Pharmacokinetics, safety, and tolerability of fedratinib in adults with moderate and severe hepatic impairment: results from the phase 1 FEDR-CP-001 trial.

Purpose: The FEDR-CP-001 (NCT03983161) trial evaluated the pharmacokinetics (PK) and safety of a single dose of fedratinib in adults with moderate or severe hepatic impairment (HI) compared with matched healthy participants with normal hepatic function.

Methods: This was a non-randomized, open-label, multicenter, phase 1 trial. Participants were aged 18-75 years and had a BMI of 18-40 kg/m.

Effect of Activated Charcoal on Mavacamten Pharmacokinetics in Healthy Participants.

Objective: To assess the effect of activated charcoal on the single-dose pharmacokinetics of mavacamten when administered 2 h or 6 h after mavacamten dosing.

Methods: In this open-label, randomized, parallel-group study, healthy adults were randomized into three groups to receive mavacamten 15 mg alone or mavacamten 15 mg plus activated charcoal 50 g administered either 2 h or 6 h after mavacamten dosing. Pharmacokinetic parameters were derived from plasma concentration-time data using noncompartmental methods.

Depth effect on point shear wave velocity elastography: Evidence in a chronic hepatitis C patient cohort.

Background And Aims: This study investigated the depth-related bias and the influence of scan plane angle on performance of point-shear-wave elastometry in a chronic hepatitis C patient cohort.

Materials And Methods: We included 104 patients affected by chronic liver disease related to the hepatitis C virus. Liver surface nodularity was the reference to diagnose cirrhosis.

A statistical method for removing unbalanced trials with multiple covariates in meta-analysis.

In meta-analysis literature, there are several checklists describing the procedures necessary to evaluate studies from a qualitative point of view, whereas preliminary quantitative and statistical investigations on the "combinability" of trials have been neglected. Covariate balance is an important prerequisite to conduct meta-analysis. We propose a method to identify unbalanced trials with respect to a set of covariates, in presence of covariate imbalance, namely when the randomized controlled trials generate a meta-sample that cannot satisfy the requisite of randomization/combinability in meta-analysis.

Relative bioavailability of fedratinib through various alternative oral administration methods in healthy adults.

Fedratinib is an oral Janus kinase 2-selective inhibitor for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis; however, some patients have difficulty with oral dosing. This randomized, phase 1, open-label, 2-part crossover study evaluated the relative bioavailability, safety, tolerability, taste, and palatability of fedratinib resulting from various alternative oral administration methods in healthy adults. Participants could receive fedratinib 400 mg orally as intact capsules along with a nutritional supplement; as contents of capsules dispersed in a nutritional supplement, delivered via nasogastric tube; or as a divided dose of 200 mg orally twice daily as intact capsules with a nutritional supplement.

MRONJ in breast cancer patients under bone modifying agents for cancer treatment-induced bone loss (CTIBL): a multi-hospital-based case series.

Background: Cancer treatment-induced bone loss (CTIBL) is the most common adverse event experienced by patients affected by breast cancer (BC) patients, without bone metastases. Bone modifying agents (BMAs) therapy is prescribed for the prevention of CTIBL, but it exposes patients to the risk of MRONJ.

Methods: This multicentre hospital-based retrospective study included consecutive non-metastatic BC patients affected by MRONJ related to exposure to low-dose BMAs for CTIBL prevention.

Gender and Sex in Medical Practice: An Exploratory Study on Knowledge, Behavior, and Attitude among Sicilian Physicians.

Personalized medicine is a new paradigm in health care, and the concept of socio-cultural gender, as opposed to biological sex, emerged in several medical approaches. This exploratory study aimed to investigate the knowledge of sex and gender in clinical medicine among Sicilian physicians. Data collection was based on an online survey sent to the members of the Medical Councils of Sicily (Italy).

Diagnostic and prognostic value of magnetic resonance imaging in the detection of tumor depth of invasion and bone invasion in patients with oral cavity cancer.

Purpose: To evaluate the accuracy of preoperative contrast-enhanced magnetic resonance imaging (MRI) in the assessment of radiological depth of invasion (rDOI) and bone invasion in patients with oral cavity cancer, and the prognostic value of preoperative rDOI.

Materials And Methods: This retrospective study included patients with surgically resected oral cavity cancer and preoperative MRI acquired within four weeks before surgery. Two readers evaluated the MRI to assess the superficial and deep bone invasion, preoperative T stage, and measured the rDOI.

A splice site mutation in the TSEN2 causes a new syndrome with craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome.

Recessive mutations in the genes encoding the four subunits of the tRNA splicing endonuclease complex (TSEN54, TSEN34, TSEN15, and TSEN2) cause various forms of pontocerebellar hypoplasia, a disorder characterized by hypoplasia of the cerebellum and the pons, microcephaly, dysmorphisms, and other variable clinical features. Here, we report an intronic recessive founder variant in the gene TSEN2 that results in abnormal splicing of the mRNA of this gene, in six individuals from four consanguineous families affected with microcephaly, multiple craniofacial malformations, radiological abnormalities of the central nervous system, and cognitive retardation of variable severity. Remarkably, unlike patients with previously described mutations in the components of the TSEN complex, all the individuals that we report developed atypical hemolytic uremic syndrome (aHUS) with thrombotic microangiopathy, microangiopathic hemolytic anemia, thrombocytopenia, proteinuria, severe hypertension, and end-stage kidney disease (ESKD) early in life.

Loss of diacylglycerol kinase ε causes thrombotic microangiopathy by impairing endothelial VEGFA signaling.

Loss of function of the lipid kinase diacylglycerol kinase ε (DGKε), encoded by the gene DGKE, causes a form of atypical hemolytic uremic syndrome that is not related to abnormalities of the alternative pathway of the complement, by mechanisms that are not understood. By generating a potentially novel endothelial specific Dgke-knockout mouse, we demonstrate that loss of Dgke in the endothelium results in impaired signaling downstream of VEGFR2 due to cellular shortage of phosphatidylinositol 4,5-biphosphate. Mechanistically, we found that, in the absence of DGKε in the endothelium, Akt fails to be activated upon VEGFR2 stimulation, resulting in defective induction of the enzyme cyclooxygenase 2 and production of prostaglandin E2 (PGE2).

Detection of pro angiogenic and inflammatory biomarkers in patients with CKD.

Cardiovascular disease (CVD) is the most common cause of death in patients with native and post-transplant chronic kidney disease (CKD). To identify new biomarkers of vascular injury and inflammation, we analyzed the proteome of plasma and circulating extracellular vesicles (EVs) in native and post-transplant CKD patients utilizing an aptamer-based assay. Proteins of angiogenesis were significantly higher in native and post-transplant CKD patients versus healthy controls.

Predicting in-hospital mortality from Coronavirus Disease 2019: A simple validated app for clinical use.

Backgrounds: Validated tools for predicting individual in-hospital mortality of COVID-19 are lacking. We aimed to develop and to validate a simple clinical prediction rule for early identification of in-hospital mortality of patients with COVID-19.

Methods And Findings: We enrolled 2191 consecutive hospitalized patients with COVID-19 from three Italian dedicated units (derivation cohort: 1810 consecutive patients from Bergamo and Pavia units; validation cohort: 381 consecutive patients from Rome unit).

Competing-risk analysis of coronavirus disease 2019 in-hospital mortality in a Northern Italian centre from SMAtteo COvid19 REgistry (SMACORE).

An accurate prediction of the clinical outcomes of European patients requiring hospitalisation for Coronavirus Disease 2019 (COVID-19) is lacking. The aim of the study is to identify predictors of in-hospital mortality and discharge in a cohort of Lombardy patients with COVID-19. All consecutive hospitalised patients from February 21st to March 30th, 2020, with confirmed COVID-19 from the IRCCS Policlinico San Matteo, Pavia, Lombardy, Italy, were included.

Progression-Free Survival Early Assessment Is a Robust Surrogate Endpoint of Overall Survival in Immunotherapy Trials of Hepatocellular Carcinoma.

Background: Radiology-based outcomes, such as progression-free survival (PFS) and objective response rate (ORR), are used as surrogate endpoints in oncology trials. We aimed to assess the surrogacy relationship of PFS with overall survival (OS) in clinical trials of systemic therapies targeting advanced hepatocellular carcinoma (HCC) by novel meta-regression methods.

Methods: A search of databases (PubMed, American Society of Clinical Oncology (ASCO), and European Society for Medical Oncology (ESMO) Meeting Libraries, Clinicaltrials.

Optimizing Sequential Systemic Therapies for Advanced Hepatocellular Carcinoma: A Decision Analysis.

An optimal sequential systemic therapy for advanced hepatocellular carcinoma (HCC) has not been discovered. We developed a decision model based on available clinical trials to identify an optimal risk/benefit strategy for sequences of novel systemic agents. A Markov model was built to simulate overall survival (OS) among patients with advanced HCC.

Performance of Radiomics Features in the Quantification of Idiopathic Pulmonary Fibrosis from HRCT.

Background: Our study assesses the diagnostic value of different features extracted from high resolution computed tomography (HRCT) images of patients with idiopathic pulmonary fibrosis. These features are investigated over a range of HRCT lung volume measurements (in Hounsfield Units) for which no prior study has yet been published. In particular, we provide a comparison of their diagnostic value at different Hounsfield Unit (HU) thresholds, including corresponding pulmonary functional tests.

Innate Immune Signaling Contributes to Tubular Cell Senescence in the Glis2 Knockout Mouse Model of Nephronophthisis.

Nephronophthisis (NPHP), the leading genetic cause of end-stage renal failure in children and young adults, is a group of autosomal recessive diseases characterized by kidney-cyst degeneration and fibrosis for which no therapy is currently available. To date, mutations in >25 genes have been identified as causes of this disease that, in several cases, result in chronic DNA damage in kidney tubular cells. Among such mutations, those in the transcription factor-encoding GLIS2 cause NPHP type 7.

Epithelial innate immunity mediates tubular cell senescence after kidney injury.

Acute kidney injury (AKI) is a common clinical condition of growing incidence. Patients who suffer severe AKI have a higher risk of developing interstitial fibrosis, chronic kidney disease, and end-stage renal disease later in life. Cellular senescence is a persistent cell cycle arrest and altered gene expression pattern evoked by multiple stressors.

Prominin-1 controls stem cell activation by orchestrating ciliary dynamics.

Proper temporal and spatial activation of stem cells relies on highly coordinated cell signaling. The primary cilium is the sensory organelle that is responsible for transmitting extracellular signals into a cell. Primary cilium size, architecture, and assembly-disassembly dynamics are under rigid cell cycle-dependent control.

Persistent increase in mitochondrial superoxide mediates cisplatin-induced chronic kidney disease.

Severe and recurrent cisplatin-induced acute kidney injury (AKI) as part of standard cancer therapy is a known risk factor for development of chronic kidney disease (CKD). The specific role of superoxide (O)-mediated disruption of mitochondrial oxidative metabolism in CKD after cisplatin treatment is unexplored. Cisplatin is typically administered in weekly or tri-weekly cycles as part of standard cancer therapy.

β-Thalassemia heterozygote state detrimentally affects health expectation.

Background: Thalassemia minor (Tm) individuals, are generally considered healthy. However, the prognosis of Tm individuals has not been extensively studied. The aim of this study was to evaluate the prognosis of Tm versus controls without β-thalassemia carrier state.

Evidence of bias in randomized clinical trials of hepatitis C interferon therapies.

Introduction: Bias may occur in randomized clinical trials in favor of the new experimental treatment because of unblinded assessment of subjective endpoints or wish bias. Using results from published trials, we analyzed and compared the treatment effect of hepatitis C antiviral interferon therapies experimental or control.

Methods: Meta-regression of trials enrolling naïve hepatitis C virus patients that underwent four therapies including interferon alone or plus ribavirin during past years.

Loss of Glis2/NPHP7 causes kidney epithelial cell senescence and suppresses cyst growth in the Kif3a mouse model of cystic kidney disease.

Enlargement of kidney tubules is a common feature of multiple cystic kidney diseases in humans and mice. However, while some of these pathologies are characterized by cyst expansion and organ enlargement, in others, progressive interstitial fibrosis and kidney atrophy prevail. The Kif3a knockout mouse is an established non-orthologous mouse model of cystic kidney disease.

Loss of diacylglycerol kinase epsilon in mice causes endothelial distress and impairs glomerular Cox-2 and PGE2 production.

Thrombotic microangiopathy (TMA) is a disorder characterized by microvascular occlusion that can lead to thrombocytopenia, hemolytic anemia, and glomerular damage. Complement activation is the central event in most cases of TMA. Primary forms of TMA are caused by mutations in genes encoding components of the complement or regulators of the complement cascade.