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Background: Patients with respiratory manifestations of acute COVID-19 infection have enlarged luminal areas of central conducting airways demonstrated on computed tomography imaging and abnormal pulmonary function. In some cases, COVID-19 symptoms may persist for more than 4 weeks, referred to as long COVID, and the effect on airway luminal area remains unknown. Herein, we report airway luminal cross-sections areas among a long COVID group, compared to individuals with an acute COVID-19. We aim to investigate if large conducting airways sizes are different between acute COVID-19 and long COVID patients. Methods: A cohort of 181 people with long COVID were screened, of which 20 people (9 men, 11 women; 55.9 ± 14.1 years) were included in analyses. Twenty age, height, and sex matched patients with an acute (< 4 weeks of persistent symptoms from diagnosis) COVID-19 infection (55.7 ± 15.2 years) served as a comparison group. We used a three-dimensional reconstruction of computed tomography imaging to measure luminal areas of the trachea, right and left main bronchi, bronchus intermediate, right and left upper lobe, and left lower lobe bronchi at proximal, middle, and distal cross-sectional points in both groups. Airway luminal area was taken as the average of the three points. We compared average lumen area of long COVID patients with acute COVID-19 individuals, using an independent samples t-test. Results: We found no significant difference comparing measurements of the following airway luminal cross-sectional areas: trachea (277.7 ± 100.4 vs. 268.0 ± 70.5 mm2 p=0.73), right main bronchus (191.0 ± 66.1 vs. 190.1 ± 49.0 mm2, p=0.96), bronchus intermediate (112.3 ± 33.4 vs. 109.3 ± 27.9 mm2, p=0.76), right upper lobe bronchus (74.4 ± 21.0 vs. 73.7 ± 25.5 mm2, p=0.92), left main bronchus (129.1 ± 50.1 vs. 136.9 ± 38.0 mm2, p=0.58), left lower lobe bronchus (57.8 ± 18.2 vs. 59.0 ± 13.4 mm2, p=0.82), and left upper lobe bronchus (80.1 ± 19.5 vs. 77.9 ± 22.9 mm2, p=0.75) in the long COVID and acute COVID-19 groups respectively. Conclusion: In patients with long COVID, compared to those with an acute COVID-19 infection, we did not see differences in central airway luminal areas. Further analysis of a larger cohort is needed to determine whether enlarged airway luminal areas, associated with acute COVID-19, persist in long COVID. This research will expand knowledge on functional consequences for patients with long COVID. Funding: F32HL154320 to JWS; 5R35HL139854 to MJJ. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: Interstitial lung disease (ILD) encompasses several pulmonary disorders associated with scarring and fibrosis of pulmonary tissue. People with idiopathic pulmonary fibrosis, a subset of ILD, have greater central airway luminal area compared to age- and sex-matched healthy controls when evaluated using microcomputed tomography, a process examining the luminal area of ex-vivo lung tissue. In this study we aimed to confirm these findings using a different method of airway assessment, three-dimensional (3D) reconstruction of computed tomography (CT) scans. Moreover, in health, males have larger central airways than height-matched females, but it remains unknown if there are sex differences in airway area among people with ILD. We hypothesized that sex differences observed in healthy people would persist among people with ILD. Methods: A cohort of 399 patients with lung CT scans were screened, of which 19 people (7 females) with ILD were included in analyses after exclusions. People with ILD were matched based on sex, age, and height to 19 healthy controls. We assessed cross-sectional luminal area at the midpoint of seven conducting airways (trachea, left and right main bronchus, intermediate bronchus, left and right upper lobe, and left lower lobe). Results from pulmonary function tests were also abstracted, as available. To examine sex differences, we compared airway luminal area, normalized to participant height, between males and females with ILD. Sex differences were analyzed using a univariate ANOVA test. Results: People with ILD had a preserved ratio of forced expiratory volume in the first second to forced vital capacity (101 ±12%predicted) and decreased diffusing capacity for carbon monoxide (55 ±23%predicted). People with ILD had airways that were between 19.6%-45.0% larger than controls (p<0.05). Composite physiologic index, a marker of ILD severity, was not different between sexes (p=0.07). Males with ILD had significantly larger, luminal areas than females in two central airways - right main bronchus (1.46±0.41 vs. 1.07±0.22 mm2/cm, p=0.04) and left upper lobe (0.54±0.10 vs. 0.43±0.08 mm2/cm, p=0.02). However, luminal area of other central airways, including: trachea (2.15±0.57 vs. 1.65±0.32 mm2/cm, p=0.051), bronchus intermediate (0.77±0.23 vs. 0.61±0.13 mm2/cm, p=0.12), right upper lobe (0.47±0.15 vs. 0.40±0.06 mm2/cm, p=0.26), left main bronchus (0.93±0.33 vs. 0.69±0.16 mm2/cm, p=0.09), and left lower lobe (0.41±0.13 vs. 0.40±0.08 mm2 /cm, p=0.79) were not different between sexes in people with ILD. Conclusion: Sex differences observed in healthy people are potentially preserved in ILD, but a more robust sample is required to fully elucidate these findings. Illuminating any sex differences in ILD pathophysiology may provide knowledge to treat and improve clinical outcomes in ILD. Funding: National Heart, Lung, and Blood Institute (F32HL154320 to JWS; 5R35HL139854 to MJJ). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

AbstractIntroductionRemote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD‐mApp).MethodsA diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC‐FTLD = 0 [N = 101]; prodromal: 0.5 [N = 49]; symptomatic ≥1 [N = 51]; not measured [N = 13]) were asked to complete ALLFTD‐mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys.ResultsIt was feasible for participants to complete the ALLFTD‐mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered the time commitment acceptable (98% of respondents). Greater disease severity was associated with poorer performance across several tests.DiscussionThese findings suggest that the ALLFTD‐mApp study protocol is feasible and acceptable for remote FTD research.HIGHLIGHTS The ALLFTD Mobile App is a smartphone‐based platform for remote, self‐administered data collection. The ALLFTD Mobile App consists of a comprehensive battery of surveys and tests of executive functioning, memory, speech and language, and motor abilities. Remote digital data collection using the ALLFTD Mobile App was feasible in a multicenter research consortium that studies FTD. Data was collected in healthy controls and participants with a range of diagnoses, particularly FTD spectrum disorders. Remote digital data collection was well accepted by participants with a variety of diagnoses.

Surgical treatment of pelvic sarcoma involving the bone is the standard of care but is associated with several sequelae and reduced functional quality of life (QOL). Treatment with photon and proton radiotherapy is associated with relapse. Carbon ion radiotherapy (CIRT) may reduce both relapse rates and treatment sequelae. The PROSPER study is a tricontinental, nonrandomized, prospective, three-arm, pragmatic trial evaluating treatments of pelvic sarcoma involving the bone. Patients aged at least 15 years are eligible for inclusion. Participants must have an Eastern Cooperative Oncology Group Performance Status score of two or less, newly diagnosed disease, and histopathologic confirmation of pelvic chordoma, chondrosarcoma, osteosarcoma, Ewing sarcoma with bone involvement, rhabdomyosarcoma (RMS) with bone involvement, or non-RMS soft tissue sarcoma with bone involvement. Treatment arms include (1) CIRT (n = 30) delivered in Europe and Asia, (2) surgical treatment with or without adjuvant radiotherapy (n = 30), and (3) proton therapy (n = 30). Arms two and three will be conducted at Mayo Clinic campuses in Arizona, Florida, and Minnesota. The primary end point is to compare the 1-year change in functional QOL between CIRT and surgical treatment. Additional comparisons among the three arms will be made between treatment sequelae, local control, and other QOL measures.

Abstract Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD19+ CD5+ clonal B lymphocytes in the blood, bone marrow, and peripheral lymphoid organs. Many patients with CLL never receive treatment for the leukemia and therapy is typically only initiated upon progression of disease-related clinical complications. Treatment options for progressing patients range from chemoimmunotherapy (CIT) to small molecule inhibitors that target pro-survival signaling pathways in leukemic B cells, such as the BTK inhibitor ibrutinib. Although therapy regimens have improved, there is still no cure for CLL, in part due to clonal evolution of the leukemic B cell. The goal of this study is to document the clonal dynamics of CLL B cells at baseline and at response evaluation(s) for alterations in clonal architecture and expression of cell surface markers associated with therapy resistance using the single cell flow cytometry analysis tool, t-distributed stochastic neighbor embedding (t-SNE). Biobanked peripheral blood mononuclear cells were obtained from patients that underwent frontline CIT or ibrutinib, or secondary ibrutinib therapy. Fourteen parameter flow cytometry was performed and subjected to tSNE analysis to document CLL B cell clonal architecture and evolution in patients undergoing the various therapies. Profound differences in treatment responses and leukemic cell clonal dynamics were observed which may inform the discovery of novel biomarkers associated with therapy resistance.

209 Background: Metastatic colorectal (CRC), pancreatic (PANC), and gastroesophageal cancers are the leading causes of GI cancer–related mortality (5-y survival: 15%, 3%, and 5%-6%, respectively) (ACS 2022). HLA LOH is a recurrent mechanism of immune escape observed in 15%-20% of GI cancers (Hecht R., ASCO GI 2022). The Tmod platform is a logic-gated chimeric antigen receptor (CAR) T-cell modular system, comprising a carcinoembryonic antigen (CEA)- or mesothelin (MSLN)-targeting CAR activator and a separate HLA-A*02-targeting blocker receptor. Both in vitro/in vivo, Tmod CAR T therapy kills cells with HLA-A*02 LOH (tumor) without harming cells with retained HLA-A*02 expression (normal). However, HLA-A*02 LOH can only be therapeutically exploited if patients are identifiable through a feasible and timely clinical workflow. Methods: We established a biobanking protocol (BASECAMP-1, NCT04981119) to determine whether HLA-A*02 LOH patients can be prospectively identified. Patients with CRC, PANC, or non-small cell lung cancer (NSCLC), and a high risk for incurable relapse, were screened first using a standard HLA assay. Heterozygous HLA-A*02 positive tumor samples were then assessed for LOH using a bioinformatic algorithm applied via the Tempus xT platform. Results: As of Sep 1, 2022, 83 patients were consented at 4 institutions. HLA status was obtained from 70 patients and 28 were identified as HLA-A*02:01 heterozygous (40%; expected frequency based on USA NMDP data, 27.6%). LOH results were available for 16 patients; 4 LOH-positive patients were identified (25%, 2 PANC, 2 NSCLC). The LOH assay sensitivity declines below a tumor purity of 40% (Hecht R., ASCO GI 2022). Six patients had a tumor purity of 20% (all with PANC, a tumor known for high stromal content), limiting possible LOH detection. The impact of tumor purity on LOH sensitivity was highlighted in a patient with a low initial sample tumor purity (30%) that resulted in a 41% probability of HLA-A*02:01 LOH (below positive threshold). A second sample with a higher tumor purity (70%), obtained from formalin-fixed, paraffin-embedded sections, resulted in a 92% probability of HLA-A*02:01 LOH (positive). Conclusions: BASECAMP-1 prospective identification of HLA-A*02 LOH is feasible in the real-world setting. The frequencies of the HLA-A*02 allele and of HLA-A*02 LOH in this cohort mirrored expected population frequencies. LOH results can be obtained within a clinically feasible workflow and timeframe, although samples with a < 40% tumor purity have a reduced sensitivity for LOH detection, an issue recurrently observed in patients with PANC. The BASECAMP-1 strategy enables prospective identification of appropriate patients for future therapeutic clinical trials using Tmod CEA and MSLN logic-gated CAR T cells. Clinical trial information: NCT04981119 .

Data from transgenic rodent models suggest that glucagon acts as an insulin secretagogue by signaling through the glucagon-like peptide 1 receptor (GLP-1R) present on β-cells. However, its net contribution to physiologic insulin secretion in humans is unknown. To address this question, we studied individuals without diabetes in two separate experiments. Each subject was studied on two occasions in random order. In the first experiment, during a hyperglycemic clamp, glucagon was infused at 0.4 ng/kg/min, increasing by 0.2 ng/kg/min every hour for 5 h. On one day, exendin-9,39 (300 pmol/kg/min) was infused to block GLP-1R, while on the other, saline was infused. The insulin secretion rate (ISR) was calculated by nonparametric deconvolution from plasma concentrations of C-peptide. Endogenous glucose production and glucose disappearance were measured using the tracer-dilution technique. Glucagon concentrations, by design, did not differ between study days. Integrated ISR was lower during exendin-9,39 infusion (213 ± 26 vs. 191 ± 22 nmol/5 h, saline vs. exendin-9,39, respectively; P = 0.02). In the separate experiment, exendin-9,39 infusion, compared with saline infusion, also decreased the β-cell secretory response to a 1-mg glucagon bolus. These data show that, in humans without diabetes, glucagon partially stimulates the β-cell through GLP-1R.

ImportanceLate-onset meningitis (LOM) has been associated with adverse neurodevelopmental outcomes in children born extremely preterm.ObjectiveTo report the incidence of LOM during birth hospitalization and neurodevelopmental outcomes at 18 to 26 months’ corrected age.Design, Setting, and ParticipantsThis cohort study is a secondary analysis of a multicenter prospective cohort of children born at 22 to 26 weeks’ gestation between 2003 and 2017 with follow-up from 2004 to 2021. The study was conducted at 25 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers.ExposuresCulture-confirmed LOM.Main Outcomes and MeasuresIncidence and microbiology of LOM (2003-2017); lumbar puncture (LP) performance in late-onset sepsis (LOS) evaluations (2011-2017); composite outcome of death or neurodevelopmental impairment (NDI; 2004-2021).ResultsAmong 13 372 infants (median [IQR] gestational age, 25.4 [24.4-26.1] weeks; 6864 [51%] boys), LOM was diagnosed in 167 (1%); LOS without LOM in 4564 (34%); and neither LOS nor LOM in 8641 (65%). The observed incidence of LOM decreased from 2% (95% CI, 1%-3%) in 2003 to 0.4% (95% CI, 0.7%-1.0%) in 2017 (P &amp;lt; .001). LP performance in LOS evaluations decreased from 36% (95% CI, 33%-40%) in 2011 to 24% (95% CI, 21%-27%) in 2017 (P &amp;lt; .001). Among infants with culture-confirmed LOS, LP performance decreased from 58% (95% CI, 51%-65%) to 45% (95% CI, 38%-51%; P = .008). LP performance varied by center among all LOS evaluations (10%-59%, P &amp;lt; .001) and among those with culture-confirmed LOS (23%-79%, P &amp;lt; .001). LOM occurred in the absence of concurrent LOS in 27 of 167 cases (16%). The most common LOM isolates were coagulase-negative Staphylococcus (98 [59%]), Candida albicans (38 [23%]), and Escherichia coli (27 [16%]). Death or NDI occurred in 22 of 46 children (48%) with LOM due to coagulase-negative Staphylococcus, 43 of 67 (64%) due to all other bacterial pathogens, and 26 of 33 (79%) due to fungal pathogens. The adjusted relative risk of death or NDI was increased among children with LOM (aOR, 1.53; 95% CI, 1.04-2.25) and among those with LOS without LOM (aOR, 1.41; 95% CI, 1.29-1.54) compared with children with neither infection.Conclusions and RelevanceIn this cohort study, LP was performed with decreasing frequency, and the observed incidence of LOM also decreased. Both LOM and LOS were associated with increased risk of death or NDI; risk varied by LOM pathogen. The full association of LOM with outcomes of children born extremely preterm may be underestimated by current diagnostic practices.

Head and neck squamous cell cancers (HNSCCs) represent a diverse group of tumors emerging within different mucosal surfaces of the oral cavity, nasopharynx, oropharynx, larynx, and hypopharynx. HNSCCs share common clinical risk factors and genomic features, including smoking, alcohol, age, male sex, aneuploidy, and TP53 mutations. Viral initiating and contributing events are increasingly recognized in HNSCCs. While both Epstein–Barr Virus (EBV) and human papilloma virus (HPV) are observed, EBV is more frequently associated with nasopharyngeal cancers whereas HPV is associated with oropharyngeal cancers. HNSCCs are associated with high tumor mutational burden and loss of tumor suppressor gene function, especially in TP53 and X-linked genes. Multiple lines of evidence suggest that HNSCCs are subject to immunologic surveillance and immune-induced evolutionary pressure that correlate with negative clinical outcomes. This review will discuss genomic mechanisms related to immune-mediated pressures and propose prognostic and therapeutic implications of detectable immune escape mechanisms that drive tumorigenesis and disease progression.