 3 ppt salinity in a fully-factorial design. After hatching, fish were transferred to common conditions of 20 °C and 20 ppt to assess the potential for persistent developmental plasticity.

Critical Reflection to Investigate Medical Student Attitudes Toward Skin Tone in Their Preclinical Years.

Introduction: Implicit racial bias, defined as unreasoned judgement based solely on an individual's skin color, is a persistent barrier to quality medical care for people of color in the United States. Early, learner-centered intervention is crucial to establish cultural competence within health professional training programs.

Methods: Over 3 academic years, preclinical, second-year medical students were asked to submit an anonymous critical reflection regarding skin tone in medicine (n=794).

Obstacles to Early Diagnosis of Acute Hepatic Porphyria: Current Perspectives on Improving Early Diagnosis and Clinical Management.

Porphyrias are, for the most part, inherited disorders of the heme biosynthetic pathway which lead to accumulation of specific intermediates responsible for most of the symptoms and signs of biochemically active disease. Acute hepatic porphyrias usually come to clinical attention primarily in women in their reproductive years who present with episodic, severe, generalized abdominal pain. Such acute attacks may also be associated with tachycardia, systemic arterial hypertension, hyponatremia, recent history of dark reddish to brownish urine, and anxiety, delirium, and sensory or motor neuropathies.

Acute hepatic porphyrias: Recommendations for diagnosis and management with real-world examples.

Acute hepatic porphyria (AHP) is a group of four rare inherited diseases, each resulting from a deficiency in a distinct enzyme in the heme biosynthetic pathway. Characterized by acute neurovisceral symptoms that may mimic other medical and psychiatric conditions, lack of recognition of the disease often leads to a delay in diagnosis and initiation of effective treatment. Biochemical testing for pathway intermediates that accumulate when the disease is active forms the basis for screening and establishing a diagnosis.

Efficacy and safety of givosiran for acute hepatic porphyria: Final results of the randomized phase III ENVISION trial.

Background & Aims: Acute hepatic porphyria (AHP) is caused by defects in hepatic heme biosynthesis, leading to disabling acute neurovisceral attacks and chronic symptoms. In ENVISION (NCT03338816), givosiran treatment for 6 months reduced attacks and other disease manifestations compared with placebo. Herein, we report data from the 36-month final analysis of ENVISION.

Pediatric Population Pharmacokinetic Modeling and Exposure-Response Analysis of Ambrisentan in Pulmonary Arterial Hypertension and Comparison With Adult Data.

This study aimed to develop a population pharmacokinetic (PK) model of ambrisentan in pediatric patients (8 to <18 years) with pulmonary arterial hypertension (PAH) and compare pediatric ambrisentan systemic exposure with previously reported adult data. Association of ambrisentan exposure with efficacy (6-minute walking distance) and safety (adverse events) were exploratory analyses. A population PK model was developed using pediatric PK data.

EXPLORE B: A prospective, long-term natural history study of patients with acute hepatic porphyria with chronic symptoms.

One-year data from EXPLORE Part A showed high disease burden and impaired quality of life (QOL) in patients with acute hepatic porphyria (AHP) with recurrent attacks. We report baseline data of patients who enrolled in EXPLORE Part B for up to an additional 3 years of follow-up. EXPLORE B is a long-term, prospective study evaluating disease activity, pain intensity, and QOL in patients with AHP with ≥1 attack in the 12 months before enrollment or receiving hemin or gonadotropin-releasing hormone prophylaxis.

Acute Liver Failure Requiring Liver Transplantation due to Acute Hepatitis A Virus Infection.

Introduction: Hepatitis A infection (HAV) is generally characterized by an acute icteric illness or may have a subclinical self-limited course, although rarely, can result in fulminant hepatitis and death. In 2019, the City of Philadelphia declared a public health emergency due to an HAV outbreak. We are reporting a series of four cases of acute liver failure (ALF) requiring liver transplantation (LT) due to acute HAV.

A Rare Case of Wilson Disease in a 72-Year-Old Patient.

Wilson disease is an autosomal recessive disorder of abnormal copper metabolism that is prevalent in the younger population, rarely presenting in patients older than 40 years. Clinical presentation may be variable, and diagnosis is often aided by clinical and biochemical tests. We report the case of a 72-year-old woman who presented with acute liver failure initially of unclear etiology.

Population Pharmacokinetic and Pharmacodynamic Analysis of Belimumab Administered Subcutaneously in Healthy Volunteers and Patients with Systemic Lupus Erythematosus.

Background: Intravenous belimumab 10 mg/kg every 4 weeks is indicated in patients with active, autoantibody-positive systemic lupus erythematosus receiving standard systemic lupus erythematosus care. Subcutaneous 200-mg weekly administration, which may prove more convenient for patients and improve adherence, is currently under investigation.

Objective: The objective of this study was to characterize the population pharmacokinetics and exposure-efficacy response of subcutaneous belimumab in a pooled analysis of pharmacokinetic data [phase I: BEL114448 (NCT01583530) and BEL116119 (NCT01516450) in healthy subjects (n = 134); phase III: BEL112341 (NCT01484496) in adults with systemic lupus erythematosus (n = 554)] and pharmacodynamic data [BEL112341 in adults with systemic lupus erythematosus (n = 833)].

Population pharmacokinetic and pharmacodynamic analyses of safinamide in subjects with Parkinson's disease.

Safinamide is an orally administered -aminoamide derivative with both dopaminergic and non-dopaminergic properties. Nonlinear mixed effects models for population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PKPD) analyses were developed using records from, respectively, 623 and 668 patients belonging to two Phase 3, randomized, placebo-controlled, double-blind efficacy studies. The aim was to estimate safinamide population PK parameters in patients with Parkinson's disease (PD) on stable levodopa therapy, and to develop a model of safinamide effect on the PD phase of normal functioning (ON-time).

Drug-Induced Liver Injury After Soy Protein Supplement Use.

Drug-induced liver injury (DILI) is an important and often elusive cause of iatrogenic hepatic injury which complicates its recognition and treatment. We describe a rare case of severe liver injury in a previously healthy individual associated with a commonly used and reportedly safe soy protein powder supplement. Discontinuation of the supplements and initiation of ursodeoxycholic acid provided symptomatic relief, decreased pruritus, and resulted in a resolution of hepatic panel labs.

Population Pharmacokinetic and Pharmacodynamic Modeling and Effects on Platelet Counts of Different Dosages of Eltrombopag in Chinese Patients With Chronic Primary Immune Thrombocytopenia.

Purpose: This study characterized the population pharmacokinetic (pop-PK) and PK/pharmacodynamic (pop-PK/PD) properties of eltrombopag and evaluated platelet count (PLTC) response to different eltrombopag dosages through simulations in Chinese adult patients with chronic primary immune thrombocytopenia (cITP).

Methods: Pop-PK and pop-PK/PD models were developed from Chinese patients with cITP. Model-based simulations were then performed to predict PLTC response.

Management of hepatic adenomatosis.

Hepatic adenomatosis (HeAs) is a rare clinical entity defined by the presence of 10 or more hepatic adenomas (HA) within the background of an otherwise normal liver parenchyma, in the absence of glycogen storage disease or anabolic steroid use. HA is a benign tumor associated with oral contraceptive use. Recent advances in pathogenesis and classification of HA have questioned the distinction between these two diseases.

Modeling and simulation support eltrombopag dosing in thrombocytopenic patients with chronic HCV infection.

Purpose: The pharmacokinetics of eltrombopag and its stimulation of platelet production were characterized in patients with chronic hepatitis C virus (HCV) infection to optimize an eltrombopag dosing regimen for treatment of HCV-related thrombocytopenia before and throughout peginterferon (pegIFN)-based antiviral therapy.

Methods: Population pharmacokinetic analysis for eltrombopag included 663 individuals (healthy subjects, n = 28; patients with HCV, n = 635). Population pharmacokinetic/pharmacodynamic analysis for platelet response involved patients with HCV only.