Covalent inhibitors of the RAS binding domain of PI3Kα impair tumor growth driven by RAS and HER2.

Genetic disruption of the RAS binding domain (RBD) of PI 3-kinase (PI3K) prevents the growth of mutant RAS driven tumors in mice and does not impact PI3K's role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3K interaction may represent an attractive strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3K lipid kinase activity such as alpelisib. Here we report compounds that bind covalently to cysteine 242 in the RBD of PI3K p110α and block the ability of RAS to activate PI3K activity.

In the Eye of the Beholder: A Stakeholder Analysis of the Value of the "Promotion in Place" Competency-Based Time-Variable Graduate Medical Education Pilot.

Purpose: Competency-based time-variable (CBTV) graduate medical education (GME) has been implemented in Canada, Europe, and the United States, yet its perceived value has not been explored. Promotion in Place (PIP) is a CBTV GME program in which residents graduating early advance to attending status with "sheltered independence" until the standard graduation date. This study describes perceived value of CBTV GME and PIP at Mass General Brigham by capturing diverse stakeholder perspectives.

Prodrug Strategy to Address Impaired Oral Absorption of a Weakly Basic TYK2 Inhibitor Caused by a Gastric Acid-Reducing Agent.

The pH-dependent solubility of the weakly basic TYK2 inhibitor posed a risk to its advancement, given that drugs with such profiles have exhibited drug-drug interaction (DDI) with stomach acid-reducing agents in humans. In a rat model of pH dependence, preadministration of famotidine caused a 2.4-fold lower exposure of when compared to control rats, implying that pH-dependent oral absorption can reduce the active drug's exposure and translate to subtherapeutic treatment.

Validation of high-sensitivity assays to quantitate cerebrospinal fluid and serum β-galactosidase activity in patients with GM1-gangliosidosis.

GM1-gangliosidosis (GM1) is a lysosomal storage disorder caused by mutations in the galactosidase beta 1 gene () that leads to reduced β-galactosidase (β-gal) activity. This enzyme deficiency results in neuronal degeneration, developmental delay, and early death. A sensitive assay for the measurement of β-gal enzyme activity is required for the development of disease-modifying therapies.

Laryngeal Vibrotactile Stimulation Is Feasible, Acceptable To People With Unexplained Chronic Cough.

Objectives: Unexplained chronic cough (UCC) is common and has significant impacts on quality of life. Ongoing cough can sensitize the larynx, increasing the urge to cough and perpetuating the cycle of chronic cough. Vibrotactile stimulation (VTS) of the larynx is a noninvasive stimulation technique that can modulate laryngeal somatosensory and motor activity.

Short and long-term acceptability and efficacy of extended-release cornstarch in the hepatic glycogen storage diseases: results from the Glyde study.

Background: Hypoglycaemia is the primary manifestation of all the hepatic types of glycogen storage disease (GSD). In 2008, Glycosade, an extended-release waxy maize cornstarch, was reported as an alternative to uncooked cornstarch (UCCS) which could prolong the duration of fasting in the GSD population. To date, there has been minimal published experience in (a) young children, (b) the ketotic forms of GSD, and (c) with daytime dosing.

"I knew the effects the whole time." Examination of facilitators and barriers to quit vaping among adolescents.

Despite declines in adolescent nicotine vaping during the COVID-19 pandemic, vaping continues to be a public health issue for many adolescents. Most studies on teen reasons for vaping and on barriers and facilitators of vaping were conducted prior to the pandemic. Because teen culture changes so rapidly, and because the pandemic had wide-reaching effects on teens and mental health, it is critical to have a current understanding what helps adolescents to quit vaping (facilitators), as well as what prevents them from quitting (barriers) in order to design effective and engaging interventions.

Janus kinase inhibitors in the treatment of pyoderma gangrenosum: case report and review.

Pyoderma gangrenosum (PG) is a rare inflammatory dermatologic condition with neutrophilic infiltration of the skin that causes pustules and ulcerations. Janus kinase (JAK) inhibitors are immunomodulating agents that have been recently described in the literature as an effective treatment for PG. We describe a patient with PG on the lower extremities successfully treated with baricitinib.

Academic Medicine and Rural Health System Partnerships: Enhancing Education While Advancing Physician Workforce Priorities.

A worsening shortage of rural physicians paralleling increasing health disparities demands attention. Past and ongoing efforts to address this shortage have had positive effects and can inform new strategies to achieve even greater impact. Interventions have included the development of regional medical school campuses and rural-focused tracks to recruit medical students from rural areas, expansion of rural-based graduate medical education (GME) programs and tracks, and use of institutional and individual financial incentives for rural-based training and/or practice.

Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase.

WRN helicase is a promising target for treatment of cancers with microsatellite instability (MSI) due to its essential role in resolving deleterious non-canonical DNA structures that accumulate in cells with faulty mismatch repair mechanisms. Currently there are no approved drugs directly targeting human DNA or RNA helicases, in part owing to the challenging nature of developing potent and selective compounds to this class of proteins. Here we describe the chemoproteomics-enabled discovery of a clinical-stage, covalent allosteric inhibitor of WRN, VVD-133214.

Idiopathic Pathological Ketotic Hypoglycemia: Finding the Needle in a Haystack.

Sick children often have a decreased appetite and experience vomiting and diarrhea; however, hypoglycemia (plasma glucose concentration ≤50 mg/dL or 2.8 mmol/L) is rare. Ketotic hypoglycemia (KH) is the most common cause of hypoglycemia presenting to an Emergency Department in a previously healthy child between 6 months and 6 years of age.

A US payer perspective health economic model assessing value of monitoring disease activity to inform discontinuation and re-initiation of DMT in multiple sclerosis.

Objectives: We evaluate the potential clinical and cost impacts of discontinuing disease-modifying therapy (DMT) in people with multiple sclerosis (PwMS) when age-related immunosenescence can reduce DMT efficacy while increasing associated risks.

Methods: A Markov model simulated clinical and cost impacts to the patient and payers when a proportion of eligible patients with relapsing remitting multiple sclerosis (RRMS) discontinue DMT. Eligibility was defined as age >55 years, an RRMS diagnosis of >5 years, and no history of relapses for 5 years.

Promotion in Place: A Model for Competency-Based, Time-Variable Graduate Medical Education.

Problem: Competency-based medical education is increasingly regarded as a preferred framework for physician training, but implementation is limited. U.S.

Presence of kratom in opioid overdose deaths: findings from coroner postmortem toxicological report.

Background: Kratom () use in the United States is becoming increasingly popular and its legal status varies widely from state to state. Multiple reports of adverse events associated with kratom use have ranged from liver injury, seizures, psychiatric disturbance, and rarely death.

Methods: This study investigated coroner autopsy reports from Kern County in California for the year 2020 which included qualitative data on substances from blood toxicological reports.

Challenges of treating catatonia in the community setting without access to electroconvulsive therapy.

Catatonia is a psychomotor syndrome resulting from an underlying psychiatric or medical disorder commonly observed in inpatient psychiatric units. While benzodiazepines and electroconvulsive therapy (ECT) are effective treatment options, the unavailability of ECT in many community psychiatric hospitals in the United States negatively affects patient outcomes. We present a 25-year-old African American male with a psychiatric diagnosis of schizophrenia complicated by malignant catatonia who was admitted to a community psychiatric hospital.

The impact of prior authorization review on orthopaedic subspecialty care: a prospective multicenter analysis.

Background: Prior authorization review (PAR), in the United States, is a process that was initially intended to focus on hospital admissions and costly high-acuity care. Over time, payors have broadened the scope of PAR to include imaging studies, prescriptions, and routine treatment. The potential detrimental effect of PAR on health care has recently been brought into the limelight, but its impact on orthopedic subspecialty care remains unclear.

Status May Differentiate Two Distinct Pathways of Gastric Adenocarcinoma Carcinogenesis.

Background: We evaluated the phenotype of sporadic gastric cancer based on HP status and binding of a tumor risk marker monoclonal, Adnab-9.

Methods: We compared a familial GC kindred with an extremely aggressive phenotype to HP-positive (HP+) and -negative (HP-) sporadic gastric adenocarcinoma (GC) patients in the same community to determine if similar phenotypes exist. This might facilitate gene discovery to understand the pathogenesis of aggressive GC phenotypes, particularly with publications implicating immune-related gene-based signatures, and the development of techniques to gauge the stance of the innate immune system (InImS), such as the FERAD ratio (blood ferritin:fecal Adnab-9 binding OD-background binding).

Endogenous Glucose Production in Patients With Glycogen Storage Disease Type Ia Estimated by Oral D-[6,6-2H2]-glucose.

Context: Glycogen storage disease type Ia (GSDIa) is an inborn metabolic disorder characterized by impaired endogenous glucose production (EGP). Monitoring of patients with GSDIa is prioritized because of ongoing treatment developments. Stable isotope tracers may enable reliable EGP monitoring.

Advocacy at the Eighth World Congress of Pediatric Cardiology and Cardiac Surgery.

The (WCPCCS) will be held in Washington DC, USA, from Saturday, 26 August, 2023 to Friday, 1 September, 2023, inclusive. The will be the largest and most comprehensive scientific meeting dedicated to paediatric and congenital cardiac care ever held. At the time of the writing of this manuscript, has 5,037 registered attendees (and rising) from 117 countries, a truly diverse and international faculty of over 925 individuals from 89 countries, over 2,000 individual abstracts and poster presenters from 101 countries, and a Best Abstract Competition featuring 153 oral abstracts from 34 countries.

Methods used to quit vaping among adolescents and associations with perceived risk, addiction, and socio-economic status.

Despite widespread evidence suggesting that e-cigarettes are harmful to youth, the prevalence of adolescent vaping continues to rise. The first aim of this cross-sectional study was to determine which methods adolescents have previously used to quit vaping and their interest in using various methods to quit vaping in the future. The second aim was to investigate the associations between vaping-related characteristics and (1) motivation to quit vaping and (2) previous use of pharmacological methods to quit vaping or previous use of unassisted quitting.