Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations.

Herein, we report the identification and optimization of a series of potent inhibitors of EGFR Exon20 insertions with significant selectivity over wild-type EGFR. A strategically designed HTS campaign, multiple iterations of structure-based drug design (SBDD), and tactical linker replacement led to a potent and wild-type selective series of molecules and ultimately the discovery of 36. Compound 36 is a potent and selective inhibitor of EGFR Exon20 insertions and has demonstrated encouraging efficacy in NSCLC EGFR CRISPR-engineered H2073 xenografts that carry an SVD Exon20 insertion and reduced efficacy in a H2073 wild-type EGFR xenograft model compared to CLN-081 (5), indicating that 36 may have lower EGFR wild-type associated toxicity.

The Development of a Multi-Modal Cancer Rehabilitation (Including Prehabilitation) Service in Sheffield, UK: Designing the Active Together Service.

Cancer patients undergoing major interventions face numerous challenges, including the adverse effects of cancer and the side effects of treatment. Cancer rehabilitation is vital in ensuring cancer patients have the support they need to maximise treatment outcomes and minimise treatment-related side effects and symptoms. The Active Together service is a multi-modal rehabilitation service designed to address critical support gaps for cancer patients. The service is located and provided in Sheffield, UK, an area with higher cancer incidence and mortality rates than the national average. The service aligns with local and regional cancer care objectives and aims to improve the clinical and quality-of-life outcomes of cancer patients by using lifestyle behaviour-change techniques to address their physical, nutritional, and psychological needs. This paper describes the design and initial implementation of the Active Together service, highlighting its potential to support and benefit cancer patients.

Development of a Series of Pyrrolopyridone MAT2A Inhibitors.

The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ'9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.

Mapping Respiratory Health Digital Interventions in South and Southeast Asia: Protocol for a Scoping Review.

BACKGROUND: The last 2 decades have been a time of exponential growth and maturation for digital health, while the global burden of respiratory disease continues to grow worldwide. Leveraging digital health interventions (DHIs) to manage and mitigate respiratory disease and its adverse health effects presents itself as an obvious path forward. OBJECTIVE: We aimed to understand the current digital landscape and enabling environment around respiratory health to reduce costs, avoid duplication, and understand the comprehensiveness of DHIs. METHODS: This study will follow a scoping review methodology as outlined by Arksey and O'Malley, the Joanna Briggs Institute, and the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) checklist. MEDLINE, Embase, CINAHL, PsycINFO, Cochrane Library, Web of Science, PakiMedNet, and MyMedR databases will be searched along with key websites, repositories, and gray literature databases. The terms "respiratory health," "digital health," "South Asia," and "Southeast Asia," as well as related terms will be searched. The results will be screened for duplicates and then against the inclusion and exclusion criteria. For the studies included, data will be extracted, collated, and analyzed. RESULTS: The scoping review was started in July 2023 and will be finalized by February 2024. Results will be presented following the World Health Organization's classification of DHIs to categorize interventions in a standardized format and the mobile health evidence reporting and assessment checklist to report on the effectiveness of interventions. Further exposition of the evidence extracted will be presented through narrative synthesis. CONCLUSIONS: As DHIs continue to proliferate, the need to understand the current landscape becomes more pertinent. In this scoping review, we will seek to more clearly understand what digital health tools and technologies are being used in the current landscape of digital health in South and Southeast Asia for respiratory health and to what extent they are addressing the respiratory health needs of the region. The results will inform recommendations on digital health tools for respiratory health in South and Southeast Asia will help funders and implementers of DHIs leverage existing technologies and accelerate innovations that address documented gaps in the studied countries. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52517.

An assay for aryl radicals using BHAS coupling.

Aryl radicals are intermediates in many reactions, but determining their presence unambiguously is often challenging. As we recently reported, reaction of 2-iodo-1,3-dimethylbenzene (7) in benzene with KOtBu and a suitable organic additive, leads to a base-induced homolytic aromatic substitution (BHAS) coupling reaction giving 2,6-dimethylbiphenyl (12) and biphenyl (3) as coupled products, together with xylene (13). In this case, biphenyl arises from a radical translocation and is the major coupling product. This paper now quantitatively investigates that reaction, which shows a very similar ratio for 3 : 12 [ca. 4 : 1] when using different sources of radical initiation. Deuterium isotope studies provide detailed mechanistic support for the proposed mechanism; when carried out in C6D6vs. C6H6, the reaction is characterised by a strong isotope effect for formation of 3-d10vs. 3, but not for formation of 12-d5vs. 12. These distinctive properties mean that the transformation can act as an assay for aryl radicals. An advantage of such a BHAS process is its sensitivity, since it involves a chain reaction that can amplify radical activity.

"My Blood, You Know, My Biology Being out There ": Consent and Participant Control of Biological Samples.

The widespread and persistent underrepresentation of groups experiencing health disparities in research involving biospecimens is a barrier to scientific knowledge and advances in health equity. To ensure that all groups have the opportunity to participate in research and feel welcome and safe doing so, we must understand how research studies may be shaped to promote inclusion. In this study, we explored the decision to participate in hypothetical research scenarios among African American adults (n = 169) that varied on the basis of four attributes (form of consent, reason for research, institutional affiliation and race of the researcher). Findings indicate that participants were largely willing to contribute to biobanks but significantly preferred opportunities where they had control over the use of their biological samples through tiered or study-specific forms of consent. Broad consent procedures, although common and perhaps preferred by participants with high trust in researchers, may amount to an exclusionary practice.

Establishing Innovative Complex Services: Learning from the Active Together Cancer Prehabilitation and Rehabilitation Service.

Prehabilitation and rehabilitation will be essential services in an ageing population to support patients with cancer to live well through their life spans. Active Together is a novel evidence-based service embedded within existing healthcare pathways in an innovative collaboration between health, academic, and charity organisations. Designed to improve outcomes for cancer patients and reduce the demand on healthcare resources, it offers physical, nutritional, and psychological prehabilitation and rehabilitation support to patients undergoing cancer treatment. The service is underpinned by behaviour change theories and an individualised and personalised approach to care, addressing the health inequalities that might come about through age, poverty, ethnicity, or culture. Meeting the challenge of delivering high-quality services across multiple stakeholders, while addressing the complexity of patient need, has required skilled leadership, flexibility, and innovation. To support patients equally, regardless of geography or demographics, future services will need to be scaled regionally and be available in locations amenable to the populations they serve. To deliver these services across wide geographic regions, involving multiple providers and complex patient pathways, will require a systems approach. This means embracing and addressing the complexity of the contexts within which these services are delivered, to ensure efficient, high-quality provision of care, while supporting staff well-being and meeting the needs of patients.

Assessment of implementation methods in sepsis: study protocol for a cluster-randomized hybrid type 2 trial.

BACKGROUND: Sepsis is the leading cause of intensive care unit (ICU) admission and ICU death. In recognition of the burden of sepsis, the Surviving Sepsis Campaign (SSC) and the Institute for Healthcare Improvement developed sepsis "bundles" (goals to accomplish over a specific time period) to facilitate SSC guideline implementation in clinical practice. Using the SSC 3-h bundle as a base, the Centers for Medicare and Medicaid Services developed a 3-h sepsis bundle that has become the national standard for early management of sepsis. Emerging observational data, from an analysis conducted for the AIMS grant application, suggest there may be additional mortality benefit from even earlier implementation of the 3-h bundle, i.e., the 1-h bundle. METHOD: The primary aims of this randomized controlled trial are to: (1) examine the effect on clinical outcomes of Emergency Department initiation of the elements of the 3-h bundle within the traditional 3 h versus initiating within 1 h of sepsis recognition and (2) examine the extent to which a rigorous implementation strategy will improve implementation and compliance with both the 1-h bundle and the 3-h bundle. This study will be entirely conducted in the Emergency Department at 18 sites. A secondary aim is to identify clinical sepsis phenotypes and their impact on treatment outcomes. DISCUSSION: This cluster-randomized trial, employing implementation science methodology, is timely and important to the field. The hybrid effectiveness-implementation design is likely to have an impact on clinical practice in sepsis management by providing a rigorous evaluation of the 1- and 3-h bundles. FUNDING: NHLBI R01HL162954. TRIAL REGISTRATION: ClinicalTrials.gov NCT05491941. Registered on August 8, 2022.

A Hierarchy of Ligands Controls Formation and Reaction of Aryl Radicals in Pd-Catalyzed Ground-State Base-Promoted Coupling Reactions.

Palladium salts and complexes were tested separately and in the presence of added ligands as potential sources of aryl radicals in ground-state coupling reactions of aryl halide with arenes under basic conditions (KOtBu). Our recently developed assay for aryl radicals was employed to test for aryl radicals. In this assay, aryl radicals derived from the test substrate, 1-iodo-2,6-dimethylbenzene 7, undergo base-promoted homolytic aromatic substitution (BHAS) with benzene to produce 2,6-dimethylbiphenyl 8 and biphenyl 9 in an approximately 1:4 ratio as well as m-xylene 10. The biphenyl arises from a diagnostic radical transfer reaction with the solvent benzene. Using substrate 7 with a range of Pd sources as potential initiators led to formation of 8, 9, and 10 in varying amounts. However, when any one of a range of diphosphinoferrocenes (e.g., dppf or dippf) or BINAP or the monophosphine, diphenylphosphinoferrocene, was added as a ligand to Pd(OAc)2, the ratio of [2,6-dimethylbiphenyl 8: biphenyl 9] moved decisively to that expected from the BHAS (radical) pathway. Further studies were conducted with dppf. When dppf was added to each of the other Pd sources, the ratio of coupled products was also diverted to that expected for radical BHAS chemistry. Deuterium isotope studies and radical trap experiments provide strong additional support for the involvement of aryl radicals. Accordingly, under these ground-state conditions, palladium sources, in the presence of defined ligands, convert aryl iodides to aryl radicals. A rationale is proposed for these observations.

Exploring the genetic diversity of Eimeria acervulina: A polymerase chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) approach.

Eimeria, protozoan parasites that can cause the disease coccidiosis, pose a persistent challenge to poultry production and welfare. Control is commonly achieved using good husbandry supplemented with routine chemoprophylaxis and/or live parasite vaccination, although widespread drug resistance and challenges to vaccine supply or cost can prove limiting. Extensive effort has been applied to develop subunit anticoccidial vaccines as scalable, cost-effective alternatives, but translation to the field will require a robust understanding of parasite diversity. Using a new Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) panel we begin to describe the genetic diversity of Eimeria acervulina populations in Africa and Europe. PCR-RFLP genotyping E. acervulina populations sampled from commercial broiler and layer chickens reared in Nigeria or the United Kingdom (UK) and Republic of Ireland (RoI) revealed comparable levels of haplotype diversity, in direct contrast to previous descriptions from the close relative E. tenella. Here, 25 distinct PCR-RFLP haplotypes were detected from a panel of 42 E. acervulina samples, including 0.7 and 0.5 haplotypes per sample in Nigeria (n = 20) and the UK/RoI (n = 14), respectively. All but six haplotypes were found to be country-specific. The PCR-RFLP markers immune mapped protein 1 (IMP1) and heat shock protein 90 (HSP90) were most informative for Nigerian E. acervulina, while microneme protein 3 (MIC3) and HSP90 were most informative in UK/RoI populations. High haplotype diversity within E. acervulina populations may indicate frequent genetic exchange and potential for rapid dissemination of genetic material associated with escape from selective barriers such as anticoccidial drugs and future subunit vaccines.

Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRASG12C with Demonstrable CNS Penetration.

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

The Detection of Date Shifting in Real-World Data.

OBJECTIVES: Analysis of health care real-world data (RWD) provides an opportunity to observe the actual patient diagnostic, treatment, and outcome events. However, researchers should understand the possible limitations of RWD. In particular, the dates in these data may be shifted from their actual values, which might affect the validity of study conclusions. METHODS: A methodology for detecting the presence of shifted dates in RWD was developed by considering various approaches to confirm the expected occurrences of medical events, including unique temporal occurrences as well as recurring seasonal or weekday patterns in diagnoses or procedures. Diagnosis and procedure data was obtained from 71 U.S. health care data provider organizations (HCOs), members of the TriNetX global research network. Synthetic data was generated for various degrees of date shifting corresponding to the diagnoses and procedures studied, yielding the resulting patterns when various degrees of shifting (including no shift) were applied. These patterns were compared with those produced for each HCO to predict the presence and degree of date shifting. These predictions were compared with statements of date shifting by the originating HCOs to determine the predictive accuracy of the methods studied. RESULTS: Twenty-eight of the 71 HCOs analyzed were predicted by methodology and confirmed by their data providers to have shifted data. Likewise, 39 were predicted and confirmed to not have shifted data. With four HCOs, agreement between predicted and stated date shifting status was not obtained. The occurrence of routine medical exams, only happening during weekdays, for these U.S. HCOs was most predictive (0.92 correlation coefficient) of the presence or absence of date shifting. CONCLUSION: The presence of date shifting for U.S. HCOs may be reliably detected assessing whether the routine exams should always occur on weekdays.

Perceived Hospital Stress, Severe Acute Respiratory Syndrome Coronavirus 2 Activity, and Care Process Temporal Variance During the COVID-19 Pandemic.

OBJECTIVES: The COVID-19 pandemic threatened standard hospital operations. We sought to understand how this stress was perceived and manifested within individual hospitals and in relation to local viral activity. DESIGN: Prospective weekly hospital stress survey, November 2020-June 2022. SETTING: Society of Critical Care Medicine's Discovery Severe Acute Respiratory Infection-Preparedness multicenter cohort study. SUBJECTS: Thirteen hospitals across seven U.S. health systems. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed 839 hospital-weeks of data over 85 pandemic weeks and five viral surges. Perceived overall hospital, ICU, and emergency department (ED) stress due to severe acute respiratory infection patients during the pandemic were reported by a mean of 43% ( sd , 36%), 32% (30%), and 14% (22%) of hospitals per week, respectively, and perceived care deviations in a mean of 36% (33%). Overall hospital stress was highly correlated with ICU stress (ρ = 0.82; p < 0.0001) but only moderately correlated with ED stress (ρ = 0.52; p < 0.0001). A county increase in 10 severe acute respiratory syndrome coronavirus 2 cases per 100,000 residents was associated with an increase in the odds of overall hospital, ICU, and ED stress by 9% (95% CI, 5-12%), 7% (3-10%), and 4% (2-6%), respectively. During the Delta variant surge, overall hospital stress persisted for a median of 11.5 weeks (interquartile range, 9-14 wk) after local case peak. ICU stress had a similar pattern of resolution (median 11 wk [6-14 wk] after local case peak; p = 0.59) while the resolution of ED stress (median 6 wk [5-6 wk] after local case peak; p = 0.003) was earlier. There was a similar but attenuated pattern during the Omicron BA.1 subvariant surge. CONCLUSIONS: During the COVID-19 pandemic, perceived care deviations were common and potentially avoidable patient harm was rare. Perceived hospital stress persisted for weeks after surges peaked.

Angiopoietin-Like4 Is a Novel Marker of COVID-19 Severity.

Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. OBJECTIVES: To assess the role of ANGPTL4 in COVID-19-related outcomes. DESIGN SETTING AND PARTICIPANTS: Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. MAIN OUTCOMES AND MEASURES: Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. RESULTS: Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per log2 increase, 1.53; 95% CI, 1.17-2.00; p = 0.002). Higher ANGPTL4 concentrations were also associated with higher proportions of venous thromboembolism and acute respiratory distress syndrome. Longitudinal ANGPTL4 concentrations were significantly different during the first 2 weeks of hospitalization in patients who subsequently died compared with survivors (p for interaction = 8.1 × 10-5). Proteomics analysis demonstrated abundance of ANGPTL4 in lung tissue compared with other organs in COVID-19. ANGPTL4 single-nuclear RNA gene expression was significantly increased in pulmonary alveolar type 2 epithelial cells and fibroblasts in COVID-19 lung tissue compared with controls. CONCLUSIONS AND RELEVANCE: ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients.

Understanding Canine 'Reactivity': Species-Specific Behaviour or Human Inconvenience?

Dogs are often referred to as "human's best friend," with many households in the United Kingdom and worldwide including a dog. Yet, whilst research highlights the myriad of human health benefits associated with canine companionship, many dogs are relinquished, or euthanized, for purported behavioral problems. A key behavior often cited in these situations is Reactivity, despite a lack of consensus in the literature (or in the lay population) as to exactly what is encompassed within this term. Resultantly, this paper reports on an online survey to investigate how the term Reactivity is understood by humans. Following the completion of a thematic analysis, six sub-themes were developed, forming three overarching theme clusters, namely; Canine Characteristics, The Importance of Human Perception and Human Capability. In sum, this research highlights the complex, nuanced and, sometimes, contradictory nature of understanding around the label of Reactivity, encompassing both canine and human factors. As such, conclusions include the proposal of a preliminary Perceived Reactivity Framework to conceptualize this seemingly multi-faceted concept.

Severe Acute Respiratory Infection-Preparedness: Protocol for a Multicenter Prospective Cohort Study of Viral Respiratory Infections.

Respiratory virus infections cause significant morbidity and mortality ranging from mild uncomplicated acute respiratory illness to severe complications, such as acute respiratory distress syndrome, multiple organ failure, and death during epidemics and pandemics. We present a protocol to systematically study patients with severe acute respiratory infection (SARI), including severe acute respiratory syndrome coronavirus 2, due to respiratory viral pathogens to evaluate the natural history, prognostic biomarkers, and characteristics, including hospital stress, associated with clinical outcomes and severity. DESIGN: Prospective cohort study. SETTING: Multicenter cohort of patients admitted to an acute care ward or ICU from at least 15 hospitals representing diverse geographic regions across the United States. PATIENTS: Patients with SARI caused by infection with respiratory viruses that can cause outbreaks, epidemics, and pandemics. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Measurements include patient demographics, signs, symptoms, and medications; microbiology, imaging, and associated tests; mechanical ventilation, hospital procedures, and other interventions; and clinical outcomes and hospital stress, with specimens collected on days 0, 3, and 7-14 after enrollment and at discharge. The primary outcome measure is the number of consecutive days alive and free of mechanical ventilation (VFD) in the first 30 days after hospital admission. Important secondary outcomes include organ failure-free days before acute kidney injury, shock, hepatic failure, disseminated intravascular coagulation, 28-day mortality, adaptive immunity, as well as immunologic and microbiologic outcomes. CONCLUSIONS: SARI-Preparedness is a multicenter study under the collaboration of the Society of Critical Care Medicine Discovery, Resilience Intelligence Network, and National Emerging Special Pathogen Training and Education Center, which seeks to improve understanding of prognostic factors associated with worse outcomes and increased resource utilization. This can lead to interventions to mitigate the clinical impact of respiratory virus infections associated with SARI.

A patent review of MAT2a inhibitors (2018-2021).

INTRODUCTION: In methylthioadenosine phosphorylase (MTAP)-deficient tumor cells, reduced S-adenosylmethionine (SAM) levels in the context of elevated methylthioadenosine (MTA) has been hypothesized to lead to inhibition of protein arginine methyltransferase 5 (PRMT5) and tumor growth inhibition. Inhibitors of methionine adenosyltransferase 2A (MAT2a) prevent the synthesis of SAM from methionine and have therefore attracted increasing attention as potential chemotherapeutic agents in cancers characterized by MTAP-loss. AREAS COVERED: This review covers patent applications between January 2018 and December 2021. 18 patent applications from 5 different applicants are evaluated. EXPERT OPINION: Recent advances in the field show a significant interest in the MAT2a therapeutic hypothesis. Agios and Ideaya in particular have capitalized on an allosteric binding mode first published by Pfizer in at least two of the filings during this time period, leading to potent, selective inhibitors. They have advanced MAT2a inhibitors to phase I clinical studies to explore their benefit to patients suffering with MTAP-deficient solid tumors or lymphoma. Whilst the other patent disclosures during this time frame have not led to disclosed candidates, the trials initiated by Agios and Ideaya studies will clearly inform on the potential for such inhibitors as viable therapeutic agents either as single agent or in combination.