"I am sick, but that's not all that I am": patient perspectives on psychological adaptation over time to inborn errors of immunity.

Inborn errors of immunity (IEI) are rare heritable disorders of the immune system predisposing to atypical infections, autoimmunity, inflammation, and risk of malignancy. Adaptation is the process of incorporating stressful experiences into one's life; these experiences may include onset of illness, receiving a diagnosis, or suffering without a diagnosis. Poor adaptation is linked to adverse outcomes including psychiatric comorbidities and decreased well-being.

Pharmacokinetics and pharmacodynamics of PTC518, an oral huntingtin lowering splicing modifier: A first-in-human study.

Aims: PTC518 is an orally administered, centrally and peripherally distributed huntingtin (HTT) pre-mRNA splicing modifier being developed for the treatment of Huntington's disease (HD) for which there is a high unmet medical need as there are currently no approved disease-modifying treatments. This first-in-human study investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PTC518 in healthy volunteers.

Methods: This phase 1, single-centre, randomized study in 77 healthy male and female volunteers evaluated the safety and tolerability and PK of PTC518 following single ascending doses and multiple ascending doses, PD as assessed by HTT mRNA and HTT protein levels after single and multiple doses, and food effects.

The need to set explicit goals for human germline gene editing public dialogues.

Given the potentially large ethical and societal implications of human germline gene editing (HGGE) the urgent need for public and stakeholder engagement (PSE) has been repeatedly expressed. However, the explicit goals of such PSE efforts often remain poorly defined. In this program report, we outline the goals of our Dutch project called De DNA dialogen (The DNA dialogues).

Factors associated with high costs of patients with metabolic dysfunction-associated steatotic liver disease: an observational study using the French CONSTANCES cohort.

Background & Aims: Despite its high prevalence in the western world metabolic dysfunction-associated steatotic liver disease (MASLD) does not benefit from targeted pharmacological therapy. We measured healthcare utilisation and identified factors associated with high-cost MASLD patients in France.

Methods: The prevalent population with MASLD (including non-alcoholic steatohepatitis) in the CONSTANCES cohort, a nationally representative sample of 200,000 adults aged between 18 and 69, was linked to the French centralised national claims database (SNDS).

Prospective head-to-head comparison of non-invasive scores for diagnosis of fibrotic MASH in patients with type 2 diabetes.

Background & Aims: Non-invasive scores have been proposed to identify patients with fibrotic, metabolic dysfunction-associated steatohepatitis (MASH), who are at the highest risk of progression to complications of cirrhosis and may benefit from pharmacologic treatments. However, data in patients with type 2 diabetes (T2DM) are lacking. The aim of this multicenter prospective study was to perform a head-to-head comparison of FAST (FibroScan-aspartate aminotransferase [AST]), MAST (MRI-AST), MEFIB (magnetic resonance elastography [MRE] plus FIB-4), and FNI (fibrotic NASH index) for detecting fibrotic MASH in patients with T2DM.

Prospective Comparison of Attenuation Imaging and Controlled Attenuation Parameter for Liver Steatosis Diagnosis in Patients With Nonalcoholic Fatty Liver Disease and Type 2 Diabetes.

Background & Aims: Similarly to the controlled attenuation parameter (CAP), the ultrasound-based attenuation imaging (ATI) can quantify hepatic steatosis. We prospectively compared the performance of ATI and CAP for the diagnosis of hepatic steatosis in patients with type 2 diabetes and nonalcoholic fatty liver disease using histology and magnetic resonance imaging-proton density fat fraction (MRI-PDFF) as references.

Methods: Patients underwent ATI and CAP measurement, MRI, and biopsy on the same day.

Hepatocellular carcinoma in patients with non-alcoholic fatty liver disease is associated with heterogeneous pattern of fat infiltration in skeletal muscles.

Objectives: To evaluate the association between fat infiltration in skeletal muscles (myosteatosis) and hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD).

Methods: In a cross-sectional cohort of 72 histologically proven NAFLD patients (n = 38 with non-alcoholic steatohepatitis; NASH), among which 20 had HCC diagnosed on biopsy, we used proton density fat fraction (PDFF) at MRI to evaluate myosteatosis in skeletal muscles (mean fat fraction and first order radiomic-based pattern) at the third lumbar level, namely in erector spinae (ES), quadratus lumborum (QL), psoas, oblique, and rectus muscles.

Results: PDFF was 70% higher in patients with HCC when compared to those without HCC (9.

Visco-Elastic Parameters at Three-Dimensional MR Elastography for Diagnosing Non-Alcoholic Steatohepatitis and Substantial Fibrosis in Mice.

Background: Nonalcoholic fatty liver disease (NAFLD) is increasing worldwide and is a growing cause of liver cirrhosis and cancer. The performance of the magnetic resonance elastography (MRE) visco-elastic parameters in diagnosing progressive forms of NAFLD, including nonalcoholic steatohepatitis (NASH) and substantial fibrosis (F ≥ 2), needs to be clarified.

Purpose: To assess the value of three-dimensional MRE visco-elastic parameters as markers of NASH and substantial fibrosis in mice with NAFLD.

Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors Use among Heart Failure Patients and the Role of Pharmacists in Early Initiation of Therapy.

Heart failure (HF) is a growing major public health and economic concern in the United States and worldwide. Heart failure mortality rates can be as high as 75% despite advances in therapies. HF is expected to be the fastest growing among all cardiovascular diseases, with HF-associated direct medical costs projected to nearly double over the next 10 years.

Comparative Analysis of a Locally Resampling MR Elastography Reconstruction Algorithm in Liver Fibrosis.

Background: In magnetic resonance elastography (MRE), the precision of the observed mechanical depends on the ratio between mechanical wavelength and spatial resolution. Since the mechanical wavelength may vary with actuation frequency, between patients and depending on position, a unique spatial resolution may not always generate an optimal ratio for multifrequency acquisitions, in patients with varying degrees of disease or in mechanically heterogeneous organs.

Purpose: To describe an MRE reconstruction algorithm that adjusts the ratio between shear wavelength and pixel size, by locally resampling the matrix of shear displacement, and to assess its performance relative to existing reconstructions in different use cases.

Prospective comparison of transient elastography, MRI and serum scores for grading steatosis and detecting non-alcoholic steatohepatitis in bariatric surgery candidates.

Background & Aims: Tools for the non-invasive diagnosis of non-alcoholic steatohepatitis (NASH) in morbidly obese patients with suspected non-alcoholic fatty liver disease (NAFLD) are an unmet clinical need. We prospectively compared the performance of transient elastography, MRI, and 3 serum scores for the diagnosis of NAFLD, grading of steatosis and detection of NASH in bariatric surgery candidates.

Methods: Of 186 patients screened, 152 underwent liver biopsy, which was used as a reference for NAFLD (steatosis [S]>5%), steatosis grading and NASH diagnosis.

Necro-inflammatory activity grading in chronic viral hepatitis with three-dimensional multifrequency MR elastography.

The purpose of this study was to assess the diagnostic value of multifrequency MR elastography for grading necro-inflammation in the liver. Fifty participants with chronic hepatitis B or C were recruited for this institutional review board-approved study. Their liver was examined with multifrequency MR elastography.

Commercial DNA tests and police investigations: a broad bioethical perspective.

Over 30 million people worldwide have taken a commercial at-home DNA test, because they were interested in their genetic ancestry, disease predisposition or inherited traits. Yet, these consumer DNA data are also increasingly used for a very different purpose: to identify suspects in criminal investigations. By matching a suspect's DNA with DNA from a suspect's distant relatives who have taken a commercial at-home DNA test, law enforcement can zero in on a perpetrator.

The SVD beamformer with diverging waves: a proof-of-concept for fast aberration correction.

The rise of ultrafast ultrasound imaging-with plane or diverging waves - paved the way to new applications of ultrasound in biomedical applications. However, propagation through complex layers (typically fat, muscle, and bone) hinder considerably the image quality, especially because of sound speed heterogeneities. In difficult-to-image patients, in the case of the hepatic steatosis for instance, a good image and a reliable sound speed quantification are crucial to provide a powerful non-invasive diagnosis tool.

Rewriting the human genome, rewriting human rights law? Human rights, human dignity, and human germline modification in the CRISPR era.

In most legal orders, human germline modification is either prohibited or severely restricted. A recurring thought in these legal frameworks is that heritable genome editing would result in practices that are at odds with principles of human rights, such as dignity, justice, and equality. However, now that CRISPR is bringing heritable genome editing within human reach, the question has risen as to whether these human rights bans still make sense.

Multifrequency magnetic resonance elastography for elasticity quantitation and optimal tissue discrimination: A two-platform liver fibrosis mimicking phantom study.

In the framework of algebraic inversion, magnetic resonance elastography (MRE) repeatability, reproducibility and robustness were evaluated on extracted shear velocities (or elastic moduli). The same excitation system was implemented at two sites equipped with clinical MR scanners of 1.5 and 3 T.

Tumor Solid Stress: Assessment with MR Elastography under Compression of Patient-Derived Hepatocellular Carcinomas and Cholangiocarcinomas Xenografted in Mice.

Malignant tumors have abnormal biomechanical characteristics, including high viscoelasticity, solid stress, and interstitial fluid pressure. Magnetic resonance (MR) elastography is increasingly used to non-invasively assess tissue viscoelasticity. However, solid stress and interstitial fluid pressure measurements are performed with invasive methods.

In vitro cytochrome P450- and transporter-mediated drug interaction potential of 6β-hydroxy-21-desacetyl deflazacort-A major human metabolite of deflazacort.

6β-Hydroxy-21-desacetyl deflazacort (6β-OH-21-desDFZ) is a major circulating but not biologically active metabolite of deflazacort (DFZ). In vitro studies were performed to evaluate cytochrome P450 (CYP)- and transporter-mediated drug interaction potentials of 6β-OH-21-desDFZ. Up to 50 µM, the highest soluble concentration in the test system, 6β-OH-21-desDFZ weakly inhibited (IC  > 50 µM) the enzyme activity of CYPs 1A2, 2B6, 2C8, 2C9, and 2D6, while moderately inhibiting CYP2C19 and CYP3A4 with IC values of approximately 50 and 35 μM, respectively.

Analysis Protocols for MRI Mapping of Renal T.

The computation of T maps from MR datasets represents an important step toward the precise characterization of kidney disease models in small animals. Here the main strategies to analyze renal T mapping datasets derived from small rodents are presented. Suggestions are provided with respect to essential software requirements, and advice is provided as to how dataset completeness and quality may be evaluated.

Experimental Protocols for MRI Mapping of Renal T.

The water proton longitudinal relaxation time, T, is a common and useful MR parameter in nephrology research. Here we provide three step-by-step T-mapping protocols suitable for different types of nephrology research. Firstly, we provide a single-slice 2D saturation recovery protocol suitable for studies of global pathology, where whole-kidney coverage is unnecessary.