Development of HC-258, a Covalent Acrylamide TEAD Inhibitor That Reduces Gene Expression and Cell Migration.

The transcription factor YAP-TEAD is the downstream effector of the Hippo pathway which controls cell proliferation, apoptosis, tissue repair, and organ growth. Dysregulation of the Hippo pathway has been correlated with carcinogenic processes. A co-crystal structure of TEAD with its endogenous ligand palmitic acid (PA) as well as with flufenamic acid (FA) has been disclosed. Here we report the development of HC-258, which derives from FA and possesses an oxopentyl chain that mimics a molecule of PA as well as an acrylamide that reacts covalently with TEAD's cysteine. HC-258 reduces the CTGF, CYR61, AXL, and NF2 transcript levels and inhibits the migration of MDA-MB-231 breast cancer cells. Co-crystallization with hTEAD2 confirmed that HC-258 binds within TEAD's PA pocket, where it forms a covalent bond with its cysteine.

Implementing front-of-pack nutrition warning labels in Mexico: important lessons for low- and middle-income countries.

OBJECTIVE: To analyse the implementation of front-of-pack nutrition labelling (FOPNL) in Mexico. DESIGN: Review of publicly accessible documents, including legislative websites, news sources, and government, intergovernmental, and advocacy reports. Usage of the policy cycle model to analyse the implementation and evaluation stages of Mexico's General Health Law, amended with FOPNL (2019-2022). RESULTS: In October 2019, the government published a draft modification of the Norma Oficial Mexicana (Official Mexican Standard) to regulate and enforce a new FOPNL warning label system. A 60-d public consultation period followed (October-December 2019), and the regulation was published in March 2020 and implementation began in October 2020. An analysis of nine key provisions of the Standard revealed that the food and beverage industry and its allies weakened some original provisions including health claims, warnings for added sweeteners and display areas. On the other hand, local and international public health groups maintained key regulations including the ban on cartoon character advertisements, standardised portions and nutrient criteria following international best practices. Early implementation appears to have high compliance and helped contribute to reformulating unhealthy products. Continued barriers to implementation include industry efforts to create double fronts and market their cartoon characters on social media and through digitalised marketing. CONCLUSION: Early success in implementing the new FOPNL system in Mexico was the result of an inclusive and participatory regulatory process dedicated to maintaining public health advances, local and international health advocacy support, and continued monitoring. Other countries proposing and enacting FOPNL should learn from the Mexican experience to maintain scientifically proven best practices, counter industry barriers and minimise delays in implementation.

Australian healthcare professionals' perspectives on the ethical and practical issues associated with genomic newborn screening.

Newborn bloodspot screening (NBS) is a successful public health initiative that seeks to identify serious, treatable medical conditions. The increasing use of genomic sequencing (GS) in a wide range of medical settings has reignited the discussion on whether GS can and should be integrated into NBS. Yet, the perspectives of healthcare professionals (HCPs) in Australia on the ethical and practical issues associated with the implementation of genomic newborn screening (GNBS) are underexplored. To address this, we conducted semi-structured interviews with 16 Australian HCPs with clinical or policy experience in NBS and/or GS to explore their perspectives on the ethical, social, and practical issues raised by integrating GS into NBS. Interviews were analyzed using inductive content analysis. When asked whether GS should be incorporated into NBS, HCPs did not feel it was currently appropriate but there was a strong consensus it may be implemented within the next decade. However, HCPs had differing perspectives on what conditions should be included and how to best handle the volume of data generated from GNBS. Our findings have important implications for determining at what point and how genomics can be integrated into NBS. The differing views expressed amongst HCPs suggest that further research is needed to explore the reasons behind this. Importantly, our participants highlighted a potential role for genetic counselors in the implementation of GNBS on a larger scale by developing educational resources to facilitate obtaining informed consent and return of results.

International Consensus Statement on Obstructive Sleep Apnea.

BACKGROUND: Evaluation and interpretation of the literature on obstructive sleep apnea (OSA) allows for consolidation and determination of the key factors important for clinical management of the adult OSA patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA). METHODS: Using previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence-based review (EBR), or evidence-based review with recommendations (EBR-R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus. RESULTS: The ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA treatment on multiple OSA-associated comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated. CONCLUSION: This review of the literature consolidates the available knowledge and identifies the limitations of the current evidence on OSA. This effort aims to create a resource for OSA evidence-based practice and identify future research needs. Knowledge gaps and research opportunities include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy.

Chronic Opioid Use and Sleep Disorders.

Opioid medications are considered a significant component in the multidisciplinary management of chronic pain. In the past two decades, the use of opioid medications has dramatically risen in part because of an increased awareness by health care providers to treat chronic pain more effectively. In addition, patients are encouraged to seek treatment. The release of a sentinel joint statement in 1997 by the American Academy of Pain Medicine and the American Pain Society in a national effort to increase awareness and support the treatment of chronic pain has undoubtedly contributed to the opioid crisis.

Obstructive sleep apnea: personalizing CPAP alternative therapies to individual physiology.

INTRODUCTION: The recent continuous positive airway pressure (CPAP) crisis has highlighted the need for alternative obstructive sleep apnea (OSA) therapies. This article serves to review OSA pathophysiology and how sleep apnea mechanisms may be utilized to individualize alternative treatment options. AREAS COVERED: The research highlighted below focuses on 1) mechanisms of OSA pathogenesis and 2) CPAP alternative therapies based on mechanism of disease. We reviewed PubMed from inception to July 2022 for relevant articles pertaining to OSA pathogenesis, sleep apnea surgery, as well as sleep apnea alternative therapies. EXPERT OPINION: Although the field of individualized OSA treatment is still in its infancy, much has been learned about OSA traits and how they may be targeted based on a patient's physiology and preferences. While CPAP remains the gold-standard for OSA management, several novel alternatives are emerging. CPAP is a universal treatment approach for all severities of OSA. We believe that a personalized approach to OSA treatment beyond CPAP lies ahead. Additional research is needed with respect to implementation and combination of therapies longitudinally, but we are enthusiastic about the future of OSA treatment based on the data presented here.

The Effect of Obstructive Sleep Apnea Treatment and Severity on Choroidal Thickness in Patients With Central Serous Chorioretinopathy.

Purpose: This work aimed to analyze the association of obstructive sleep apnea (OSA) with choroidal thickness (CT) in patients with central serous chorioretinopathy (CSC). Methods: We identified patients in the Stanford Research Repository with a diagnosis of CSC and OSA. Age- and sex-matched controls with either CSC or OSA only were also identified. CT was measured at 5 points (subfoveal, and 1500 and 3000 µm nasal and temporal) by 2 graders. In addition to OSA treatment and severity, we also investigated the association of Oxygen Desaturation Index and nocturnal oxygen saturation nadir with subfoveal CT (SFCT). Results: A total of 57 patients and 72 eyes met the study inclusion criteria. The mean SFCT was significantly different across the 3 groups: OSA-only was the thinnest, followed by CSC with OSA, and CSC-only was the thickest (194.2 µm, 295.1 µm, and 357.8 µm, respectively, P < .001). SFCT was thicker in CSC with OSA compared with those with only OSA (P < .05). OSA treatment status and OSA severity did not show a significant difference in SFCT in multivariable modeling. Nocturnal oxygen saturation nadir was positively associated with SFCT, but this did not reach significance.. Conclusions: SFCT is significantly different in patients with OSA alone, CSC with OSA, and CSC alone. While OSA treatment status did not demonstrate a significant difference in SFCT in this study, future studies should evaluate patients for OSA in patients known to have CSC and atypically thin CT to further investigate the novel metrics leveraged in this study.

Acute on Chronic Neuromuscular Respiratory Failure in the Intensive Care Unit: Optimization of Triage, Ventilation Modes, and Extubation.

Critical care management of acute respiratory failure in patients with neuromuscular disease (NMD) such as amyotrophic lateral sclerosis (ALS) is not standardized and is challenging for many critical care specialists. Progressive hypercapnic respiratory failure and ineffective airway clearance are key issues in this patient population. Often at the time of hospital presentation, patients are already supported by home mechanical ventilatory support with noninvasive ventilation (NIV) and an airway clearance regimen. Prognosis is poor once a patient develops acute respiratory failure requiring intubation and invasive mechanical ventilatory support, commonly leading to tracheostomy or palliative-focused care.  We focus on this understudied group of patients with ALS without tracheostomy and incorporate existing data to propose a technical approach to the triage and management of acute respiratory failure, primarily for those who require intubation and mechanical ventilatory support for reversible causes, and also for progression of end-stage disease. Optimizing management in this setting improves both quality and quantity of life. Neuromuscular patients with acute respiratory failure require protocolized and personalized triage and treatment. Here, we describe the technical methods used at our single institution. The triage phase incorporates comprehensive evaluation for new etiologies of hypoxia and hypercapnia, which are not initially presumed to be secondary to progression or end-stage neuromuscular respiratory failure. In select patients, this may involve intubation or advanced adjustments of NIV machines. Next, once the acute etiology(s) is identified and treated, the focus shifts: training and use of mechanical airway clearance to optimize pulmonary function, facilitation of NIV wean or successful extubation to NIV, and transition to a stable regimen for home ventilation. The comprehensive protocol described here incorporates multi-institutional approaches and effectively optimizes acute respiratory failure in patients with neuromuscular pulmonary disease.

Sleep medicine exposure offered by United States residency training programs.

STUDY OBJECTIVES: To understand the sleep medicine educational exposure among parent specialties of sleep medicine fellowships, we conducted an online survey among Accreditation Council of Graduate Medical Education-approved training programs. METHODS: Target respondents were program directors of family medicine, otolaryngology, psychiatry, neurology, pediatrics, and pulmonary and critical care training programs in the United States. The survey was based on the Sleep Education Survey, a peer-reviewed, published survey created by the American Academy of Neurology Sleep Section. The modified 18-question survey was emailed via Survey Monkey per published methods totaling 3 requests approximately 1 week apart in January 2017. RESULTS: A total of 1228 programs were contacted, and 479 responses were received for an overall response rate of 39%. Some programs in every specialty group offered a sleep medicine elective or a required rotation to trainees. Pulmonary and critical care and neurology reported the highest percentages of sleep medicine rotation as an option for housestaff (85.7% and 90.8%, respectively), and pulmonary and critical care had the highest portion of programs indicating a rotation requirement (75.4%). Teaching format was a mixture of didactic lectures, sleep center/laboratory exposure, and case reports, with lectures being the most common format. Didactics averaged 4.75 h/y. Few programs reported trainees subsequently pursuing sleep medicine fellowship (<10% produced a fellow over 5 years), and even fewer reported having a trainee who pursued grant funding for sleep-related research over 5 years. CONCLUSIONS: There is wide variability and overall low exposure to sleep medicine education among United States "parent" Accreditation Council of Graduate Medical Education training programs whose medical boards offer sleep medicine certification.

Noninvasive Ventilator Devices and Modes.

Noninvasive ventilation has become an increasingly common treatment strategy for patients with diverse conditions involving chronic respiratory failure. An intimate understanding of various advanced respiratory devices and modes is essential in the management of these patients. Pressure-limited modes of ventilation are more commonly used than volume modes for noninvasive ventilation owing to enhanced patient comfort and synchrony with the ventilator, as well as improved leak compensation. Common pressure modes include spontaneous/timed and pressure control, with volume-assured pressure support being an additive feature available on certain devices. Evidence guiding the optimal mode of ventilation for specific diseases is limited.

Strategies in the Management of Adolescent Obesity.

PURPOSE OF REVIEW: We review the current options to manage adolescent obesity which include nutrition, physical activity, behavior modification, sleep management, pharmacotherapy and surgery. Since lifestyle interventions alone are often not effective in adolescents, a multi-disciplinary treatment approach is necessary in management. RECENT FINDINGS: Medications (often used off-label) and metabolic/bariatric surgery are effective treatment strategies to treat adolescents with severe obesity. SUMMARY: The use of pharmacotherapy and surgery is limited due to lack of pediatric obesity tertiary care centers. With more centers, the treatment of adolescent obesity will improve and aid to decrease the prevalence of adult obesity.

The Effect of Obstructive Sleep Apnea on Absolute Risk of Central Serous Chorioretinopathy.

PURPOSE: To determine the incidence of central serous chorioretinopathy (CSC) stratified by age, sex, and diagnosis with obstructive sleep apnea (OSA), and to determine whether some patients with newly diagnosed CSC may be candidates for OSA evaluation. DESIGN: Retrospective cohort study. METHODS: We used the IBM MarketScan database to select 59,016,145 commercially insured patients in the United States between 2007 and 2016. We identified patients' first diagnosis with CSC, and defined patients as having OSA if they had a diagnosis following a sleep study. We specified Cox proportional hazard models with interactions between age, sex, and OSA status to determine patients' risk of developing CSC. We estimated the positive predictive value (PPV) that a new diagnosis of CSC would have in predicting a subsequent diagnosis of OSA. RESULTS: Risk of CSC increased with age in years (hazard ratio [HR] = 1.030, P < .001) and OSA diagnosis (HR = 1.081, P < .033), and was lower in women (HR = 0.284, P < .001). We estimated the annual incidence of CSC was 9.6 and 23.4 per 100,000 women and men, respectively. Incidence was higher in women and men with OSA (17.2 and 40.8 per 100,000). The PPV of CSC diagnosis as a predictor of OSA was highest in the fifth decade of life. CONCLUSION: The incidence of CSC in our patient sample is higher than previously reported. Risk of CSC is higher in men than in women, and OSA increases risk of CSC in both men and women. Some patients, particularly older male patients, may be good candidates for OSA evaluation following a CSC diagnosis.

Consensus-Based Care Recommendations for Pulmonologists Treating Adults with Myotonic Dystrophy Type 1.

PURPOSE OF REVIEW: Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects approximately 1 in 2,500 individuals globally [Ashizawa et al.: Neurol Clin Pract 2018;8(6):507-20]. In patients with DM1, respiratory muscle weakness frequently evolves, leading to respiratory failure as the main cause of death in this patient population, followed by cardiac complications [de Die-Smulders et al.: Brain 1998;121(Pt 8):1557-63], [Mathieu et al.: Neurology 1999;52(8):1658-62], [Groh et al.: Muscle Nerve 2011;43(5):648-51]. This paper provides a more detailed outline on the diagnostic and management protocols, which can guide pulmonologists who may not have experience with DM1 or who are not part of a neuromuscular multidisciplinary clinic. A group of neuromuscular experts in DM1 including pulmonologists, respiratory physiotherapists and sleep specialists discussed respiratory testing and management at baseline and during follow-up visits, based on their clinical experience with patients with DM1. The details are presented in this report. RECENT FINDINGS: Myotonic recruited 66 international clinicians experienced in the treatment of people living with DM1 to develop and publish consensus-based care recommendations targeting all body systems affected by this disease [Ashizawa et al.: Neurol Clin Pract. 2018;8(6):507-20]. Myotonic then worked with 12 international respiratory therapists, pulmonologists and neurologists with long-standing experience in DM respiratory care to develop consensus-based care recommendations for pulmonologists using a methodology called the Single Text Procedure. This process generated a 7-page document that provides detailed respiratory care recommendations for the management of patients living with DM1. This consensus is completely based on expert opinion and not backed up by empirical evidence due to limited clinical care data available for respiratory care management in DM patients. Nevertheless, we believe it is of relevance for professionals treating adults with myotonic dystrophy because it addresses practical issues related to respiratory management and care, which have been adapted to meet the specific issues in patients with DM1. SUMMARY: The resulting recommendations are intended to improve respiratory care for the most vulnerable of DM1 patients and lower the risk of untoward respiratory complications and mortality by providing pulmonologist who are less experienced with DM1 with practical indications on which tests and when to perform them, adapting the general respiratory knowledge to specific issues related to this multiorgan disease.

Effects of Chronic Opioid Use on Sleep and Wake.

Chronic use of opioids negatively affects sleep on 2 levels: sleep architecture and breathing. Patients suffer from a variety of daytime sequelae. There may be a bidirectional relationship between poor sleep quality, sleep-disordered breathing, and daytime function. Opioids are a potential cause of incident depression. The best therapeutic option is withdrawal of opioids, which proves difficult. Positive airway pressure devices are considered first-line treatment for sleep-related breathing disorders. New generation positive pressure servo ventilators are increasingly popular as a treatment option for opioid-induced sleep-disordered breathing. Treatments to improve sleep quality, sleep-related breathing disorders, and quality of life in patients who use opioids chronically are discussed.

Continuous positive airway pressure therapy in obstuctive sleep apnea: benefits and alternatives.

INTRODUCTION: Obstructive sleep apnea (OSA) is a highly prevalent condition affecting persons of all age with an increasing public health burden. It is implicated in cardiovascular disease, metabolic syndrome, neurocognitive impairment, reductions in quality of life, and increased motor vehicle accidents. The goals of OSA treatment are to improve sleep and daytime symptoms, and minimize cardiovascular risks.Areas covered: Continuous positive airway pressure (CPAP) is considered the gold standard therapy that delivers pressurized air into the upper airway to relieve obstruction during sleep. Although CPAP is an effective modality of treatment for OSA, adherence to therapy is highly variable. This article highlights the benefits of CPAP therapy, along with alternative treatment options including oral appliance, implantable and wearable devices, and surgery. Expert commentary: CPAP therapy is the gold standard treatment option and should continue to be offered to those who suffer from OSA. Alternative options are available for those who are unable to adhere to CPAP or choose an alternative treatment modality. The most interesting advances have been incorporating orthodontic procedures in conjunction with myofunctional therapy in prepubertal children, raising the possibility of OSA prevention by initiating treatment early in life.