Fratricide-resistant CD7-CAR T cells in T-ALL.

T cell acute lymphoblastic leukemia (T-ALL) is difficult to treat when it relapses after therapy or is chemoresistant; the prognosis of patients with relapsed or refractory T-ALL is generally poor. We report a case series of 17 such patients who received autologous chimeric antigen receptor (CAR) T cells expressing an anti-CD7 CAR and an anti-CD7 protein expression blocker (PEBL), which prevented CAR T cell fratricide. Despite high leukemic burden and low CAR T cell dosing, 16 of the 17 patients attained minimal residual disease-negative complete remission within 1 month. The remaining patient had CD7- T-ALL cells before infusion, which persisted after infusion. Toxicities were mild: cytokine release syndrome grade 1 in ten patients and grade 2 in three patients; immune effector cell-associated neurotoxicity syndrome grade 1 in two patients. Eleven patients remained relapse-free (median follow-up, 15 months), including all nine patients who received an allotransplant. The first patient is in remission 55 months after infusion without further chemotherapy or transplantation; circulating CAR T cells were detectable for 2 years. T cells regenerating after lymphodepletion lacked CD7 expression, were polyclonal and responded to SARS-CoV-2 vaccination; CD7+ immune cells reemerged concomitantly with CAR T cell disappearance. In conclusion, autologous anti-CD7 PEBL-CAR T cells have powerful antileukemic activity and are potentially an effective option for the treatment of T-ALL.

Immune Cell Profiles of Patients with Sickle Cell Disease during Parvovirus B19-Induced Transient Red Cell Aplasia.

Parvovirus B19 frequently infects children and targets cells of the erythroid lineage. Although healthy children rarely suffer severe disease, children with sickle cell disease (SCD) can experience transient red cell aplasia (TRCA), hospitalization, and life-threatening anemia upon first virus exposure. Given that children with SCD can also suffer chronic inflammation and that parvovirus B19 has been associated with autoimmune disease in other patient populations, we asked if parvovirus B19 infections contributed to acute and chronic immune abnormalities in children with SCD. Nineteen hospitalized patients with SCD and parvovirus B19-induced TRCA were evaluated. Blood tests included CBC, flow cytometry, and total antibody isotype analyses. Cytokine/chemokine analyses were performed on nasal wash (NW) samples, representing a common site of viral entry. Unusually high white blood cell count (WBC) and absolute neutrophil count (ANC) values were observed in some patients. A correlation matrix with Day 0 values from the 19 patients then identified two mutually exclusive phenotype clusters. Cluster 1 included WBC, ANC, absolute reticulocyte count (ARC), absolute lymphocyte count (ALC), lactate dehydrogenase (LDH), NW cytokines/chemokines, % naïve cells among B cell and T cell populations, and parvovirus-specific IgG. This cluster was negatively associated with virus load, suggesting a signature of successful adaptive immunity and virus control. Cluster 2 included virus load, % CD38+CD24- cells among CD19+ B cells (termed 'plasmablasts' for simplicity), % HLA-DRlow cells among CD19+ B cells, IgG4, and % memory phenotypes among B cell and T cell populations. Plasmablast percentages correlated negatively with parvovirus-specific IgG, possibly reflecting a non-specific trigger of cell activation. All patients were released from the hospital within 1 week after admission, and the highest WBC and ANC values were eventually reduced. Nonetheless, a concern remained that the acutely abnormal immune profiles caused by parvovirus B19 infections could exacerbate chronic inflammation in some patients. To avoid the numerous sequelae known to affect patients with SCD following hospitalizations with parvovirus B19, rapid development of a parvovirus B19 vaccine is warranted.

Impact of Age on Pharmacogenomics and Treatment Outcomes of B-Cell Acute Lymphoblastic Leukemia.

PURPOSE: Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear. METHODS: Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes. RESULTS: Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2-, DUX4-, and KMT2A-rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases. CONCLUSION: Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

Smartphone-based hyperspectral imaging for ice sheet and proglacial applications in South-West Greenland.

Hyperspectral imaging is a valuable analytical technique with significant benefits for environmental monitoring. However, the application of these technologies remains limited, largely by the cost and bulk associated with available instrumentation. This results in a lack of high-resolution data from more challenging and extreme environmental settings, limiting our knowledge and understanding of the effects of climate change in these regions. In this article we challenge these limitations through the application of a low-cost, smartphone-based hyperspectral imaging instrument to measurement and monitoring activities at the Greenland Ice Sheet. Datasets are captured across a variety of supraglacial and proglacial locations covering visible and near infrared wavelengths. Our results are comparable to the existing literature, despite being captured with instrumentation costing over an order of magnitude less than currently available commercial technologies. Practicalities for field deployment are also explored, demonstrating our approach to be a valuable addition to the research field with the potential to improve the availability of datasets from across the cryosphere, unlocking a wealth of data collection opportunities that were hitherto infeasible.

The challenges and opportunities of offering and integrating training in clinical molecular genetics and clinical cytogenetics: A survey of LGG Fellowship Program Directors.

Purpose: The specialty of Laboratory Genetics and Genomics (LGG) was created in 2017 in an effort to reflect the increasing convergence in technologies and approaches between clinical molecular genetics and clinical cytogenetics. However, there has not yet been any formal evaluation of the merging of these disciplines and the challenges faced by Program Directors (PDs) tasked with ensuring the successful training of laboratory geneticists under the new model. Methods: An electronic multi-question Qualtrics survey was created and was sent to the PD for each of the Accreditation Council for Graduate Medical Education-accredited LGG fellowship programs at the time. The data were collected, and the responses were aggregated for each question. Results: All of the responding PDs had started training at least 1 LGG fellow. PDs noted challenges with funding, staff shortages, molecular/cytogenetics content integration, limited total training time, increased remote work, increased sendout testing, and a lack of prior cytogenetics knowledge among incoming fellows. Conclusion: This survey attempted to assess the challenges that LGG PDs have been facing in offering and integrating clinical molecular genetics and clinical cytogenetics fellowship training. Common challenges between programs were noted, and a set of 6 concluding comments are provided to facilitate future discussion.

ESMO Recommendations on clinical reporting of genomic test results for solid cancers.

BACKGROUND: Genomic tumour profiling has a crucial role in the management of patients with solid cancers, as it helps selecting and prioritising therapeutic interventions based on prognostic and predictive biomarkers, as well as identifying markers of hereditary cancers. Harmonised approaches to interpret the results of genomic testing are needed to support physicians in their decision making, prevent inequalities in precision medicine and maximise patient benefit from available cancer management options. METHODS: The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group assembled a group of international experts to propose recommendations for preparing clinical genomic reports for solid cancers. These recommendations aim to foster best practices in integrating genomic testing within clinical settings. After review of available evidence, several rounds of surveys and focused discussions were conducted to reach consensus on the recommendation statements. Only consensus recommendations were reported. Recommendation statements were graded in two tiers based on their clinical importance: level A (required to maintain common standards in reporting) and level B (optional but necessary to achieve ideal practice). RESULTS: Genomics reports should present key information in a front page(s) followed by supplementary information in one or more appendices. Reports should be structured into sections: (i) patient and sample details; (ii) assay and data analysis characteristics; (iii) sample-specific assay performance and quality control; (iv) genomic alterations and their functional annotation; (v) clinical actionability assessment and matching to potential therapy indications; and (vi) summary of the main findings. Specific recommendations to prepare each of these sections are made. CONCLUSIONS: We present a set of recommendations aimed at structuring genomics reports to enhance physician comprehension of genomic profiling results for solid cancers. Communication between ordering physicians and professionals reporting genomic data is key to minimise uncertainties and to optimise the impact of genomic tests in patient care.

The Effects of Intra-Articular Triamcinolone and Autologous Protein Solution on Metabolic Parameters in Horses.

Intra-articular corticosteroids are a popular treatment choice for joint-associated pain and inflammation in horses despite recent work on the metabolic effects of these drugs. The goal of this project was to compare metabolic effects between intra-articular (IA) triamcinolone acetonide (TA) and an autologous protein solution (APS). Five mixed-breed geldings (4-9 years) were utilized for this project. Three identical and consecutive 28-day treatment blocks were used, with metacarpophalangeal IA treatments consisting of equal volumes of saline, a commercially available APS, or 9 mg of TA. Regular plasma and serum samples were collected for ACTH, cortisol, glucose, insulin, and thyroid hormone analysis, in addition to thyrotropin-releasing hormone (TRH) and oral sugar tests (OSTs). Significant treatment effects of IA TA were present at 48 h post-injection in both the TRH and the OST. There was also significant suppression by IA TA of baseline ACTH and cortisol between 2 h and 96 h post-treatment, hyperglycemia between 12 h and 48 h, and hyperinsulinemia at 32 h post-treatment. There were no treatment effects with respect to any measured thyroid hormones, nor were there any significant treatment effects of APS noted. Results suggest at least 2 days and up to 7 days should elapse between a single 9 mg IA TA treatment and OST and/or TRH testing. This study found that TA exhibits significant effects on ACTH, cortisol, glucose, and insulin, while the APS does not.

Studies of the Crystallization and Dissolution of Individual Suspended Sodium Chloride Aerosol Particles.

Aerosols transform between physical phases, as they respond to variations in environmental conditions. There are many industries that depend on these dynamic processes of crystallization and dissolution. Here, a single particle technique (an electrodynamic balance) is used to explore the crystallization and dissolution dynamics of a model system, sodium chloride. The physical and environmental factors that influence the dynamics of crystal formation from a saline droplet (whose initial radius is ∼25 µm) and the kinetics of water adsorption onto dried particles are examined. The drying relative humidity (RH) is shown to impact the physical properties of the dried particle. When a saline droplet is injected into an airflow at an RH close to the efflorescence RH (ERH, 45%), an individual single crystal forms. By contrast, when a compositionally equivalent saline droplet is injected into dry air (RH ∼ 0%), a salt crystal made of multiple crystalline particles is formed. Subsequent to crystallization, the crystal shape, morphology, and surface area were all found to affect the dissolution dynamics of the dried particle. Additionally, we report that the difference between the deliquesce RH and environmental RH significantly impacts the dissolution time scale.

Diet-induced obesity affects influenza disease severity and transmission dynamics in ferrets.

Obesity, and the associated metabolic syndrome, is a risk factor for increased disease severity with a variety of infectious agents, including influenza virus. Yet, the mechanisms are only partially understood. As the number of people, particularly children, living with obesity continues to rise, it is critical to understand the role of host status on disease pathogenesis. In these studies, we use a diet-induced obese ferret model and tools to demonstrate that, like humans, obesity resulted in notable changes to the lung microenvironment, leading to increased clinical disease and viral spread to the lower respiratory tract. The decreased antiviral responses also resulted in obese animals shedding higher infectious virus for a longer period, making them more likely to transmit to contacts. These data suggest that the obese ferret model may be crucial to understanding obesity's impact on influenza disease severity and community transmission and a key tool for therapeutic and intervention development for this high-risk population.

Secondary bone marrow graft loss after third-party virus-specific T cell infusion: Case report of a rare complication.

Virus-specific T cells (VST) from partially-HLA matched donors have been effective for treatment of refractory viral infections in immunocompromised patients in prior studies with a good safety profile, but rare adverse events have been described. Here we describe a unique and severe adverse event of VST therapy in an infant with severe combined immunodeficiency, who receives, as part of a clinical trial (NCT03475212), third party VSTs for treating cytomegalovirus viremia following bone marrow transplantation. At one-month post-VST infusion, rejection of graft and reversal of chimerism is observed, as is an expansion of T cells exclusively from the VST donor. Single-cell gene expression and T cell receptor profiling demonstrate a narrow repertoire of predominantly activated CD4+ T cells in the recipient at the time of rejection, with the repertoire overlapping more with that of peripheral blood from VST donor than the infused VST product. This case thus demonstrates a rare but serious side effect of VST therapy.

DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma.

Fibrolamellar carcinoma (FLC) is a liver tumor with a high mortality burden and few treatment options. A promising therapeutic vulnerability in FLC is its driver mutation, a conserved DNAJB1-PRKACA gene fusion that could be an ideal target neoantigen for immunotherapy. In this study, we aim to define endogenous CD8 T cell responses to this fusion in FLC patients and evaluate fusion-specific T cell receptors (TCRs) for use in cellular immunotherapies. We observe that fusion-specific CD8 T cells are rare and that FLC patient TCR repertoires lack large clusters of related TCR sequences characteristic of potent antigen-specific responses, potentially explaining why endogenous immune responses are insufficient to clear FLC tumors. Nevertheless, we define two functional fusion-specific TCRs, one of which has strong anti-tumor activity in vivo. Together, our results provide insights into the fragmented nature of neoantigen-specific repertoires in humans and indicate routes for clinical development of successful immunotherapies for FLC.

Toward Standardized Aerovirology: A Critical Review of Existing Results and Methodologies.

Understanding the airborne survival of viruses is important for public health and epidemiological modeling and potentially to develop mitigation strategies to minimize the transmission of airborne pathogens. Laboratory experiments typically involve investigating the effects of environmental parameters on the viability or infectivity of a target airborne virus. However, conflicting results among studies are common. Herein, the results of 34 aerovirology studies were compared to identify links between environmental and compositional effects on the viability of airborne viruses. While the specific experimental apparatus was not a factor in variability between reported results, it was determined that the experimental procedure was a major factor that contributed to discrepancies in results. The most significant contributor to variability between studies was poorly defined initial viable virus concentration in the aerosol phase, causing many studies to not measure the rapid inactivation, which occurs quickly after particle generation, leading to conflicting results. Consistently, studies that measured their reference airborne viability minutes after aerosolization reported higher viability at subsequent times, which indicates that there is an initial loss of viability which is not captured in these studies. The composition of the particles which carry the viruses was also found to be important in the viability of airborne viruses; however, the mechanisms for this effect are unknown. Temperature was found to be important for aerosol-phase viability, but there is a lack of experiments that directly compare the effects of temperature in the aerosol phase and the bulk phase. There is a need for repeated measurements between different research groups under identical conditions both to assess the degree of variability between studies and also to attempt to better understand already published data. Lack of experimental standardization has hindered the ability to quantify the differences between studies, for which we provide recommendations for future studies. These recommendations are as follows: measuring the reference airborne viability using the "direct method"; use equipment which maximizes time resolution; quantify all losses appropriately; perform, at least, a 5- and 10-min sample, if possible; report clearly the composition of the virus suspension; measure the composition of the gas throughout the experiment. Implementing these recommendations will address the most significant oversights in the existing literature and produce data which can more easily be quantitatively compared.

Relationship between drug-induced movement disorders and psychosis in adults living in precarious housing or homelessness.

BACKGROUND: Studies have reported positive associations between drug-induced movement disorders (DIMDs) and symptoms of psychosis in patients with schizophrenia. However, it is not clear which subtypes of symptoms are related to each other, and whether one symptom precedes another. The current report assessed both concurrent and temporal associations between DIMDs and symptoms of psychosis in a community-based sample of homeless individuals. METHODS: Participants were recruited in Vancouver, Canada. Severity of DIMDs and psychosis was rated annually, allowing for the analysis of concurrent associations between DIMDs and Positive and Negative Syndrome Scale (PANSS) five factors. A brief version of the PANSS was rated monthly using five psychotic symptoms, allowing for the analysis of their temporal associations with DIMDs. Mixed-effects linear and logistic regression models were used to assess the associations. RESULTS: 401 participants were included, mean age of 40.7 years (SD = 11.2) and 77.4% male. DIMDs and symptoms of psychosis were differentially associated with each other, in which the presence of parkinsonism was associated with greater negative symptoms, dyskinesia with disorganized symptoms, and akathisia with excited symptoms. The presence of DIMDs of any type was not associated with depressive symptoms. Regarding temporal associations, preceding delusions and unusual thought content were associated with parkinsonism, whereas dyskinesia was associated with subsequent conceptual disorganization. CONCLUSIONS: The current study found significant associations between DIMDs and symptoms of psychosis in individuals living in precarious housing or homelessness. Moreover, there were temporal associations between parkinsonism and psychotic symptoms (delusions or unusual thought content), and the presence of dyskinesia was temporally associated with higher odds of clinically relevant conceptual disorganization.

Additive effects of TPMT and NUDT15 on thiopurine toxicity in children with acute lymphoblastic leukemia across multiethnic populations.

BACKGROUND: Thiopurines such as mercaptopurine (MP) are widely used to treat acute lymphoblastic leukemia (ALL). Thiopurine-S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) inactivate thiopurines, and no-function variants are associated with drug-induced myelosuppression. Dose adjustment of MP is strongly recommended in patients with intermediate or complete loss of activity of TPMT and NUDT15. However, the extent of dosage reduction recommended for patients with intermediate activity in both enzymes is currently not clear. METHODS: MP dosages during maintenance were collected from 1768 patients with ALL in Singapore, Guatemala, India, and North America. Patients were genotyped for TPMT and NUDT15, and actionable variants defined by the Clinical Pharmacogenetics Implementation Consortium were used to classify patients as TPMT and NUDT15 normal metabolizers (TPMT/NUDT15 NM), TPMT or NUDT15 intermediate metabolizers (TPMT IM or NUDT15 IM), or TPMT and NUDT15 compound intermediate metabolizers (TPMT/NUDT15 IM/IM). In parallel, we evaluated MP toxicity, metabolism, and dose adjustment using a Tpmt/Nudt15 combined heterozygous mouse model (Tpmt+/-/Nudt15+/-). RESULTS: Twenty-two patients (1.2%) were TPMT/NUDT15 IM/IM in the cohort, with the majority self-reported as Hispanics (68.2%, 15/22). TPMT/NUDT15 IM/IM patients tolerated a median daily MP dose of 25.7 mg/m2 (interquartile range = 19.0-31.1 mg/m2), significantly lower than TPMT IM and NUDT15 IM dosage (P < .001). Similarly, Tpmt+/-/Nudt15+/- mice displayed excessive hematopoietic toxicity and accumulated more metabolite (DNA-TG) than wild-type or single heterozygous mice, which was effectively mitigated by a genotype-guided dose titration of MP. CONCLUSION: We recommend more substantial dose reductions to individualize MP therapy and mitigate toxicity in TPMT/NUDT15 IM/IM patients.

An assessment of the airborne longevity of group A Streptococcus.

Group A streptococcus (GAS) infections result in more than 500 000 deaths annually. Despite mounting evidence for airborne transmission of GAS, little is known about its stability in aerosol. Measurements of GAS airborne stability were carried out using the Controlled Electrodynamic Levitation and Extraction of Bioaerosols onto a Substrate (CELEBS) instrument. CELEBS measurements with two different isolates of GAS suggest that it is aerostable, with approximately 70 % of bacteria remaining viable after 20 min of levitation at 50 % relative humidity (RH), with lower survival as RH was reduced. GAS airborne viability loss was driven primarily by desiccation and efflorescence (i.e. salt crystallization), with high pH also potentially playing a role, given reduced survival in bicarbonate containing droplet compositions. At low enough RH for efflorescence to occur, a greater proportion of organic components in the droplet appeared to protect the bacteria from efflorescence. These first insights into the aerosol stability of GAS indicate that airborne transmission of these respiratory tract bacteria may occur, and that both the composition of the droplet containing the bacteria, and the RH of the air affect the duration of bacterial survival in this environment. Future studies will explore a broader range of droplet and air compositions and include a larger selection of GAS strains.

A qualitative study of barriers and facilitators for health behavior change in low-income men with prostate cancer.

PURPOSE: Low-income prostate cancer survivors, who typically have worse outcomes and greater all-cause mortality, often have poor health-promoting behaviors. Our objective was to assess perceived facilitators of and barriers to healthy behavior change by interviewing low-income men with prostate cancer who received no-cost treatment through a state-funded program. METHODS: Between September 2021 and April 2022, we conducted semi-structured interviews with 19 men (ages 60-75). Purposive sampling was utilized from participants of a cohort of men with prostate cancer from low-income backgrounds. Interviews were recorded, transcribed, and then coded by the authors to generate salient themes via thematic analysis. RESULTS: We found internal characteristics and structural characteristics that functioned independently and in concert to promote and/or hinder healthy behavior change. Internal characteristics such as motivations (prostate cancer diagnosis, self-perceptions, support system, and preferences) and determination, defined as level of motivation, drove behavior actualization. Structural characteristics that influenced behavior change included resources (access to food and opportunities for exercise) and social support. CONCLUSIONS: These outcomes suggest that motivation and determination can serve as protective facilitators encouraging healthy behaviors despite structural barriers low-income prostate cancer survivors may face. However, motivations challenged by financial constraints were not sufficient to guide healthy behavior change. With this in mind, we recommend that interventions promoting healthy behavior change among this population should focus on identifying and strengthening internal assets such as motivations, self-perceptions, preferences, and support systems.

Multilayer depressive symptom networks in adults with bodily pain living in precarious housing or homelessness.

Housing insecurity is associated with co-occurring depression and pain interfering with daily activities. Network analysis of depressive symptoms along with associated risk or protective exposures may identify potential targets for intervention in patients with co-occurring bodily pain. In a community-based sample of adults (n = 408) living in precarious housing or homelessness in Vancouver, Canada, depressive symptoms were measured by the Beck Depression Inventory; bodily pain and impact were assessed with the 36-item Short Form Health Survey. Network and bootstrap permutation analyses were used to compare depressive symptoms endorsed by Low versus Moderate-to-Severe (Mod + Pain) groups. Multilayer networks estimated the effects of risk and protective factors. The overall sample was comprised of 78% men, mean age 40.7 years, with 53% opioid use disorder and 14% major depressive disorder. The Mod + Pain group was characterized by multiple types of pain, more persistent pain, more severe depressive symptoms and a higher rate of suicidal ideation. Global network connectivity did not differ between the two pain groups. Suicidal ideation was a network hub only in the Mod + Pain group, with high centrality and a direct association with exposure to lifetime trauma. Antidepressant medications had limited impact on suicidal ideation. Guilt and increased feelings of failure represented symptoms from two other communities of network nodes, and completed the shortest pathway from trauma exposure through suicidal ideation, to the non-prescribed opioid exposure node. Interventions targeting these risk factors and symptoms could affect the progression of depression among precariously housed patients.

Comparisons of Pediatric and Adult SARS-CoV-2-Specific Antibodies up to 6 Months after Infection, Vaccination, or Hybrid Immunity.

BACKGROUND: Characterization of longitudinal SARS-CoV-2-specific antibody responses in children following infection and vaccination is needed to inform SARS-CoV-2 vaccine policy decisions for children, which may differ from adults. METHODS: We enrolled individuals at the time of SARS-CoV-2 infection or vaccination for longitudinal serological testing and compared SARS-CoV-2-spike-specific IgG and neutralization activity in children and adults stratified by infection and vaccination status using enzyme-linked immunosorbent and virus neutralization assays. RESULTS: Between June 2020 and December 2022, we collected sera from 669 participants aged 40 days to 55 years, including 330 unvaccinated individuals with laboratory-confirmed SARS-CoV-2 infection, 180 vaccinated SARS-CoV-2-naïve individuals, and 159 vaccinated previously infected individuals. Half (n = 330, 49.3%) were children. SARS-CoV-2-specific IgG and neutralization activity in children < 12 years old in response to infection persisted at higher levels than those of adults through at least 6 months (spike-specific IgG levels, 2.05 [95% CI: 1.4-3.1] times higher than adults; neutralizing activity, median 88.8 vs 75.2%, respectively, p = .04). In addition, all pediatric participants had significantly higher IgG levels compared with adults at 6 months following infection or vaccination, regardless of prior infection status. Vaccine-induced SARS-CoV-2-specific IgG responses in previously infected individuals persisted at higher levels than those from infection alone at 6 months (median AUC, children 5-11 years old, 9115 vs 368; adolescents 3613 vs 475; adults 1956 vs 263, all p < .001). CONCLUSIONS: These data demonstrate the robust and persistent immunologic response of SARS-CoV-2 vaccination in children and emphasize the benefit of vaccination after SARS-CoV-2 infection.

Diet-induced obesity impacts influenza disease severity and transmission dynamics in ferrets.

Obesity, and the associated metabolic syndrome, is a risk factor for increased disease severity with a variety of infectious agents, including influenza virus. Yet the mechanisms are only partially understood. As the number of people, particularly children, living with obesity continues to rise, it is critical to understand the role of host status on disease pathogenesis. In these studies, we use a novel diet-induced obese ferret model and new tools to demonstrate that like humans, obesity resulted in significant changes to the lung microenvironment leading to increased clinical disease and viral spread to the lower respiratory tract. The decreased antiviral responses also resulted in obese animals shedding higher infectious virus for longer making them more likely to transmit to contacts. These data suggest the obese ferret model may be crucial to understanding obesity's impact on influenza disease severity and community transmission, and a key tool for therapeutic and intervention development for this high-risk population. Teaser: A new ferret model and tools to explore obesity's impact on respiratory virus infection, susceptibility, and community transmission.