Evaluating the epizootic and zoonotic threat of an H7N9 low-pathogenicity avian influenza virus (LPAIV) variant associated with enhanced pathogenicity in turkeys.

Between 2013 and 2017, the A/Anhui/1/13-lineage (H7N9) low-pathogenicity avian influenza virus (LPAIV) was epizootic in chickens in China, causing mild disease, with 616 fatal human cases. Despite poultry vaccination, H7N9 has not been eradicated. Previously, we demonstrated increased pathogenesis in turkeys infected with H7N9, correlating with the emergence of the L217Q (L226Q H3 numbering) polymorphism in the haemagglutinin (HA) protein. A Q217-containing virus also arose and is now dominant in China following vaccination. We compared infection and transmission of this Q217-containing 'turkey-adapted' (ty-ad) isolate alongside the H7N9 (L217) wild-type (wt) virus in different poultry species and investigated the zoonotic potential in the ferret model. Both wt and ty-ad viruses demonstrated similar shedding and transmission in turkeys and chickens. However, the ty-ad virus was significantly more pathogenic than the wt virus in turkeys but not in chickens, causing 100 and 33% mortality in turkeys respectively. Expanded tissue tropism was seen for the ty-ad virus in turkeys but not in chickens, yet the viral cell receptor distribution was broadly similar in the visceral organs of both species. The ty-ad virus required exogenous trypsin for in vitro replication yet had increased replication in primary avian cells. Replication was comparable in mammalian cells, and the ty-ad virus replicated successfully in ferrets. The L217Q polymorphism also affected antigenicity. Therefore, H7N9 infection in turkeys can generate novel variants with increased risk through altered pathogenicity and potential HA antigenic escape. These findings emphasize the requirement for enhanced surveillance and understanding of A/Anhui/1/13-lineage viruses and their risk to different species.

Polygenic hazard score models for the prediction of Alzheimer's free survival using the lasso for Cox's proportional hazards model.

The prediction of the susceptibility of an individual to a certain disease is an important and timely research area. An established technique is to estimate the risk of an individual with the help of an integrated risk model, that is, a polygenic risk score with added epidemiological covariates. However, integrated risk models do not capture any time dependence, and may provide a point estimate of the relative risk with respect to a reference population. The aim of this work is twofold. First, we explore and advocate the idea of predicting the time-dependent hazard and survival (defined as disease-free time) of an individual for the onset of a disease. This provides a practitioner with a much more differentiated view of absolute survival as a function of time. Second, to compute the time-dependent risk of an individual, we use published methodology to fit a Cox's proportional hazard model to data from a genetic SNP study of time to Alzheimer's disease (AD) onset, using the lasso to incorporate further epidemiological variables such as sex, APOE (apolipoprotein E, a genetic risk factor for AD) status, 10 leading principal components, and selected genomic loci. We apply the lasso for Cox's proportional hazards to a data set of 6792 AD patients (composed of 4102 cases and 2690 controls) and 87 covariates. We demonstrate that fitting a lasso model for Cox's proportional hazards allows one to obtain more accurate survival curves than with state-of-the-art (likelihood-based) methods. Moreover, the methodology allows one to obtain personalized survival curves for a patient, thus giving a much more differentiated view of the expected progression of a disease than the view offered by integrated risk models. The runtime to compute personalized survival curves is under a minute for the entire data set of AD patients, thus enabling it to handle datasets with 60,000-100,000 subjects in less than 1 h.

The Ability of Physical Performance Measures to Identify Fall Risk in Older Adults Living With Dementia: A Systematic Review and Meta-Analysis.

OBJECTIVES: To determine whether physical performance measures commonly used in clinical settings can discriminate fallers from nonfallers and predict falls in older adults with dementia. DESIGN: Systematic review and meta-analysis. SETTING AND PARTICIPANTS: Older adults with dementia residing in the community, hospitals, and residential care facilities. METHODS: MEDLINE, Embase, PsycINFO, CINAHL, SPORTDiscus, the Cochrane Library, and the PEDro databases were searched from inception until December 27, 2023 (PROSPERO registration number: CRD42022303670). Retrospective or prospective studies that evaluated the associations between physical performance measures and falls in older adults with dementia were included. A random effects model was used to calculate the standardized mean difference (SMD) and 95% CI for each physical performance measure between fallers and nonfallers. Sensitivity analyses were conducted on the longitudinal studies to determine the ability of physical performance measures to predict future falls. RESULTS: Twenty-eight studies were included in this review (n = 3542). The 5-time chair stand test [SMD = 0.23 (0.01, 0.45)], the Berg Balance Scale [SMD = -0.52 (-0.87, -0.17)], postural sway when standing on the floor [SMD = 0.25 (0.07, 0.43)] and on a foam surface [SMD = 0.45 (0.25, 0.66)], and the Short Physical Performance Battery total score [SMD = -0.46 (-0.66, -0.27)] could discriminate fallers from nonfallers. Sensitivity analyses showed that gait speed could predict future falls in longitudinal cohort studies [SMD = -0.29 (-0.49, -0.08)]. Subgroup analyses showed that gait speed [SMD = -0.21 (-0.38, -0.05)] and the Timed Up and Go test [SMD = 0.54 (0.16, 0.92)] could identify fallers staying in residential care facilities or hospitals. CONCLUSIONS AND IMPLICATIONS: The 5-time chair stand test, the Berg Balance Scale, postural sway when standing on the floor and a foam surface, and the Short Physical Performance Battery can be used to predict falls in older adults with dementia. Gait speed and the Timed Up and Go test can be used to predict falls in institutionalized older adults with dementia. Clinicians are recommended to use these physical performance measures to assess fall risk in older adults with dementia.

Assessment of Survival Kinetics for Emergent Highly Pathogenic Clade 2.3.4.4 H5Nx Avian Influenza Viruses.

High pathogenicity avian influenza viruses (HPAIVs) cause high morbidity and mortality in poultry species. HPAIV prevalence means high numbers of infected wild birds could lead to spill over events for farmed poultry. How these pathogens survive in the environment is important for disease maintenance and potential dissemination. We evaluated the temperature-associated survival kinetics for five clade 2.3.4.4 H5Nx HPAIVs (UK field strains between 2014 and 2021) incubated at up to three temperatures for up to ten weeks. The selected temperatures represented northern European winter (4 °C) and summer (20 °C); and a southern European summer temperature (30 °C). For each clade 2.3.4.4 HPAIV, the time in days to reduce the viral infectivity by 90% at temperature T was established (DT), showing that a lower incubation temperature prolonged virus survival (stability), where DT ranged from days to weeks. The fastest loss of viral infectivity was observed at 30 °C. Extrapolation of the graphical DT plots to the x-axis intercept provided the corresponding time to extinction for viral decay. Statistical tests of the difference between the DT values and extinction times of each clade 2.3.4.4 strain at each temperature indicated that the majority displayed different survival kinetics from the other strains at 4 °C and 20 °C.

An expert panel on the adequacy of safety data and physiological roles of dietary bovine osteopontin in infancy.

Human milk, due to its unique composition, is the optimal standard for infant nutrition. Osteopontin (OPN) is abundant in human milk but not bovine milk. The addition of bovine milk osteopontin (bmOPN) to formula may replicate OPN's concentration and function in human milk. To address safety concerns, we convened an expert panel to assess the adequacy of safety data and physiological roles of dietary bmOPN in infancy. The exposure of breastfed infants to human milk OPN (hmOPN) has been well-characterized and decreases markedly over the first 6 months of lactation. Dietary bmOPN is resistant to gastric and intestinal digestion, absorbed and cleared from circulation within 8-24 h, and represents a small portion (<5%) of total plasma OPN. Label studies on hmOPN suggest that after 3 h, intact or digested OPN is absorbed into carcass (62%), small intestine (23%), stomach (5%), and small intestinal perfusate (4%), with <2% each found in the cecum, liver, brain, heart, and spleen. Although the results are heterogenous with respect to bmOPN's physiologic impact, no adverse impacts have been reported across growth, gastrointestinal, immune, or brain-related outcomes. Recombinant bovine and human forms demonstrate similar absorption in plasma as bmOPN, as well as effects on cognition and immunity. The panel recommended prioritization of trials measuring a comprehensive set of clinically relevant outcomes on immunity and cognition to confirm the safety of bmOPN over that of further research on its absorption, distribution, metabolism, and excretion. This review offers expert consensus on the adequacy of data available to assess the safety of bmOPN for use in infant formula, aiding evidence-based decisions on the formulation of infant formula.

HLH and Recurrent EBV Lymphoma as the presenting manifestation of MAGT1 Deficiency: A Systematic Review of the Expanding Disease Spectrum.

Magnesium transporter 1 (MAGT1) gene loss-of-function variants lead to X-linked MAGT1 deficiency with increased susceptibility to EBV infection and N-glycosylation defect (XMEN), a condition with a variety of clinical and immunological effects. In addition, MAGT1 deficiency has been classified as a congenital disorder of glycosylation (CDG) due to its unique role in glycosylation of multiple substrates including NKG2D, necessary for viral protection. Due to the predisposition for EBV, this etiology has been linked with hemophagocytic lymphohistiocytosis (HLH), however only limited literature exists. Here we present a complex case with HLH and EBV-driven classic Hodgkin lymphoma (cHL) as the presenting manifestation of underlying immune defect. However, the patient's underlying immunodeficiency was not identified until his second recurrence of Hodgkin disease, recurrent episodes of Herpes Zoster, and after he had undergone autologous hematopoietic stem cell transplant (HSCT) for refractory Hodgkin lymphoma. This rare presentation of HLH and recurrent lymphomas without some of the classical immune deficiency manifestations of MAGT1 deficiency led us to review the literature for similar presentations and to report the evolving spectrum of disease in published literature. Our systematic review showcased that MAGT1 predisposes to multiple viruses (including EBV) and adds risk of viral-driven neoplasia. The roles of MAGT1 in the immune system and glycosylation were highlighted through the multiple organ dysfunction showcased by the previously validated Immune Deficiency and Dysregulation Activity (IDDA2.1) score and CDG-specific Nijmegen Pediatric CDG Rating Scale (NPCRS) score for the patient cohort in the systematic review.

Conformational Dynamics of the Nucleosomal Histone H2B Tails Revealed by Molecular Dynamics Simulations.

Epigenetic modifications of histone N-terminal tails play a critical role in regulating the chromatin structure and biological processes such as transcription and DNA repair. One of the key post-translational modifications (PTMs) is the acetylation of lysine residues on histone tails. Epigenetic modifications are ubiquitous in the development of diseases, such as cancer and neurological disorders. Histone H2B tails are critical regulators of nucleosome dynamics, biological processes, and certain diseases. Here, we report all-atomistic molecular dynamics (MD) simulations of the nucleosome to demonstrate that acetylation of the histone tails changes their conformational space and interaction with DNA. We perform simulations of H2B tails, critical regulators of gene regulation, in both the lysine-acetylated (ACK) and unacetylated wild type (WT) states. To explore the effects of salt concentration, we use two different NaCl concentrations to perform simulations at microsecond time scales. Salt can modulate the effects of electrostatic interactions between the DNA phosphate backbone and histone tails. Upon acetylation, H2B tails shift their secondary structure helical propensity. The number of contacts between the DNA and the H2B tail decreases. We characterize the conformational dynamics of the H2B tails by principal component analysis (PCA). The ACK tails become more compact at increased salt concentrations, but conformations from the WT tails display the most contacts with DNA at both salt concentrations. Mainly, H2B acetylation may increase the DNA accessibility for regulatory proteins to bind, which can aid in gene regulation and NCP stability.

Antisera against flagellin A or B inhibits Pseudomonas aeruginosa motility as measured by novel video microscopy assay.

Flagellum-mediated motility is essential to Pseudomonas aeruginosa (P. aeruginosa) virulence. Antibody against flagellin reduces motility and inhibits the spread of the bacteria from the infection site. The standard soft-agar assay to demonstrate anti-flagella motility inhibition requires long incubation times, is difficult to interpret, and requires large amounts of antibody. We have developed a time-lapse video microscopy method to analyze anti-flagellin P. aeruginosa motility inhibition that has several advantages over the soft agar assay. Antisera from mice immunized with flagellin type A or B were incubated with Green Fluorescent Protein (GFP)-expressing P. aeruginosa strain PAO1 (FlaB+) and GFP-expressing P. aeruginosa strain PAK (FlaA+). We analyzed the motion of the bacteria in video taken in ten second time intervals. An easily measurable decrease in bacterial locomotion was observed microscopically within minutes after the addition of small volumes of flagellin antiserum. From data analysis, we were able to quantify the efficacy of anti-flagellin antibodies in the test serum that decreased P. aeruginosa motility. This new video microscopy method to assess functional activity of anti-flagellin antibodies required less serum, less time, and had more robust and reproducible endpoints than the standard soft agar motility inhibition assay.

Assessing the impact of jail-initiated medication for opioid use disorder: A multisite analysis of the SOMATICS collaborative.

The objective of this study was to estimate the associations of jail-initiated medication for opioid use disorder (MOUD) and patient navigation (PN) with opioid use disorder (OUD) at 6 months post-release. Three randomized trials (combined N = 330) were combined to assess whether MOUD (extended-release naltrexone or interim methadone) initiated prior to release from jail with or without PN would reduce the likelihood of a DSM-5 diagnosis of OUD 6 months post-release relative to enhanced treatment-as-usual (ETAU). Across the three studies, assignment to MOUD compared to ETAU was not associated with an OUD diagnosis at 6 months post-release (69% vs. 75%, respectively, OR = 0.67, 95% CI: 0.42 to 1.20). Similarly, PN compared to MOUD without PN was not associated with an OUD diagnosis (63% vs 77%, respectively, OR = 0.61, 95% CI: 0.27 to 1.53). Results underscore the need to further optimize the effectiveness of MOUD for patients initiating treatment in jail, beginning with an emphasis on post-release treatment adherence.

Comparison of an AI-Generated Case Report With a Human-Written Case Report: Practical Considerations for AI-Assisted Medical Writing.

INTRODUCTION:  The utility of ChatGPT has recently caused consternation in the medical world. While it has been utilized to write manuscripts, only a few studies have evaluated the quality of manuscripts generated by AI (artificial intelligence). OBJECTIVE:  We evaluate the ability of ChatGPT to write a case report when provided with a framework. We also provide practical considerations for manuscript writing using AI. METHODS: We compared a manuscript written by a blinded human author (10 years of medical experience) with a manuscript written by ChatGPT on a rare presentation of a common disease. We used multiple iterations of the manuscript generation request to derive the best ChatGPT output. Participants, outcomes, and measures: 22 human reviewers compared the manuscripts using parameters that characterize human writing and relevant standard manuscript assessment criteria, viz., scholarly impact quotient (SIQ). We also compared the manuscripts using the "average perplexity score" (APS), "burstiness score" (BS), and "highest perplexity of a sentence" (GPTZero parameters to detect AI-generated content). RESULTS: The human manuscript had a significantly higher quality of presentation and nuanced writing (p<0.05). Both manuscripts had a logical flow. 12/22 reviewers were able to identify the AI-generated manuscript (p<0.05), but 4/22 reviewers wrongly identified the human-written manuscript as AI-generated. GPTZero software erroneously identified four sentences of the human-written manuscript to be AI-generated. CONCLUSION:  Though AI showed an ability to highlight the novelty of the case report and project a logical flow comparable to the human manuscript, it could not outperform the human writer on all parameters. The human manuscript showed a better quality of presentation and more nuanced writing. The practical considerations we provide for AI-assisted medical writing will help to better utilize AI in manuscript writing.

Reaching back to enhance the future: the American Association for the Surgery of Trauma Diversity, Equity and Inclusion Pipeline Program.

Objectives: There are significant disparities in the surgical workforce in comparison with medical student demographics. Pipeline programs have shown to be effective in addressing gaps. The American Association for the Surgery of Trauma Diversity, Equity and Inclusion Committee designed a longitudinal pipeline program with high school student mentees and surgeon mentors providing an in-person hands-on workshop. Methods: The mentee demographics and socioeconomic status at the time of application were determined using overall percentages and the Area Deprivation Index (ADI). Program application essays were qualitatively analyzed for common themes. The pre-workshop and post-workshop and 6-month follow-up surveys were analyzed for mentee experience and areas for improvement. Results: Mentees selected were 30% male (N=3 of 10), 70% female (N=7 of 10), 50% black or African American (N=5 of 10) and 30% Hispanic or Latinx (N=3 of 10). The majority of mentees were in the most disadvantaged groups in their state by the ADI (N=8 of 9, 89%). Many of the application essays highlighted a personal loss as driving the interest in a health career with several of those losses based on 'gun violence'. There was under-representation in medicine racial/ethnic or gender concordance for 80% (N=8 of 10) of the mentee-mentor pairings. In the pre-workshop survey, even those students with high-grade point averages and strong academic achievement in science courses indicated low confidence in their ability to succeed. Most students (N=7 of 10, 70%) reported a strong positive connection with their mentor in the post-workshop survey. There was a reduction in self-identified modifiable barriers to success for 83% (N=5 of 6) of the mentees. One-third of students who responded to the 6-month survey indicated that they had issues with maintaining contact with their mentors after the workshop. Conclusion: The pipeline program was able to reach the target demographic and increase interest in surgery. Positive mentee/mentor relationships were formed. There are improvements to be made in longitudinal components of the program to ensure lasting results. Level of evidence: III.

Prediction of disease-free survival for precision medicine using cooperative learning on multi-omic data.

In precision medicine, both predicting the disease susceptibility of an individual and forecasting its disease-free survival are areas of key research. Besides the classical epidemiological predictor variables, data from multiple (omic) platforms are increasingly available. To integrate this wealth of information, we propose new methodology to combine both cooperative learning, a recent approach to leverage the predictive power of several datasets, and polygenic hazard score models. Polygenic hazard score models provide a practitioner with a more differentiated view of the predicted disease-free survival than the one given by merely a point estimate, for instance computed with a polygenic risk score. Our aim is to leverage the advantages of cooperative learning for the computation of polygenic hazard score models via Cox's proportional hazard model, thereby improving the prediction of the disease-free survival. In our experimental study, we apply our methodology to forecast the disease-free survival for Alzheimer's disease (AD) using three layers of data. One layer contains epidemiological variables such as sex, APOE (apolipoprotein E, a genetic risk factor for AD) status and 10 leading principal components. Another layer contains selected genomic loci, and the last layer contains methylation data for selected CpG sites. We demonstrate that the survival curves computed via cooperative learning yield an AUC of around $0.7$, above the state-of-the-art performance of its competitors. Importantly, the proposed methodology returns (1) a linear score that can be easily interpreted (in contrast to machine learning approaches), and (2) a weighting of the predictive power of the involved data layers, allowing for an assessment of the importance of each omic (or other) platform. Similarly to polygenic hazard score models, our methodology also allows one to compute individual survival curves for each patient.

Attitudes towards Telemedicine among Pregnant People and Parents of Toddlers in an Urban Safety-net Setting.

OBJECTIVE: To understand attitudes towards telemedicine and to further elucidate benefits, disadvantages, and visit preferences in a largely minority, urban safety-net setting. METHODS: Between 2020 and 2021, pregnant people, and parents of children younger than two years old were recruited from outpatient clinics. Interviews were conducted via phone, recorded, transcribed, and translated. Data were analyzed using content analysis. RESULTS: Seventy-four (74) individuals participated including 42 pregnant people and 32 parents. Most participants cited advantages to telemedicine including safety, convenience, improved access, and less disruption of work schedules, and wished to continue to have the telemedicine option available after the pandemic. CONCLUSIONS: Patients seeking care in safety-net settings, many of whom are working parents, noted that telemedicine improves access to care by providing an efficient and accessible option that overcomes barriers related to transportation and work schedules. Their experiences highlight the importance of continuing to offer telemedicine services.

Deletion of an immune evasion gene, steD, from a live Salmonella enterica serovar Typhimurium vaccine improves vaccine responses in aged mice.

Introduction: Non-typhoidal Salmonella (NTS) generally causes self-limiting gastroenteritis. However, older adults (≥65 years) can experience more severe outcomes from NTS infection. We have previously shown that a live attenuated S. Typhimurium vaccine, CVD 1926 (I77 ΔguaBA ΔclpP ΔpipA ΔhtrA), was immunogenic in adult but not aged mice. Here we describe modification of CVD 1926 through deletion of steD, a Salmonella effector responsible for host immune escape, which we hypothesized would increase immunogenicity in aged mice. Methods: Mel Juso and/or mutuDC cells were infected with S. Typhimurium I77, CVD 1926, and their respective steD mutants, and the MHC-II levels were evaluated. Aged (18-month-old) C57BL/6 mice received two doses of PBS, CVD 1926, or CVD 1926 ΔsteD perorally (109 CFU) and the number of FliC-specific CD4+ T cells were determined. Lastly, aged C57BL/6 mice received three doses of PBS, CVD 1926, or CVD 1926 ΔsteD perorally (109 CFU) and then were challenged perorally with wild-type S. Typhimurium SL1344 (108 CFU). These animals were also evaluated for antibody responses. Results: MHC-II induction was higher in cells treated with steD mutants, compared to their respective parental strains. Compared to PBS-vaccinated mice, CVD 1926 ΔsteD elicited significantly more FliC-specific CD4+ T cells in the Peyer's Patches. There were no significant differences in FliC-specific CD4+ T cells in the Peyer's patches or spleen of CVD 1926- versus PBS-immunized mice. CVD 1926 and CVD 1926 ΔsteD induced similar serum and fecal anti-core and O polysaccharide antibody titers after three doses. After two immunizations, the proportion of seroconverters for CVD 1926 ΔsteD was 83% (10/12) compared to 42% (5/12) for CVD 1926. Compared to PBS-immunized mice, mice immunized with CVD 1926 ΔsteD had significantly lower S. Typhimurium counts in the spleen, cecum, and small intestine upon challenge. In contrast, there were no differences in bacterial loads in the tissues of PBS-vaccinated and CVD 1926-immunized animals. Conclusion: These data suggest that the steD deletion enhanced the immunogenicity of our live attenuated S. Typhimurium vaccine. Deletion of immune evasion genes could be a potential strategy to improve the immunogenicity of live attenuated vaccines in older adults.

Last but not least: emerging roles of the autophagy-related protein ATG4D.

The evolutionarily conserved ATG4 cysteine proteases regulate macroautophagy/autophagy through the priming and deconjugation of the Atg8-family proteins. In mammals there are four ATG4 family members (ATG4A, ATG4B, ATG4C, ATG4D) but ATG4D has been relatively understudied. Heightened interest in ATG4D has been stimulated by recent links to human disease. Notably, genetic variations in human ATG4D were implicated in a heritable neurodevelopmental disorder. Genetic analyses in dogs, along with loss-of-function zebrafish and mouse models, further support a neuroprotective role for ATG4D. Here we discuss the evidence connecting ATG4D to neurological diseases and other pathologies and summarize its roles in both autophagy-dependent and autophagy-independent cellular processes.Abbrevation: ATG: autophagy related; BafA1: bafilomycin A1; BCL2: BCL2 apoptosis regulator; BH3: BCL2 homology region 3; CASP3: caspase 3; EV: extracellular vesicle; GABA: gamma aminobutyric acid; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; GFP: green fluorescent protein; LIR: LC3-interacting region; MAP1LC3: microtubule associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MYC: MYC proto-oncogene, bHLH transcription factor; PE: phosphatidylethanolamine; PS: phosphatidylserine; QKO: quadruple knockout; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel; SQSTM1: sequestosome 1.

Early-stage lung cancer is driven by a transitional cell state dependent on a KRAS-ITGA3-SRC axis.

Glycine-12 mutations in the GTPase KRAS (KRASG12) are an initiating event for development of lung adenocarcinoma (LUAD). KRASG12 mutations promote cell-intrinsic rewiring of alveolar type-II progenitor (AT2) cells, but to what extent such changes interplay with lung homeostasis and cell fate pathways is unclear. Here, we generated single-cell RNA-seq (scRNA-seq) profiles from AT2-mesenchyme organoid co-cultures, mice, and stage-IA LUAD patients, identifying conserved regulators of AT2 transcriptional dynamics and defining the impact of KRASG12D mutation with temporal resolution. In AT2WT organoids, we found a transient injury/plasticity state preceding AT2 self-renewal and AT1 differentiation. Early-stage AT2KRAS cells exhibited perturbed gene expression dynamics, most notably retention of the injury/plasticity state. The injury state in AT2KRAS cells of patients, mice, and organoids was distinguishable from AT2WT states via altered receptor expression, including co-expression of ITGA3 and SRC. The combination of clinically relevant KRASG12D and SRC inhibitors impaired AT2KRAS organoid growth. Together, our data show that an injury/plasticity state essential for lung repair is co-opted during AT2 self-renewal and LUAD initiation, suggesting that early-stage LUAD may be susceptible to interventions that target specifically the oncogenic nature of this cell state.

Exposure-Response and Subgroup Analyses to Support Body Weight-Based Dosing of Brentuximab Vedotin in Children and Young Adults with Newly Diagnosed High-Risk Classical Hodgkin Lymphoma.

PURPOSE: To evaluate the relationships between brentuximab vedotin (BV) pharmacokinetics, age, and body weight (BW) with efficacy and safety in pediatric and young adult patients with previously untreated, high-risk classical Hodgkin lymphoma (cHL) in the phase 3 AHOD1331 study. PATIENTS AND METHODS: Overall, 296 patients (age 2-21 years) in the overall population were randomized to and received BV + chemotherapy; the pharmacokinetic subpopulation comprised 24 patients (age <13 years). Age- and/or BW-based (pharmacokinetic surrogates) subgroup analyses of efficacy and safety were conducted for the overall population. Exposure-response analyses were limited to the pharmacokinetic subpopulation. RESULTS: There were no visible trends in disease characteristics across pediatric age subgroups, while BW increased with age. Observed antibody-drug conjugate exposures in patients aged <12 years were lower than those in adults administered BV 1.8 mg/kg every 3 weeks (Q3W), as exposure increased with BW. Nevertheless, no detrimental impact on event-free survival (EFS) was seen in younger subgroups: 3-year EFS was 96.2% (2-<12-years) and 92.0% (12-<18-years), with no events observed in those aged <6 years. Neither early response nor lack of need for radiation therapy was associated with high pharmacokinetic exposure. No evidence of exposure-driven grade ≥2 or ≥3 peripheral neuropathy or grade ≥3 neutropenia was seen in exposure-safety and BW-based subgroup analyses; the incidence of these safety events was comparable across pediatric age subgroups, despite lower exposure in younger children. CONCLUSIONS: No further adjustments based on age or BW are required for the BV dose (1.8 mg/kg Q3W) approved in children.