Synthesis and crystal structures of two racemic 2-heteroaryl-3-phenyl-2,3-di-hydro-4H-pyrido[3,2-e][1,3]thia-zin-4-ones.

3-Phenyl-2-(thio-phen-3-yl)-2,3-di-hydro-4H-pyrido[3,2-e][1,3]thia-zin-4-one (C17H12N2OS2, 1) and 2-(1H-indol-3-yl)-3-phenyl-2,3-di-hydro-4H-pyrido[3,2-e][1,3]thia-zin-4-one 0.438-hydrate (C21H15N3OS·0.438H2O, 2) crystallize in space groups P21/n and C2/c, respectively. The asymmetric unit in each case is comprised of two parent mol-ecules, albeit of mixed chirality in the case of 1 and of similar chirality in 2 with the enanti-omers occupying the neighboring asymmetric units. Structure 2 also has water mol-ecules (partial occupancies) that form continuous channels along the b -axis direction. The thia-zine rings in both structures exhibit an envelope conformation. Inter-molecular inter-actions in 1 are defined only by C-H⋯O and C-H⋯N hydrogen bonds between crystallographically independent mol-ecules. In 2, hydrogen bonds of the type N-H⋯O between independent mol-ecules and C-H⋯N(π) type, and π-π stacking inter-actions between the pyridine rings of symmetry-related mol-ecules are observed.

Electrophilic As-functionalisation of σ-arsolido complexes.

The σ-arsolido complex [Mo(AsC4Me4)(CO)3(η5-C5H5)] is alkylated at arsenic by MeOTf to afford the pentamethylarsole complex [Mo(MeAsC4Me4)(CO)3(η5-C5H5)](OTf) while iodomethane affords a mixture of [Me2AsC4Me4]I, [MoMe(CO)3(η5-C5H5)], [MoI(CO)3(η5-C5H5)] and the arsole complexes cisoid- and transoid-[MoI(MeAsC4Me4)(CO)2(η5-C5H5)] and transoid-[Mo{C(O)Me}(MeAsC4Me4)(CO)2(η5-C5H5)], The arsole ligand in [Mo(MeAsC4Me4)(CO)3(η5-C5H5)](OTf) is readily liberated by NaI in acetone to afford free MeAsC4Me4 and [MoI(CO)3(η5-C5H5)]. In a similar manner, the reaction of [Mo(AsC4Ph4)(CO)3(η5-C5H5)] with MeI affords MeAsC4Ph4 and [MoI(CO)3(η5-C5H5)], while [Mo{AsC4(SiMe3)-2-Me2-3,4}(CO)3(η5-C5H5)] with MeOTf affords [Mo{MeAsC4(SiMe3)-2-Me2-3,4}(CO)3(η5-C5H5)](OTf). The reaction of [Mo(AsC4Me4)(CO)3(η5-C5H5)] with activated alkynes (RCCR: R = CF3, CO2Me) does not proceed via [4 + 2] cyclo-addition but rather electrophilic attack at arsenic followed by metallacyclisation with incorporation of a carbonyl ligand in the spirocyclic complexes [Mo{As(C4Me4)CRCRCO}(CO)2(η5-C5H5)].

Longitudinal analysis of the lung proteome reveals persistent repair months after mild to moderate COVID-19.

In order to assess homeostatic mechanisms in the lung after COVID-19, changes in the protein signature of bronchoalveolar lavage from 45 patients with mild to moderate disease at three phases (acute, recovery, and convalescent) are evaluated over a year. During the acute phase, inflamed and uninflamed phenotypes are characterized by the expression of tissue repair and host defense response molecules. With recovery, inflammatory and fibrogenic mediators decline and clinical symptoms abate. However, at 9 months, quantified radiographic abnormalities resolve in the majority of patients, and yet compared to healthy persons, all showed ongoing activation of cellular repair processes and depression of the renin-kallikrein-kinin, coagulation, and complement systems. This dissociation of prolonged reparative processes from symptom and radiographic resolution suggests that occult ongoing disruption of the lung proteome is underrecognized and may be relevant to recovery from other serious viral pneumonias.

Augmenting CAR T Cell Functions with LIGHT.

Chimeric antigen receptor (CAR) T-cell therapy has resulted in remarkable clinical success in the treatment of B-cell malignancies. However, its clinical efficacy in solid tumors is limited, primarily by target antigen heterogeneity. To overcome antigen heterogeneity, we developed CAR T cells that overexpress LIGHT, a ligand of both LTßR on cancer cells and HVEM on immune cells. LIGHT-expressing CAR T cells displayed both antigen-directed cytotoxicity mediated by the CAR and antigen-independent killing mediated through the interaction of LIGHT with LTßR on cancer cells. Moreover, CAR T cells expressing LIGHT had immunostimulatory properties that improved the cells' proliferation and cytolytic profile. These data indicate that LIGHT-expressing CAR T cells may provide a way to eliminate antigen-negative tumor cells to prevent antigen-negative disease relapse.

σ-Arsolido complexes.

The σ-stannyl complexes [M(SnnBu3)(CO)n(η5-C5H5)] (n = 3, M = Mo, W; n = 2, M = Fe) serve as mild reagents for the installation of σ-arsolyl ligands in transmetallation reactions with As-chloro-arsoles ClAsC4R4 (R = Me, Ph) to afford [M(σ-AsC4R4)(CO)n(η5-C5H5)]. The reaction of [Cr(SnnBu3)(CO)3(η5-C5H5)] with ClAsC4Ph4 most likely proceeds in a similar manner but is immediately followed by rapid formation of (AsC4Ph4)2 and [Cr2(CO)6(η5-C5H5)2]. The reaction of [Mo(SnnBu3)(CO)3(η5-C5H5)] with ClAsC4(SiMe3)-2,5-Me2-3,4 is accompanied by monodesilylation to afford [Mo{σ-AsC4(SiMe3)-2-Me2-3,4}(CO)3(η5-C5H5)]. The slow reaction of [Fe(SnnBu3)(CO)2(η5-C5H5)] with ClAsC4Me4 produced only traces of [Fe(σ-AsC4Me4)(CO)2(η5-C5H5)] due to competition with the Diels-Alder type dimerisation of the haloarsole. Although attempts to decarbonylate the σ-arsolyl complexes were unsuccessful, computational analysis suggests that the trigonal 'XL' arsolenium coordination mode is viable.

A community case detection tool to promote help-seeking for mental health care among children and adolescents in Ugandan refugee settlements: a stepped wedge cluster randomised trial.

BACKGROUND: Strategies to promote mental health care help-seeking among children are needed, especially in low-income and middle-income countries and in complex settings. The aim of this trial was to compare a vignette-based, community-level, proactive case detection tool (CCDT) against standard awareness raising for promoting mental health help-seeking among children and adolescents. METHODS: This stepped wedge cluster randomised trial was conducted in the Bidi Bidi, Kyaka II, Kyangwali, Omugo, and Rhino refugee settlements in Uganda. Community gatekeepers received a 2-day training session on using the CCDT to proactively detect children with mental health concerns and encourage children (or their caregivers) to use the mental health-care service run by Transcultural Psychosocial Organization Uganda. At baseline, organisations implemented routine detection or mental health awareness-raising activities. At cross-over to CCDT implementation, gatekeepers used the tool in their daily activities. The primary outcome was mental health-care service use by children and adolescents. Child population size estimates at the zone level were not available. Therefore, service use was calculated using total population size. We report the effect of CCDT implementation as an incidence rate ratio (IRR), which we produced from a model that accounts for calendar time, exposure time, and person-time. IRRs were estimated for the analysis of effect over time in the per-protocol and intention-to-treat populations. The trial is registered with the ISRCTN registry, number ISRCTN19056780. FINDINGS: 28 administrative zones were selected for trial participation by October, 2021. Between Jan 1, and Nov 8, 2022, seven clusters of four zones sequentially crossed over from routine care to CCDT implementation in 1-month intervals. The CCDT was implemented by 177 trained community gatekeepers. In 9 months, 2385 children visited a mental health-care service; of these, 1118 (47%) were girls and 1267 (53%) were boys (mean age 12·18 years [SD 4.03]). 1998 children made a first or re-entry visit to a service; of these, 937 (47%) were girls and 1061 (53%) were boys (mean age 12·08 years [SD 4·06]). Compared to standard awareness-raising activities, CCDT implementation was associated with an increase in mental health-care service use in the first month after implementation (20·91-fold change [95% CI 12·87-33·99]). Despite a slight decline in service use over time in both the CCDT and pre-CCDT zones, CCDT zones maintained a time-average 16·89-fold increase (95% CI 8·15-34·99) in mental health service use. INTERPRETATION: The CCDT enabled community gatekeepers to increase mental health-care service use by children and adolescents. Vignette-based strategies rooted in the community could become a valuable contribution towards reducing the mental health-care gap among children, especially when accompanied by accessible mental health-care services. FUNDING: Sint Antonius Stichting Projects. TRANSLATIONS: For the Arabic, French and Spanish translations of the abstract see Supplementary Materials section.

Infant consumption of 100% lactose-based and reduced lactose infant formula in the United States: Review of NHANES data from 1999 to 2020.

OBJECTIVES: An acceptable alternative to human milk is US Food and Drug Administration (US FDA)-registered infant formula, which must meet the requirements of the US FDA Infant Formula Act. Human milk contains lactose, but some infant formulas may contain alternative carbohydrate sources such as corn syrup solids, maltodextrin, and sucrose. Recent research shows that infant-formula made with corn syrup solids may be associated with increased obesity risk in the first 5 years of life. A previous study found that of all formulas purchased, 59.0% were lactose-reduced. More US infants consume infant formula with nonlactose carbohydrates more frequently than is medically necessary. The purpose of this study is to use National Health and Nutrition Examination Survey (NHANES) data to describe the type and prevalence of nonlactose carbohydrates consumed in infant formula. METHODS: NHANES data from 1999 to 2020 was used to perform cross-sectional analyses and analyses of comparison of prevalence over time on consumption of nonlactose carbohydrate sources in infant formulas. RESULTS: We identified 3709 unique infant IDs associated with 36,084 feeding sessions. More than half of the feeding sessions involved a formula with at least one nonlactose carbohydrate. Feeding sessions involving a formula with at least one nonlactose carbohydrate increased by 163% from 1999-2004 to 2017-2020; formulas containing single or multiple nonlactose carbohydrate types account for the increase in prevalence. CONCLUSIONS: This study highlights an increase in the consumption of infant formula containing a nonlactose carbohydrate. More studies are needed to understand the short- and long-term effects of early exposure to these carbohydrates.

Improved Survival With Adjuvant Cyclooxygenase 2 Inhibition in PIK3CA-Activated Stage III Colon Cancer: CALGB/SWOG 80702 (Alliance).

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Observational studies have associated aspirin or cyclooxygenase 2 (COX-2) inhibitor usage either before or after colorectal cancer diagnosis with lower risk of recurrence and suggest that PIK3CA mutational status is predictive of better response to COX-2 inhibition. To prospectively test whether adding the COX-2 inhibitor celecoxib to standard adjuvant chemotherapy reduces the risk of recurrence and improves survival, the National Cancer Institute sponsored the CALGB/SWOG 80702 trial (ClinicalTrials.gov identifier: NCT01150045) for patients with stage III resected colon cancer. Although the primary hypothesis for all patients did not show a statistically significant improvement in disease-free survival (DFS) with celecoxib, subgroup analysis by PIK3CA mutational status was a preplanned study. PIK3CA gain-of-function mutations were detected in 259 of 1,197 tumors with available whole-exome sequencing data. When stratified by PIK3CA status, patients with PIK3CA gain-of-function mutations treated with celecoxib exhibited improved DFS (adjusted hazard ratio [HR], 0.56 [95% CI, 0.33 to 0.96]) compared with PIK3CA wildtype patients (adjusted HR, 0.89 [95% CI, 0.70 to 1.14]), although the interaction test was nonsignificant (Pinteraction = .13). Overall survival was similarly improved for patients with PIK3CA gain-of-function mutations (adjusted HR, 0.44 [95% CI, 0.22 to 0.85]) compared with PIK3CA wildtype patients (adjusted HR, 0.94 [95% CI, 0.68 to 1.30]; Pinteraction = .04). Although the test for heterogeneity in DFS did not reach statistical significance, the results suggest potential utility of PIK3CA to consider selective usage of COX-2 inhibitors in addition to standard treatment for stage III colon cancer.

Immune activation is associated with neurocognitive performance in Ugandan Adolescents living with HIV.

We examined relationships between neurocognition and immune activation in Ugandan adolescents with perinatally acquired HIV (PHIV). Eighty-nine adolescents in Kampala, Uganda (32 virally suppressed [<400 copies/mL] PHIV and 57 socio-demographically matched HIV- controls) completed a tablet-based neurocognitive test battery. Control derived z-scores for 12 individual tests and a global/overall z-score were calculated. We measured plasma (soluble CD14 and CD163), monocyte (proportions of monocyte subsets), and T cell (expression of CD38 and HLA-DR on CD4+ and CD8+) activation and gut markers. Spearman's rank correlations and median regressions examined associations between test performance and immune activation. Median [IQR] age was 15[13-16] years, 40% were females. Median time on ART was 10 years [7-11] for PHIV; 87% had viral load <50 copies/mL. Compared to controls, global z-scores were lower among PHIV (p=0.05), and significantly worse on tests of executive functioning and delayed recall (p's≤0.05). Overall, monocyte activation significantly correlated with worse test performance on global z-score (r=0.21, p=0.04), attention, processing speed, and motor speed (r=0.2-0.3, p≤0.01). T cell activation was significantly correlated with worse performance on tests of learning, executive functioning, and working memory (r=0.2-0.4, p≤0.04). In PHIV, after adjusting for age, sex, and ART duration, activated CD4 T cells remained associated with worse memory (ß-0.3, 95% CI, -0.55, -.07, p=0.01). PHIV with virologic suppression on ART show evidence of worse neurocognitive test performance compared to controls. Monocyte and T cell activation is correlated with worse neurocognition in Ugandan youth with and without HIV which has not been previously investigated in this setting.

The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.

BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. METHODS: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses. RESULTS: Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients. CONCLUSIONS: Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Genomic Profiling of Rare Undifferentiated Sarcomatoid Subtypes of Pancreatic Carcinomas: In Search of Therapeutic Targets.

PURPOSE: The highly aggressive undifferentiated sarcomatoid carcinoma (USC) subtype of pancreatic ductal adenocarcinoma (PDAC) remains poorly characterized because of its rarity. Previous case reports suggest that immune checkpoint inhibitors could be a promising treatment strategy, but the prevalence of established predictive biomarkers of response is largely unknown. The objective of this study was to leverage comprehensive genomic profiling of USC PDAC tumors to determine the prevalence of biomarkers associated with potential response to targeted therapies. METHODS: USC tumors (n = 20) underwent central pathology review by a board-certified gastrointestinal pathologist to confirm the diagnosis. These samples were compared with non-USC PDAC tumors (N = 5,562). Retrospective analysis of DNA and RNA next-generation sequencing data was performed. RESULTS: USC PDACs were more frequently PD-L1+ by immunohistochemistry than non-USC PDAC (63% v 16%, respectively, P < .001). Furthermore, USC PDAC had an increase in neutrophils (8.99% v 5.55%, P = .005) and dendritic cells (1.08% v 0.00%, q = 0.022) and an increased expression of PDCD1LG2 (4.6% v 1.3%, q = 0.001), PDCD1 (2.0% v 0.8%, q = 0.060), and HAVCR2 (45.9% v 21.7%, q = 0.107) than non-USC PDAC. Similar to non-USC PDAC, KRAS was the most commonly mutated gene (86% v 90%, respectively, P = 1). CONCLUSION: To our knowledge, this work represents the largest molecular analysis of USC tumors to date and showed an increased expression of immune checkpoint genes in USC tumors. These findings provide evidence for further investigation into immune checkpoint inhibitors in USC tumors.

Managing STEMIs without a Catheterization Lab: A Simulated Scenario to Improve Emergency Clinician Recognition and Execution of Thrombolysis in the Setting of Rural STEMI Management.

Audience: The targeted audience for this simulation is Emergency Medicine (EM) residents. Medical students, advanced practice providers, and staff physicians could all also find educational merit in this scenario. Background: Cardiovascular disease is the leading cause of death in the United States according to the CDC.1 Coronary artery disease caused 375,000 deaths 2021 alone, and about 5% of all adult patients have a prior history of coronary artery disease.2 Furthermore, chest pain itself is a common chief complaint encountered in the ED, with nearly 8 million visits annually occurring throughout the United States, with 10-20% of those patients ultimately being diagnosed with an acute coronary syndrome3, including ST-elevation myocardial infarction (STEMI). Given this, it is essential that EM residents are well prepared to care for all patients presenting with chest pain, regardless of the acute care or emergency setting.Throughout their training, most EM residents typically learn and evaluate patients at a large tertiary or quaternary medical center with 24-hour catheterization laboratory availability. For patients presenting with electrocardiogram (EKG) findings consistent with STEMI, the standard of care is for the patient to undergo cardiac catheterization and stent placement within 90 minutes of arrival. Unfortunately, only half of patients living in rural areas have a cardiac catheterization-capable facility available to them within a 60-minute driving radius, making it difficult for those patients to undergo cardiac catheterization within the desired time frame.4 These patients remain candidates for thrombolytic therapy, but given infrequent opportunities to learn about and deploy thrombolytic agents during residency training, graduating EM residents may be unfamiliar with indications, dosing, and contraindications before they begin practice. Furthermore, the recent EM workforce data suggests that although there may be an oversupply of 8,000 emergency physicians by 2030, robust practice opportunities for emergency physicians remain in rural settings.5 Although historically EM graduates have not selected rural areas for practice, with only approximately 8% of emergency physicians practicing in rural areas,6 it is likely that given the opportunities present and perceived saturation in many non-rural settings, more EM graduates will pursue practice in a rural setting. With these changing practice dynamics in mind, this simulation provides the opportunity for residents and medical students to experience the management of a STEMI in the rural setting, with a focus upon the indications, contraindications, dosing, and disposition of a patient receiving thrombolytics. Educational Objectives: By the end of this simulation, learners will be able to:Diagnose ST elevation myocardial infarction accurately and initiate thrombolysis in the rural setting without timely access to cardiac catheterization.Engage the simulated patient in a shared decision-making conversation, clearly outlying the benefits and risks of thrombolysis.Identify the indications and contraindications for thrombolysis in ST elevation myocardial infarction.Arrange for transfer to a tertiary care center following completion of thrombolysis. Educational Methods: This scenario is a simulated encounter in a rural emergency department setting requiring the diagnosis of a STEMI, a discussion with the patient regarding the risks and benefits of thrombolysis prior to administration, administration of thrombolysis, and transfer of patient to a higher level of care. Research Methods: The educational content of this simulation as a teaching instrument was evaluated by the learner utilizing an internally developed survey after case completion. This survey was reviewed for precision of language and assessment of learning objectives by our simulation faculty and other members of our West Virginia University Emergency Medicine Department of Medical Education. The learner was asked to specify any prior experience with rural STEMI management as well as quantify via a five-point Likert Scale, where 1 = very uncomfortable and 5 = very comfortable, their level of comfort with thrombolysis before and after the scenario as well as their comfort with having a shared decision-making conversation with patients with regards to thrombolysis. Learners were also asked to rank the helpfulness of this simulation in preparing them for administering thrombolytics for STEMI in a rural setting on a five-point Likert scale, where 1 = not helpful and 5 =very helpful. An open response section was also provided to allow learners the opportunity to comment directly on any aspect of the simulation. Results: Data was collected anonymously from 16 PGY1-3 resident learners via surveys with a 100% response rate. Overall, the feedback received regarding the simulation was positive. There was a low average comfort level with administering thrombolytics and having a shared decision-making conversation regarding administering thrombolytics. There was a high average rating of the helpfulness of this simulation in preparing residents for this conversation as well as managing STEMIs in a rural setting. Subjective comments regarding the simulation were universally positive. Discussion: The management of STEMI in the rural emergency department differs significantly from the environment in which many EM residents train. As a leading cause of death in the United States, STEMI management is a vital component of EM resident education. Although the concept of thrombolysis in the rural setting is discussed, the opportunity for real-world experience in its execution is often limited despite many graduates ultimately working in rural emergency departments. This simulation sought to provide a realistic patient encounter to promote familiarity and comfort in the identification, patient discussion and execution of thrombolysis in the treatment of a STEMI. The educational content was shown to be effective via learner survey completion.

Developing a membrane-proximal CD33-targeting CAR T cell.

BACKGROUND: CD33 is a tractable target in acute myeloid leukemia (AML) for chimeric antigen receptor (CAR) T cell therapy, but clinical success is lacking. METHODS: We developed 3P14HLh28Z, a novel CD33-directed CD28/CD3Z-based CAR T cell derived from a high-affinity binder obtained through membrane-proximal fragment immunization in humanized mice. RESULTS: We found that immunization exclusively with the membrane-proximal domain of CD33 is necessary for identification of membrane-proximal binders in humanized mice. Compared with clinically validated lintuzumab-based CAR T cells targeting distal CD33 epitopes, 3P14HLh28Z showed enhanced in vitro functionality as well as superior tumor control and increased overall survival in both low antigen density and clinically relevant patient-derived xenograft models. Increased activation and enhanced polyfunctionality led to enhanced efficacy. CONCLUSIONS: Showing for the first time that a membrane-proximal CAR is superior to a membrane-distal one in the setting of CD33 targeting, our results demonstrate the rationale for targeting membrane-proximal epitopes with high-affinity binders. We also demonstrate the importance of optimizing CAR T cells for functionality in settings of both low antigen density and clinically relevant patient-derived models.

Positron Emission Tomography Imaging of Tumor Proliferation and DNA Repair.

ABSTRACT: Positron emission tomography (PET) is an established tool for molecular imaging of cancers, and its role in diagnosis, staging, and phenotyping continues to evolve and expand rapidly. PET imaging of increased glucose utilization with 18F-fluorodeoxyglucose is now entrenched in clinical oncology practice for improving prognostication and treatment response assessment. Additional critical processes for cancer cell survival can also be imaged by PET, helping to inform individualized treatment selections for patients by improving our understanding of cell survival mechanisms and identifying relevant active mechanisms in each patient. The critical importance of quantifying cell proliferation and DNA repair pathways for prognosis and treatment selection is highlighted by the nearly ubiquitous use of the Ki-67 index, an established histological quantitative measure of cell proliferation, and BRCA mutation testing for treatment selection. This review focuses on PET advances in imaging and quantifying cell proliferation and poly(ADP-ribose)polymerase expression that can be used to complement cancer phenotyping approaches that will identify the most effective treatments for each individual patient.

Radiation Oncology Training in the Philippines: Bridging Gaps for Improved Cancer Care in Low- and Middle-Income Countries.

PURPOSE: Radiation oncology in the Philippines, a large lower- and middle-income country in Southeast Asia, is facing a critical shortage in manpower, with only 113 radiation oncologists (ROs) over 55 radiotherapy (RT) centers serving 100 million population. Paramount to workforce expansion is ensuring that training programs can produce adequately trained specialists. In this study, we describe the current state of radiation oncology training programs in the Philippines. METHODS: This is a cross-sectional observational analysis of the nine radiation oncology residency training programs in the Philippines. Data were collected from a survey of the program directors, the Philippine Radiation Oncology Society database, and a PubMed literature search. RESULTS: Eight of the nine programs are in the National Capital Region. Since program standardization in 2005, there have been 82 four-year residency graduates, with up to 18 new graduates annually. Faculty-to-trainee ratio ranges from 0.5 to 2.67. In terms of technology, all programs have intensity-modulated RT and high-dose-rate brachytherapy, but only six are equipped with computed tomography-based image guidance and stereotactic capabilities. Clinical education schemes vary per institution regarding curriculum implementation, resident activities, and methods of evaluation. Required resident case logs are not met for lung, GI, genitourinary, bone and soft tissue, and hematologic malignancies. In total, there are only 22 resident-led publications from 10 unique individuals in two training programs. CONCLUSION: Program expansions are warranted to meet the projected demand for ROs in the Philippines, but training programs must first improve key aspects of staffing, technology, clinical education, and research. Addressing training challenges related to resource limitations necessitates local and international collaborations with higher-capacity centers to bridge gaps for continued quality improvement with the aim of ultimately delivering better overall cancer care.

Gastrointestinal Acute Radiation Syndrome: Mechanisms, Models, Markers, and Medical Countermeasures.

There have been a number of reported human exposures to high dose radiation, resulting from accidents at nuclear power plants (e.g., Chernobyl), atomic bombings (Hiroshima and Nagasaki), and mishaps in industrial and medical settings. If absorbed radiation doses are high enough, evolution of acute radiation syndromes (ARS) will likely impact both the bone marrow as well as the gastrointestinal (GI) tract. Damage incurred in the latter can lead to nutrient malabsorption, dehydration, electrolyte imbalance, altered microbiome and metabolites, and impaired barrier function, which can lead to septicemia and death. To prepare for a medical response should such an incident arise, the National Institute of Allergy and Infectious Diseases (NIAID) funds basic and translational research to address radiation-induced GI-ARS, which remains a critical and prioritized unmet need. Areas of interest include identification of targets for damage and mitigation, animal model development, and testing of medical countermeasures (MCMs) to address GI complications resulting from radiation exposure. To appropriately model expected human responses, it is helpful to study analogous disease states in the clinic that resemble GI-ARS, to inform on best practices for diagnosis and treatment, and translate them back to inform nonclinical drug efficacy models. For these reasons, the NIAID partnered with two other U.S. government agencies (the Biomedical Advanced Research and Development Authority, and the Food and Drug Administration), to explore models, biomarkers, and diagnostics to improve understanding of the complexities of GI-ARS and investigate promising treatment approaches. A two-day workshop was convened in August 2022 that comprised presentations from academia, industry, healthcare, and government, and highlighted talks from 26 subject matter experts across five scientific sessions. This report provides an overview of information that was presented during the conference, and important discussions surrounding a broad range of topics that are critical for the research, development, licensure, and use of MCMs for GI-ARS.

How much do adverse childhood experiences contribute to adolescent anxiety and depression symptoms? Evidence from the longitudinal study of Australian children.

This study aims to: (i) examine the association between adverse childhood experiences (ACEs) and elevated anxiety and depressive symptoms in adolescents; and (ii) estimate the burden of anxiety and depressive symptoms attributable to ACEs.Data were analyzed from 3089 children followed between Waves 1 (age 4-5 years) and 7 (16-17 years) of the Longitudinal Study of Australian Children. Logistic regression was used to estimate the associations between ACEs and child-reported elevated anxiety and depressive symptoms at age 16-17. Anxiety and depressive symptoms were measured using the Children's Anxiety Scale and Short Mood and Feelings Questionnaire, respectively. The punaf command available in STATA 14 was used to calculate the population attributable fraction (PAF).Before the age of 18 years, 68.8% of the children had experienced two or more ACEs. In the analysis adjusted for confounding factors, including co-occurring ACEs, both history and current exposure to bullying victimisation and parental psychological distress were associated with a statistically significant increased likelihood of elevated anxiety and depressive symptoms at age 16-17. Overall, 47% of anxiety symptoms (95% CI for PAF: 35-56) and 21% of depressive symptoms (95% CI: 12-29) were attributable to a history of bullying victimisation. Similarly, 17% (95% CI: 11-25%) of anxiety and 15% (95% CI: 4-25%) of depressive symptoms at age 16-17 years were attributable to parental psychological distress experienced between the ages of 4-15 years.The findings demonstrate that intervention to reduce ACEs, especially parental psychological distress and bullying victimisation, may reduce the substantial burden of mental disorders in the population.

Differential landscape of immune evasion in oncogenic RAS-driven primary and metastatic colorectal cancers.

Oncogenic drivers such as KRAS extensively modulate the tumor inflammatory microenvironment (TIME) of colorectal cancer (CRC). The influence of KRAS on modulating immune cell composition remains unclear. The objective of this study was to identify signatures of infiltrative immune cells and distinctive patterns that differ between RAS wild-type (WT) and oncogenic mutant (MT) CRC that explain immune evasion in MT tumors. A total of 7,801 CRC specimens were analyzed using next-generation DNA sequencing, whole-exome sequencing, and/or whole transcriptome sequencing. Deficiency of mismatch repair (dMMR)/microsatellite instability (MSI) and tumor mutation burden (TMB) were also assessed. KRAS mutations were present in 48% of CRC, similarly distributed in patients younger than vs. 50 years and older. In microsatellite stable (MSS) KRAS MT tumors, composition of the TIME included higher neutrophil infiltration and lower infiltration of B cells. MSI-H/dMMR was significantly more prevalent in RAS WT (9.1%) than in KRAS MT (2.9%) CRC. In MSS CRC, TMB-high cases were significantly higher in RAS MT (3.1%) than in RAS WT (2.1%) tumors. KRAS and NRAS mutations are associated with increased neutrophil infiltration, with codon-specific differences. These results demonstrate significant differences in the TIME of RAS mutant CRC that match previous reports of immunoevasive characteristics of such tumors.

Oxaliplatin-Based Adjuvant Chemotherapy in Older Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 12 Trials.

PURPOSE: A number of studies suggest that older patients may have reduced or no benefit from the addition of oxaliplatin to fluoropyrimidines as adjuvant chemotherapy for stage III colon cancer (CC). MATERIALS AND METHODS: We studied the prognostic impact of age, as well as treatment adherence/toxicity patterns according to age, in patients with stage III CC who received 3 or 6 months of infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (CAPOX) on the basis of data collected from trials from the ACCENT and IDEA databases. Associations between age and time to recurrence (TTR), disease-free survival (DFS), overall survival (OS), survival after recurrence (SAR), and cancer-specific survival (CSS) were assessed by a Cox model or a competing risk model, stratified by studies and adjusted for sex, performance status, T and N stage, and year of enrollment. RESULTS: A total of 17,909 patients were included; 24% of patients were age older than 70 years (n = 4,340). Patients age ≥70 years had higher rates of early treatment discontinuation. Rates of grade ≥3 adverse events were similar between those older and younger than 70 years, except for diarrhea and neutropenia that were more frequent in older patients treated with CAPOX (14.2% v 11.2%; P = .01 and 12.1% v 9.6%; P = .04, respectively). In multivariable analysis, TTR was not significantly different between patients <70 years and those ≥70 years, but DFS, OS, SAR, and CSS were significantly shorter in those patients ≥70 years. CONCLUSION: In patients ≥70 years with stage III CC fit enough to be enrolled in clinical trials, oxaliplatin-based adjuvant chemotherapy was well tolerated and led to similar TTR compared with younger patients, suggesting similar efficacy. TTR may be a more appropriate end point for efficacy in this patient population.

Mechanisms of Exercise Intolerance Across the Breast Cancer Continuum: A Pooled Analysis of Individual Patient Data.

PURPOSE: The purpose of this study is to evaluate the prevalence of abnormal cardiopulmonary responses to exercise and pathophysiological mechanism(s) underpinning exercise intolerance across the continuum of breast cancer (BC) care from diagnosis to metastatic disease. METHODS: Individual participant data from four randomized trials spanning the BC continuum ([1] prechemotherapy [n = 146], [2] immediately postchemotherapy [n = 48], [3] survivorship [n = 138], and [4] metastatic [n = 47]) were pooled and compared with women at high-risk of BC (BC risk; n = 64). Identical treadmill-based peak cardiopulmonary exercise testing protocols evaluated exercise intolerance (peak oxygen consumption; V̇O2peak) and other resting, submaximal, and peak cardiopulmonary responses. The prevalence of 12 abnormal exercise responses was evaluated. Graphical plots of exercise responses were used to identify oxygen delivery and/or uptake mechanisms contributing to exercise intolerance. Unsupervised, hierarchical cluster analysis was conducted to explore exercise response phenogroups. RESULTS: Mean V̇O2peak was 2.78 ml O2.kg-1·min-1 (95% confidence interval [CI], -3.94, -1.62 mL O2.kg-1·min-1; P < 0.001) lower in the pooled BC cohort (52 ± 11 yr) than BC risk (55 ± 10 yr). Compared with BC risk, the pooled BC cohort had a 2.5-fold increased risk of any abnormal cardiopulmonary response (odds ratio, 2.5; 95% confidence interval, 1.2, 5.3; P = 0.014). Distinct exercise responses in BC reflected impaired oxygen delivery and uptake relative to control, although considerable inter-individual heterogeneity within cohorts was observed. In unsupervised, hierarchical cluster analysis, six phenogroups were identified with marked differences in cardiopulmonary response patterns and unique clinical characteristics. CONCLUSIONS: Abnormal cardiopulmonary response to exercise is common in BC and is related to impairments in oxygen delivery and uptake. The identification of exercise response phenogroups could help improve cardiovascular risk stratification and guide investigation of targeted exercise interventions.