Safety, pharmacokinetics, and pharmacodynamics of sofnobrutinib, a novel non-covalent BTK inhibitor, in healthy subjects: First-in-human phase I study.

Bruton's tyrosine kinase (BTK) is a potential therapeutic target for allergic and autoimmune diseases. This first-in-human phase I study evaluated safety, pharmacokinetic, and pharmacodynamic profiles of sofnobrutinib (formerly AS-0871), a highly selective, orally available, non-covalent BTK inhibitor, in healthy adult subjects. Single ascending doses (SAD; 5-900 mg) and multiple ascending doses (MAD; 50-300 mg twice daily [b.

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on Premutation.

The premutation of the fragile X messenger ribonucleoprotein 1 () gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region and increased levels of mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death.

Genome-wide association study of aromatase inhibitor discontinuation due to musculoskeletal symptoms.

Objective: Aromatase inhibitors (AIs) are commonly used to treat hormone receptor positive (HR +) breast cancer. AI-induced musculoskeletal syndrome (AIMSS) is a common toxicity that causes AI treatment discontinuation. The objective of this genome-wide association study (GWAS) was to identify genetic variants associated with discontinuation of AI therapy due to AIMSS and attempt to replicate previously reported associations.

Raising Knowledge and Awareness of Fragile X Syndrome in Serbia, Georgia, and Colombia: A Model for Other Developing Countries?

Fragile X syndrome is the most common monogenetic cause of inherited intellectual disability and syndromic autism spectrum disorder. Fragile X syndrome is caused by an expansion (full mutation ≥200 CGGs repeats, normal 10-45 CGGs) of the fragile X mental retardation 1 () gene, epigenetic silencing of the gene, which leads to reduction or lack of the gene's product: the fragile X mental retardation protein. In this cross-sectional study, we assessed general and pharmacotherapy knowledge (GK and PTK) of fragile X syndrome and satisfaction with education in neurodevelopmental disorders (NDDs) among senior medical students in Serbia (N=348), Georgia (N=112), and Colombia (N=58).

Recurrent cutaneous hyalohyphomycosis secondary to Purpureocillium lilacinum in an immunocompetent individual.

Purpureocillium lilacinum, previously classified as Paecilomyces lilacinus, is a ubiquitous hyaline hyphomycete considered to be an emerging opportunistic human pathogen that is resistant to traditional antifungal agents. This case report describes what is to our knowledge the only published case of P. lilacinum recrudescence in an immunocompetent host despite initial best-practice treatment with 10 weeks of voriconazole and surgical excision.

Laser plume containment during flexible transnasal laryngoscopy.

Objective: To evaluate a negative pressure microenvironment designed to contain laser plume during flexible transnasal laryngoscopy.

Methods: The Negative Pressure Face Shield (NPFS) was previously reported as well tolerated with initial use on 30 patients. Diagnostic transnasal laryngoscopy was performed on an additional 108 consecutive patients who were evaluated by questionnaires and sequential pulse oximetry.

Negative pressure face shield for flexible laryngoscopy in the COVID-19 era.

Objective: Introduce novel methods and materials to limit microdroplet spread when performing transnasal aerosol generating procedures in the COVID-19 era.

Methods: Prototypes of a negative pressure face shield (NPFS) were tested then used clinically to create a suction-clearing negative pressure microenvironment with controlled access to the nose and mouth. Air pressure measurements within prototypes were followed by prospective evaluation of 30 consecutive patients treated with the device assessed through questionnaires and monitoring oximetry.

Best Practices in Fragile X Syndrome Treatment Development.

Preclinical studies using animal models of fragile X syndrome have yielded several agents that rescue a wide variety of phenotypes. However, translation of these treatments to humans with the disorder has not yet been successful, shedding light on a variety of limitations with both animal models and human trial design. As members of the Clinical Trials Committee of the National Fragile X Foundation, we have discussed a variety of recommendations at the level of preclinical development, transition from preclinical to human projects, family involvement, and multi-site trial planning.

FORWARD: A Registry and Longitudinal Clinical Database to Study Fragile X Syndrome.

Background And Objective: Advances in the care of patients with fragile X syndrome (FXS) have been hampered by lack of data. This deficiency has produced fragmentary knowledge regarding the natural history of this condition, healthcare needs, and the effects of the disease on caregivers. To remedy this deficiency, the Fragile X Clinic and Research Consortium was established to facilitate research.

Clinicians' experiences with the fragile X clinical and research consortium.

The objectives of the study were to assess the attitudes and experiences of clinicians involved in a consortium of clinics serving people with fragile X-associated disorders to gauge satisfaction with the consortium and its efforts to improve quality of life for patients and the community. An internet survey was sent to 26 fragile X (FX) clinic directors participating in the Fragile X Clinical and Research Consortium (FXCRC). Respondents were asked to complete 19 questions on consortium performance and outcomes relevant for their own clinic.

Safety and efficacy of re-treatments with pyronaridine-artesunate in African patients with malaria: a substudy of the WANECAM randomised trial.

Background: Sparse data on the safety of pyronaridine-artesunate after repeated treatment of malaria episodes restrict its clinical use. We therefore compared the safety of pyronaridine-artesunate after treatment of the first episode of malaria versus re-treatment in a substudy analysis.

Methods: This planned substudy analysis of the randomised, open-label West African Network for Clinical Trials of Antimalarial Drugs (WANECAM) phase 3b/4 trial was done at six health facilities in Mali, Burkina Faso, and Guinea in patients (aged ≥6 months and bodyweight ≥5 kg) with uncomplicated microscopically confirmed Plasmodium spp malaria (parasite density <200 000 per μL blood) and fever or history of fever.

Pharmacokinetic interaction between pyronaridine-artesunate and metoprolol.

The objectives of this study were to characterize any drug-drug interaction between the antimalarial Pyramax (pyronaridine-artesunate [PA]) and the CYP2D6 probe substrate metoprolol and to assess the safety of 60-day or 90-day PA redosing, particularly with regard to liver biochemistry parameters. Healthy adult subjects were randomized to arm A (n = 26) or arm B (n = 30), with the arm A subjects administered 100 mg metoprolol tartrate in the first period, 100 mg metoprolol tartrate with the third of three daily doses of PA in the second period, and three daily doses of PA alone in the 90-day redosing period. The arm B subjects received the three-day PA regimen in the first period, with redosing of the regimen after 60 days in the second period.

Associations between laryngeal and cough dysfunction in motor neuron disease with bulbar involvement.

True vocal fold (TVF) dysfunction may lead to cough ineffectiveness. In individuals with motor neuron disease (MND), cough impairment in the context of dysphagia increases risk for aspiration and respiratory failure. This study characterizes differences and associations between TVF kinematics and airflow during cough in individuals with bulbar MND.

Social status moderates the relationship between facial structure and aggression.

A growing body of evidence has linked individual differences in facial structure-in particular, the facial width-to-height ratio (FWHR)-to social behaviors, including aggression, cheating, and nonreciprocation of trust. In the research reported here, we extended this work by demonstrating that the association between FWHR and aggression is moderated by subjective and objective measures of social status. In Study 1 (N = 237 college students), FWHR was positively correlated with aggressive behavior, but only among men reporting relatively low social status.

Tragedy into drama: an american history of tourniquet use in the current war.

Background: Although the scientific results of recent tourniquet advances in first aid are well recorded, the process by which tourniquet use advances were made is not. The purpose of the present report is to distill historical aspects of this tourniquet story during the current wars in Afghanistan and Iraq to aid scientists, leaders, and clinicians in the process of development of future improvements in first aid.

Methods: The process of how developments of this tourniquet story happened recently is detailed chronologically and thematically in a ?who did what, when, where, why, and how? way.

Safety and efficacy of pyronaridine-artesunate in uncomplicated acute malaria: an integrated analysis of individual patient data from six randomized clinical trials.

Background: Pyronaridine-artesunate (PA) is indicated for the treatment of acute uncomplicated Plasmodium falciparum and Plasmodium vivax malaria.

Methods: Individual patient data on safety outcomes were integrated from six randomized clinical trials conducted in Africa and Asia in patients with microscopically confirmed P. falciparum (five studies) or P.

Developing the communicative participation item bank: Rasch analysis results from a spasmodic dysphonia sample.

Purpose: The purpose of this study was to conduct the initial psychometric analyses of the Communicative Participation Item Bank-a new self-report instrument designed to measure the extent to which communication disorders interfere with communicative participation. This item bank is intended for community-dwelling adults across a range of communication disorders.

Method: A set of 141 candidate items was administered to 208 adults with spasmodic dysphonia.

Emergency thoracic ultrasound in the differentiation of the etiology of shortness of breath (ETUDES): sonographic B-lines and N-terminal pro-brain-type natriuretic peptide in diagnosing congestive heart failure.

Objectives: Sonographic thoracic B-lines and N-terminal pro-brain-type natriuretic peptide (NT-ProBNP) have been shown to help differentiate between congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD). The authors hypothesized that ultrasound (US) could be used to predict CHF and that it would provide additional predictive information when combined with NT-ProBNP. They also sought to determine optimal two- and eight-zone scanning protocols when different thresholds for a positive scan were used.

Developing a scale of communicative participation: a cognitive interviewing study.

Purpose: To revise and improve the instructions, candidate items and response format for a tool to measure communicative participation.

Method: Cognitive interviewing techniques, designed to study the process that respondents use to answer survey questions, were used to test a bank of candidate items for a measure of communicative participation. Twelve participants with spasmodic dysphonia (SD), a neurologic condition characterized by voice and speech changes, were asked to complete a sample questionnaire and then were interviewed regarding the clarity of instructions, candidate items and response format.