Ann Arbor Research Articles

7.H. Round table: Advancing societal goals through health systems: Insights from the Renewed HSPA Framework

Abstract The purpose of this workshop, entitled ‘Advancing societal goals through health systems: Insights from the renewed HSPA framework,’ is to take a deeper look at the intricate relationships between health systems and broader societal objectives. We will dissect the contributions of health systems to societal well-being, a concept that stretches beyond mere economic growth to include social cohesion, environmental sustainability, and economic development. The session will examine the renewed global Health System Performance Assessment Framework, which serves as a tool for policymakers to better understand how health systems fit together and explains how they perform. This framework allows for a clearer interpretation of health data and provides a pathway to pinpoint health system issues and design that are most likely to enhance performance and resilience. The workshop will delve into the three dimensions of societal well-being-social cohesion, economic development, and environmental sustainability-nested within the HSPA framework. We will explore the health system’s role in advancing these dimensions, such as fostering community bonds, supporting economic growth through a healthy workforce, and contributing to the sustainable management of environmental resources. Integrating health system performance into societal goals is a practical obligation to create a resilient, cohesive, and economically robust society. This workshop will engage stakeholders in a discourse to translate this integration into multisectoral and actionable policies, aligning health system goals with societal aspirations for a sustainable future. This workshop will focus on: How health system assessments can capture contributions to societal goals, underpinning sustainable economic and environmental practices. Real-world case studies showcasing health systems’ role in fostering societal well-being and advancing public health policies. Interactive discussions will shed light on how health systems can be pivotal in achieving the Sustainable Development Goals, particularly in the face of modern challenges such as climate change, demographic shifts, and economic pressures. Key messages • Health systems play a pivotal role in advancing societal well-being beyond traditional health outcomes. • The renewed HSPA framework is a robust tool for policymakers to align health system performance with broader societal goals. Speakers/Panelists Scott Greer University of Michigan, European Observatory on Health Systems and Policies, Ann Arbor, USA Andrea Schmidt Austrian Public Health Institute, Vienna, Austria

Modeling Operations in System-Level Real-Time Control for Urban Flooding Reduction and Water Quality Improvement—An Open-Source Benchmarked Case

Advancements in smart sensing and control technologies enable urban drainage engineers to retrofit stormwater storage facilities with real-time control devices for mitigating stormwater in-site overflow, downstream flooding, and overloaded total suspended solids (TSS) in drainage pipes. While the smart technology can improve the performance of the static drainage systems, coordinatively controlling multiple valve and gate operations poses a significant challenge, especially at a large-scale watershed. Using a benchmark stormwater model located at Ann Arbor, Michigan, USA, we assessed the impact of different real-time control strategies (local individual downstream control and system-level multiple control) on balancing flooding mitigation at downstream outlets and TSS reduction at upstream storage units, such as detention ponds. We examined changes in peak water depth, outflow, and TSS as indicators to assess changes in water quantity and quality. The results indicate that system-level control can reduce peak water depth by up to 7.3%, reduce flood duration by up to 34%, and remove up to 67% of total suspended solids compared with a baseline uncontrolled system, with the outflow from upstream detention ponds being the most important hydraulic indicator for control strategy rule set-up. We find that system-level control does not always outperform the individual downstream controls, particularly in alleviating flooding duration at some downstream outlets. With urban growth and a changing climate, this research provides a foundation for quantifying the benefits of real-time control methods as an adaptive stormwater management solution that addresses both water quantity and quality challenges.

Primary diffuse large B-cell lymphoma of bone in adults: A SEER population-based study.

Primary diffuse large B-cell lymphoma of the bone (PB-DLBCL) is an extremely rare type of extra-nodal lymphoma. The clinical characteristics, management, and survival outcomes of adult PB-DLBCL patients remain poorly defined. To explore the clinical manifestations, staging, therapeutic options, prognostic factors and outcomes of adult patients with PB-DLBCL and to create a model to predict survival outcomes. Data of adult PB-DLBCL patients were obtained from the Surveillance, Epidemiology, and End Results (SEER) Program 18 registries database from 2000 to 2018. The Kaplan-Meier survival analysis was conducted to calculate survival rates. Univariate Cox regression, best subset selection (BESS), and least absolute shrinkage and selection operator (LASSO), followed by backward stepwise multivariable Cox regression, were used to construct the nomogram. The nomograms were evaluated using the concordance index (C-index), calibration curves and decision curve analysis (DCA). Diffuse large B-cell lymphoma (DLBCL) (67.51%) was the most frequent type of primary bone lymphoma. The most involved sites were the spine and lower-limb long bones. For the whole cohort, the 3-, 5-, 10- and 15-year overall survival (OS) rates were 74.9%, 70.5%, 60.0%, and 49.9%, and corresponding disease-specific survival (DSS) rates were 79.7%, 77.8%, 75.1%, and 71.4%, respectively. For OS, age, Ann Arbor stage, primary site and therapy were confirmed as final factors to develop the nomogram in adult PB-DLBCL patients, whereas for DSS, Age, marital status, Ann Arbor stage, number of bone lesions, therapy and year of diagnosis were confirmed as final factors in developing the nomogram. The nomograms demonstrated good accuracy and clinical utility. Established nomograms can accurately predict the survival of patients with PB-DLBCL and help clinicians optimize treatment.

The Lookout Project: A Student-Run Mail-Based Overdose Response Kit Distribution Program Through Social Media During COVID-19.

Naloxone distribution and overdose education are key preventive strategies to reduce opioid overdose deaths. This paper describes the development and evaluation of The Lookout Project (TLP), a 501(c)(3) organization led by college students and based in Ann Arbor, Michigan. This research aimed to examine the outreach of TLP with hopes of creating a reproducible mail-based kit distribution program for college student-run organizations to replicate. TLP used a targeted social media advertising campaign to ask participants 7 multiple-choice questions concerning their demographics, previous incarcerations, experiences with intranasal naloxone (IN), and if they had watched the optional informational video in the opioid overdose response kit (OORK) order form. TLP's team distributed over 900 OORKs from August 3, 2020, to January 4, 2022, first by word of mouth and then through social media advertising that began on February 13, 2021. Of the 657 respondents who agreed to participate in research, the majority identified as white (76.0%, n = 400), did not identify with any specified ethnicity group (60.2%, n = 318), were female (60.8%, n = 356), were between the ages of 18 and 22 (35.4%, n = 209), had not been previously incarcerated (95.6%, n = 564), and did watch the hyperlinked video detailing how to respond to an overdose (74.7%, n = 438). Additionally, several kit recipients (2.8%, n = 19) responded to a follow-up survey. Of those, 7 people reported using the IN provided by TLP to reverse an overdose (36.8%, n = 7). TLP, a nonprofit organization founded by college students, shows potential for informing other student-run organizations about naloxone distribution programs using social media advertising.

Clinical study of immune-targeting combined with attenuated chemotherapy in the treatment of children with classic Hodgkin lymphoma

Objective: To evaluate the efficacy and safety of brentuximab vedotin (BV) combined with rituximab and attenuated chemotherapy in the treatment of children with classic Hodgkin lymphoma (cHL). Methods: A prospective, non-randomized, risk-assigned study. Clinical data (including age, gender, B symptoms, bulky disease, CD30 and Epstein-Barr virus-encoded RNA(EBER) expression, clinical stage, risk stratification, etc.) of 28 intermediate to high-risk cHL children diagnosed and treated at Beijing Children's Hospital Affiliated to Capital Medical University from October 2022 to May 2024 were collected. Immuno-targeted combined with attenuated chemotherapy was administered based on risk stratification and early treatment response. The patients were followed up until May 1st, 2024. The infusion reactions and adverse reactions after treatment were recorded. Results: In all 28 patients, there were 22 males and 6 females, the age was 12 (5,16) years, 16 cases (57%) presented with bulky disease and 10 cases (36%) with B symptoms. The most common pathological type was nodular sclerosis (14 cases, 50%). There were 7 cases of stage Ⅱ, 14 cases of stage Ⅲ and 7 cases of stage Ⅳ according to the Ann Arbor staging system. There were 5 cases in the intermediate-risk group and 23 cases in the high-risk group. EBER was positive in 20 cases (71%) and negative in 6 cases (21%), and CD30 antigen was expressed in tumor cells of all enrolled children. Treatment duration: 5 cases (18%) received 4 courses of treatment, 21 cases (75%) received 6 courses of treatment, and 2 cases (7%) received 8 courses of treatment, 25 cases (89%) achieved complete metabolism response (CMR) through early assessment after 2 courses of chemotherapy. The CMR rates were 100% in intermediate-risk group and 87% in high-risk group, respectively. Four patients (14%) finally received residual field radiotherapy. Toxicities included grade Ⅰ-Ⅱ myelosuppression, early infusion reaction and mild peripheral neuropathy, only one case of grade 3 adverse events was recorded and did not affect sequential treatment. At the end of treatment and 3 months of follow-up, the levels of IgA, IgG and IgM were all decreased compared with the baseline before chemotherapy, and the total B cell count began to be lower than the level before chemotherapy at the early stage of treatment (after 2 courses). The total B cell count monitored during treatment was 50 (0, 101)×106/L and was 12 (0, 25)×106/L at the end of treatment. The follow-up time was 6 (3, 13) months, all 28 children had event-free survival and all achieved complete remission. At 6 and 9 months of follow-up, IgA, IgG, IgM and total B cell counts returned to pre-chemotherapy baseline levels, respectively. Conclusion: BV combined with rituximab attenuated chemotherapy has demonstrated efficacy and a tolerable safety profile in the treatment of cHL in children, and significantly reduce radiation rate.

Baseline and interim 18F-FDG PET/CT metabolic parameters predict the efficacy and survival in patients with diffuse large B-cell lymphoma.

The prognostic value of 18F-FDG PET/CT metabolic parameters, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), in diffuse large B-cell lymphoma (DLBCL) remains inadequately explored. This study aims to assess the correlation between these parameters and patient outcomes. A cohort of 156 DLBCL patients underwent 18F-FDG PET/CT imaging at baseline and after 3-4 cycles of R-CHOP or CHOP-like regimen. The third quartiles of liver uptake values were used as thresholds for calculating MTV and TLG. Patient outcomes were analyzed based on Ann Arbor staging and the 5-PS score. A nomogram was developed to predict overall survival (OS). Patients with low baseline TLG exhibited significantly better outcomes compared to those with high baseline TLG in both Ann Arbor stages I-II and III-IV (1-year PFS: 78.9% vs. 40%, p=0.016; OS: 94.7% vs. 40%, p=0.005 for stage I-II; 1-year PFS: 74.1% vs. 46.8%, p=0.014; OS: 85.4% vs. 71.8%, p=0.007 for stage III-IV). In interim PET/CT patients with a 5-PS score >3, the high ΔTLG group had superior prognosis (1-year PFS: 82.3% vs. 35.7%, p=0.003; OS: 88.2% vs. 85.7%, p=0.003). The nomogram achieved a C-index of 0.9 for OS prediction. The findings suggest that baseline TLG is a robust prognostic indicator for patients with DLBCL, particularly in early stages, while ΔTLG effectively distinguishes those with favorable outcomes in higher-risk groups. These metabolic parameters from 18F-FDG PET/CT could enhance treatment decision-making and patient management strategies.

12422 Linsitinib Inhibits Proliferation And Induces Apoptosis Of IGF-1R And TSH-R Expressing Cells

Abstract Disclosure: M. Luffy: None. A. Ganz: None. J. Ropertz: None. R. Douglas: Employee; Self; Sling Therapeutics. R. Zeidan: Employee; Self; Sling Therapeutics. J. Kent: Employee; Self; Sling Therapeutics. J. Wolf: None. G.J. Kahaly: Grant Recipient; Self; Sling Therapeutics. Background: The insulin-like growth factor 1 receptor (IGF-1R) and the thyrotropin receptor (TSH-R) are expressed on orbital target cells and thyrocytes. Targeting these pathways effectively improves thyroid eye disease (TED). Methods: The inhibitory effect of Linsitinib, a small molecule targeting the IGF-1R (Sling Therapeutics, Ann Arbor, MI, USA), on cell proliferation was investigated in an IGF-1R expressing cell line, NCI-H295R (ATCC, Manassas, VA, USA) and a Chinese Hamster Ovary (CHO) cell line overexpressing the TSH-R (QuidelOrtho, San Diego, CA, USA). An IGF-1R antagonist, Teprotumumab (BioVision, Milpitas, CA, USA) served as control. Both cell lines were plated in a 96-well format and treated with four concentrations of both compounds for 24 hours. After addition of tetrazolium, absorbance was measured (GloMax luminometer, Promega, Madison, WI, USA). Furthermore, the half-maximal inhibitory concentration (IC50) of TSH-R-Ab induced stimulation (stimulatory monoclonal antibody, mAb, M22, RSR, Cardiff, UK) of the TSH-R cell line was evaluated with a cell-based bioassay for blocking TSH-R-Ab (Thyretain TBI, QuidelOrtho). Cells were treated with ten rising concentrations of either Linsitinib, Linsitinib + Metformin, Teprotumumab, or a blocking TSH-R mAb (K1-70, RSR). The Kruskal-Wallis and/or the two-tailed Mann-Whitney tests were used for statistical comparisons. Results: Linsitinib strongly inhibited the proliferation of both cell lines at the following concentrations: 31,612.5 ng/mL (-78%, P=0.0031, IGF-1R cell line and -75%, P=0.0059, TSH-R cell line), as well as at 63,225 ng/mL (-73%, P=0.0073, IGF-1R cell line and -73%, P=0.0108, TSH-R cell line). Linsitinib induced morphologically confirmed apoptosis of both cell lines across all tested concentrations (Luna-FL cell counter, Logos Biosystems, Annandale, VA, USA). Compared to Teprotumumab, Linsitinib inhibited markedly more the proliferation of the IGF-1R cell line at all concentrations (Linsitinib versus Teprotumumab, P=0.0286). Teprotumumab inhibition ranged from -21 to -31% of the IGF-1R cell line across all concentrations, while it was significant only at 15,806.25 ng/mL with the TSH-R cell line (-15%, P=0.0396). In addition, in the TSH-R-Ab blocking bioassay, all tested compounds demonstrated strong inhibition across all ten dilutions (100%). The IC50 of Linsitinib was lower than Teprotumumab (147.1 ng/mL versus 160.6 ng/mL). Combining Metformin to Linsitinib did not further lower the IC50. Not surprisingly, the TSH-R blocking mAb K1-70 had the lowest IC50 of 20.57 ng/mL. Conclusions: Linsitinib effectively induces apoptosis and inhibits proliferation of both IGF-1R and TSH-R expressing target cells, also displaying a lower IC50 in the blocking TSH-R-Ab bioassay compared to Teprotumumab, hence demonstrating its therapeutic potential for TED. Presentation: 6/2/2024

Conserved allomorphs of MR1 drive the specificity of MR1-restricted TCRs.

Major histocompatibility complex class-1-related protein (MR1), unlike human leukocyte antigen (HLA) class-1, was until recently considered to be monomorphic. MR1 presents metabolites in the context of host responses to bacterial infection. MR1-restricted TCRs specific to tumor cells have been described, raising interest in their potential therapeutic application for cancer treatment. The diversity of MR1-ligand biology has broadened with the observation that single nucleotide variants (SNVs) exist within MR1 and that allelic variants can impact host immunity. The TCR from a MR1-restricted T-cell clone, MC.7.G5, with reported cancer specificity and pan-cancer activity, was cloned and expressed in Jurkat E6.1 TCRαβ- β2M- CD8+ NF-κB:CFP NFAT:eGFP AP-1:mCherry cells or in human donor T cells. Functional activity of 7G5.TCR-T was demonstrated using cytotoxicity assays and by measuring cytokine release after co-culture with cancer cell lines with or without loading of previously described MR1 ligands. MR1 allele sequencing was undertaken after the amplification of the MR1 gene region by PCR. In vivo studies were undertaken at Labcorp Drug Development (Ann Arbor, MI, USA) or Epistem Ltd (Manchester, UK). The TCR cloned from MC.7.G5 retained MR1-restricted functional cytotoxicity as 7G5.TCR-T. However, activity was not pan-cancer, as initially reported with the clone MC.7.G5. Recognition was restricted to cells expressing a SNV of MR1 (MR1*04) and was not cancer-specific. 7G5.TCR-T and 7G5-like TCR-T cells reacted to both cancer and healthy cells endogenously expressing MR1*04 SNVs, which encode R9H and H17R substitutions. This allelic specificity could be overcome by expressing supraphysiological levels of the wild-type MR1 (MR1*01) in cell lines. Healthy individuals harbor T cells reactive to MR1 variants displaying self-ligands expressed in cancer and benign tissues. Described "cancer-specific" MR1-restricted TCRs need further validation, covering conserved allomorphs of MR1. Ligands require identification to ensure targeting MR1 is restricted to those specific to cancer and not normal tissues. For the wider field of immunology and transplant biology, the observation that MR1*04 may behave as an alloantigen warrants further study. .

B-281 Performance Characteristics Evaluation of the ARK Diagnostics Immunoassay for Xylazine/4-HydroxyXylazine in Urine

Abstract Background Xylazine exposure is currently common in some US cities, but routine laboratory testing is not available. We evaluated the ARK Diagnostics immunoassay for qualitative detection of xylazine/4-hydroxy Xylazine in urine, prior to its anticipated release as a Forensic Use Only assay. Evaluation of performance characteristics of the ARK assay were conducted at two university hospitals, using either the semi-quantitative application of the assay, as performed on the Roche Cobas 503 analyzer (Institution A), or the qualitative application of the assay, as performed on the Beckman Coulter AU480 analyzer (Institution B). Methods Xylazine (X) and 4-hydroxy Xylazine (4-OHX) were obtained from Cayman Chemical (Ann Arbor, MI). Pooled xylazine-free urine was spiked either with X or 4-OHX in the range of 0-2000 ng/mL. De-identified, to-be-discarded patient urine samples were obtained from among those submitted for routine drugs-of-abuse panel testing. X measurements on all samples were performed by LC-MS/MS; samples were segregated into X-NEGATIVE (X<10 ng/mL) and X-POSITIVE (X>=10 ng/mL). The ARK assay was conducted according to manufacturer’s instructions, either as a semi-quantitative assay (Institution A, Roche analyzer) or as a qualitative assay (Institution B, Beckman Coulter analyzer), with 10 ng/mL as the manufacturer-specified cutoff for ARK POSITIVE, using manufacturer-supplied calibration standards ranging from 0-500 ng/mL X. Results The ARK semi-quantitative analysis (Roche analyzer) showed essentially equivalent curvilinear response curves for either X or 4-OHX at concentrations below 1000 ng/mL; for the semi-quantitative ARK assay, we use “>1200 ng/mL” for X-ARK >1200 ng/mL. By mixing studies (Roche), there were neither positive nor negative interferences observed as assessed for common drugs of abuse or for common therapeutic drugs. The presence of hemoglobin, bilirubin or moderate lipemia were devoid of assay interference. Precision studies for manufacturer-supplied controls were as follows: intra-assay CVs were 6.9% for the NEGATIVE control (5.1±0.35 ng/mL) and 5.9% for the POSITIVE control (15.7±0.53 ng/mL) (n=20); interassay CVs were 7.8% for the NEGATIVE control (5.1±0.40 ng/mL) and 5.7% for the POSITIVE control (15.9±0.90 ng/mL) (n=20). For the qualitative ARK assay as performed on the Beckman analyzer, POSITIVE and NEGATIVE controls ran invariably according to their designations. For the semi-quantitative assay application (Roche analyzer): among 78 X-NEGATIVE samples by LC-MS/MS, there were 0% ARK-POSITIVE results (false-positive rate=0%); among 74 X-POSITIVE samples by LC-MS/MS, there was one ARK-NEGATIVE result (false-negative rate=1.4%); this sample (X=65 ng/mL) was found to have a high amorphous crystalline content, and was unable to be reanalyzed. For the qualitative assay application (Beckman Coulter analyzer): among 78 X-NEGATIVE samples there was one ARK-POSITIVE sample (false-positive rate=1.3%) for a sample with xylazine=8.8 ng/mL by LC-MS/MS, with undetectable 4-OHX (<10 ng/mL); among 74 X-POSITIVE samples, there were no ARK-NEGATIVE results (false-negative rate=0%). Conclusions The ARK xylazine immunoassay demonstrated acceptable analytical performance with respect to detection of xylazine in urine at 10 ng/mL. With additional consideration of the assay’s cross reactivity with the major xylazine metabolite, 4-OH-xylazine, the assay was judged to be highly suitable for routine use as a screening test for detection of xylazine exposure via urine testing.

Validation of a Commercial ELISA Kit for Non-Invasive Measurement of Biologically Relevant Changes in Equine Cortisol Concentrations

The measurement of fecal cortisol/corticosterone metabolites (FCMs) is often used to quantify the stress response. The sampling method is relatively non-invasive, reduces concern for elevation of cortisol from the sampling method, and has been shown to measure cortisol more consistently without the daily diurnal rhythm observed in blood. Commercial ELISA (enzyme-linked immunoassay) kits offer benefits over previously validated immunoassay methods but lack validation. The objective of this study was to evaluate a commercial ELISA kit (Arbor AssaysTM DetectX® Cortisol ELISA kit, K003-H1, Ann Arbor, MI, USA) and provide analytical and biologic validation of equine fecal and plasma samples. Horses (4 male, 4 female, mean ± SD: 4 ± 5 yr) were transported for 15 min with limited physical and visual contact via a livestock trailer. Blood and fecal samples were collected pre- and post-transportation. Parallelism, accuracy, and precision tests were used to analytically validate this kit. Data were analyzed using PROC MIXED in SAS 9.4. Plasma cortisol concentrations increased in response to trailering (254.5 ± 26.4 nmol/L, 0 min post-transportation) compared to pre-transportation (142.8 ± 26.4 nmol/L). FCM concentrations increased 24 h post-trailering (10.8 ± 1.7 ng/g) when compared to pre-transportation (7.4 ± 1.7 ng/g). These data support that changes in FCMs can be observed 24 h post-stressor. In conclusion, the Arbor AssaysTM DetectX® Cortisol ELISA kit is a reliable, economic option for the measurement of biologically relevant changes in cortisol in equine plasma and FCMs.

Long-term cause-specific mortality in adolescent and young adult Hodgkin lymphoma patients treated with contemporary regimens-A nationwide Danish cohort study.

The documented treatment-induced excess mortality in Hodgkin lymphoma (HL) has spurred important treatment changes over recent decades. This study aimed to examine mortality among young HL patients treated with contemporary strategies, including historical data comparison. This nationwide study included 1348 HL patients, diagnosed in 1995-2015 and aged 15-40 at diagnosis. Among the patients, 66.5% had Ann Arbor stage I-II and 33.5% had stage III-IV disease. With a median follow-up of 14.76 years, 139 deaths occurred, yielding a 5-year overall survival of 94.6%. Older age, advanced disease, earlier treatment periods and extensive regimens were associated with higher overall mortality risk. The cumulative risk of HL-related death showed an initial sharp rise, with a plateau at 5.3% 10-year post-diagnosis. Deaths due to cardiovascular or pulmonary diseases and second cancers initially had minimal risk, gradually reaching 1.2% and 2.0% at the 20-year mark respectively. HL cases had a 7.5-fold higher mortality hazard than the background population. This study suggests that contemporary HL treatment still poses excess mortality risk, but recent changes have notably reduced overall and cause-specific mortality compared to earlier eras. Balancing treatment efficacy and toxicity remains crucial, but our findings highlight improved outcomes with modern treatment approaches.

A machine learning approach in a monocentric cohort for predicting primary refractory disease in Diffuse Large B-cell lymphoma patients.

Primary refractory disease affects 30-40% of patients diagnosed with DLBCL and is a significant challenge in disease management due to its poor prognosis. Predicting refractory status could greatly inform treatment strategies, enabling early intervention. Various options are now available based on patient and disease characteristics. Supervised machine-learning techniques, which can predict outcomes in a medical context, appear highly suitable for this purpose. Retrospective monocentric cohort study. Adult patients with a first diagnosis of DLBCL admitted to the hematology unit from 2017 to 2022. We evaluated in our Center five supervised machine-learning (ML) models as a tool for the prediction of primary refractory DLBCL. One hundred and thirty patients with Diffuse Large B-cell lymphoma (DLBCL) were included in this study between January 2017 and December 2022. The variables used for analysis included demographic characteristics, clinical condition, disease characteristics, first-line therapy and PET-CT scan realization after 2 cycles of treatment. We compared five supervised ML models: support vector machine (SVM), Random Forest Classifier (RFC), Logistic Regression (LR), Naïve Bayes (NB) Categorical classifier and eXtreme Gradient Boost (XGboost), to predict primary refractory disease. The performance of these models was evaluated using the area under the receiver operating characteristic curve (ROC-AUC), accuracy, false positive rate, sensitivity, and F1-score to identify the best model. After a median follow-up of 19.5 months, the overall survival rate was 60% in the cohort. The Overall Survival at 3 years was 58.5% (95%CI, 51-68.5) and the 3-years Progression Free Survival was 63% (95%CI, 54-71) using Kaplan-Meier method. Of the 124 patients who received a first line treatment, primary refractory disease occurred in 42 patients (33.8%) and 2 patients (1.6%) experienced relapse within 6 months. The univariate analysis on refractory disease status shows age (p = 0.009), Ann Arbor stage (p = 0.013), CMV infection (p = 0.012), comorbidity (p = 0.019), IPI score (p<0.001), first line of treatment (p<0.001), EBV infection (p = 0.008) and socio-economics status (p = 0.02) as influencing factors. The NB Categorical classifier emerged as the top-performing model, boasting a ROC-AUC of 0.81 (95% CI, 0.64-0.96), an accuracy of 83%, a F1-score of 0.82, and a low false positive rate at 10% on the validation set. The eXtreme Gradient Boost (XGboost) model and the Random Forest Classifier (RFC) followed with a ROC-AUC of 0.74 (95%CI, 0.52-0.93) and 0.67 (95%CI, 0.46-0.88) respectively, an accuracy of 78% and 72% respectively, a F1-score of 0.75 and 0.67 respectively, and a false positive rate of 10% for both. The other two models performed worse with ROC-AUC of 0.65 (95%CI, 0.40-0.87) and 0.45 (95%CI, 0.29-0.64) for SVM and LR respectively, an accuracy of 67% and 50% respectively, a f1-score of 0.64 and 0.43 respectively, and a false positive rate of 28% and 37% respectively. Machine learning algorithms, particularly the NB Categorical classifier, have the potential to improve the prediction of primary refractory disease in DLBCL patients, thereby providing a novel decision-making tool for managing this condition. To validate these results on a broader scale, multicenter studies are needed to confirm the results in larger cohorts.

Structural analysis of the TPI-Manchester, a thermolabile variant of human triosephosphate isomerase

Human triosephosphate isomerase G122R, also known as TPI-Manchester, is a thermolabile variant detected in a screening of more than 3400 individuals from a population in Ann Arbor, Michigan. Here, the crystallographic structure of G122R was solved to determine the molecular basis of its thermal stability. Structural analysis revealed an increase in the flexibility of residues at the dimer interface, even though R122 is about 20 Å away, suggesting that long-range electrostatic interactions may play a key role in the mutation effect.

High-grade B-cell lymphoma with 11q aberration in the HIV setting: a clinicopathological study of 10 cases and literature review

High-grade B-cell lymphoma with 11q aberration (HGBL-11q) is a distinct lymphoma entity according to the 5th edition of the WHO classification of hematolymphoid tumors. It lacks MYC translocation but carries proximal gains and/or telomeric losses of chromosome 11q. This rare type of B-cell lymphoma is less frequently reported in people living with HIV (PLWH), and its exact frequency remains unclear. Our goal was to retrospectively analyze its frequency in a cohort of aggressive B-cell lymphomas in PLWH, including Burkitt lymphoma (BL, n = 35), diffuse large B-cell lymphoma (DLBCL, n = 48), high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS, n = 13), which was diagnosed as AIDS-related lymphoma (ARL) at our institution. In total, 10/96 (10.4%) cases harbored the typical 11q aberration pattern, predominantly those that had been classified as BL (6/35, 17.1%), DLBCL (2/48, 4.2%), and HGBL, NOS (2/13, 15.4%). We also evaluated 7 cases of AIDS-related HGBL-11q (AR-HGBL-11q) reported in the literature. The median age of our cohort was 35 years, and all the patients were male. Most cases (70%) had a history of HIV infection for over 1 year, and all were involved in lymph nodes (100%), frequently involved extranodal sites (60%), and Ann Arbor stage III/IV. In histomorphology, the cases exhibited diverse cytological features, reminiscent of BL (6 cases), DLBCL (2 cases), and HGBL (2 cases). A comparison of the combined cohort of 17 AR-HGBL-11q cases with 11 ARL cases that lacked both MYC rearrangement and 11q aberration at our institution showed that HGBL-11q cases were characterized by strikingly coarse apoptotic debris (P < 0.001), background rich in eosinophils (P = 0.002), higher expression of the germinal centre marker LMO2 (P = 0.080), lower expression of MUM1 (P = 0.004), BCL2 (P = 0.007), and LEF1 (P = 0.080), and lower positivity for EBER in situ hybridisation (P = 0.027). Notably, one case in our series was EBV-positive, a finding not previously reported in the literature. Furthermore, comparing the prognosis between these two groups, AR-HGBL-11q showed a relatively favorable prognosis (P = 0.15), although the difference was not statistically significant. We analyzed this rare lymphoma entity in the HIV setting and highlighted the importance of integrating histomorphological and immunophenotypic features in its diagnosis and classification.

Developing a systems-focused tool for modeling lung cancer screening resource needs

BackgroundEarly detection through screening dramatically improves lung cancer survival rates, including among war Veterans, who are at heightened risk. The effectiveness of low dose computed tomography scans in lung cancer screening (LCS) prompted the Veteran’s Affairs Lung Precision Oncology Program (VA LPOP) to increase screening rates. We aimed to develop an adaptive population health tool to determine adequate resource allocation for the program, with a specific focus on primary care providers, nurse navigators, and radiologists.MethodsWe developed a tool using C + + that uses inputs that represents the process of the VA LCS program in Ann Arbor, Michigan to calculate FTEs of human resource needs to screen a given population. Further, we performed a sensitivity analysis to understand how resource needs are impacted by changes in population, screening eligibility, and time allocated for the nurse navigators’ tasks.ResultsUsing estimates from the VA LCS Program as demonstrative inputs, we determined that the greatest number of full-time equivalents required were for radiologists, followed by nurse navigators and then primary care providers, for a target population of 75,000. An increase in the population resulted in a linear increase of resource needs, with radiologists experiencing the greatest rate of increase, followed by nurse navigators and primary care providers. These resource requirements changed with primary care providers, nurse navigators and radiologists demonstrating the greatest increase when 1–20, 20–40 and > 40% of Veterans accepted to be screened respectively. Finally, when increasing the time allocated to check eligibility by the nurse navigator from zero to three minutes, there was a linear increase in the full-time equivalents required for the nurse navigator.ConclusionVariation of resource utilization demonstrated by our user facing tool emphasizes the importance of tailored strategies to accommodate specific population demographics and downstream work. We will continue to refine this tool by incorporating additional variability in system parameters, resource requirements following an abnormal test result, and resource distribution over time to reach steady state. While our tool is designed for a specific program in one center, it has wider applicability to other cancer screening programs.

Compound Containment: A Reigning Power’s Military-Economic Countermeasures against a Challenging Power. By Dong Jung Kim. Ann Arbor: University of Michigan Press, 2022. 200p. $70.00 cloth, $29.95 paper.

Compound Containment: A Reigning Power’s Military-Economic Countermeasures against a Challenging Power. By Dong Jung Kim. Ann Arbor: University of Michigan Press, 2022. 200p. $70.00 cloth, $29.95 paper.

Abstract 25: The Blood Pressure Effects of a Just-in-time-adaptive Intervention for Physical Activity and Diet in Patients with Hypertension: A Randomized Controlled Trial

Background: Emerging data suggest mobile health interventions are a promising approach for managing hypertension, but large-scale studies are lacking. The myBPmyLife mobile application is a just-in-time adaptive intervention incorporating behavioral change strategies such as goal setting, prompts, visualizations, and feedback to encourage increased physical activity and lower-sodium food choices. Methods: The study was a prospective, randomized-controlled trial that enrolled patients with hypertension from the University of Michigan Health in Ann Arbor, MI, and the Hamilton Community Health Network, a series of federally qualified health center clinics, in Flint, MI. Participants were randomized 1:1 to either the intervention group receiving the myBPmyLife mobile application or the control group and followed for 6 months. Participants in both groups received a smartwatch and a Bluetooth blood pressure (BP) monitor and were prompted to perform BP measurements once weekly. The primary outcome was systolic BP (SBP) change from baseline to 6 months. Secondary outcomes included change from baseline to 6 months in mean daily step count assessed by smartwatch and mean daily sodium intake assessed by the Block sodium screener. Results: The study enrolled 602 participants between December 2021 and July 2023. Mean age was 59.6 years (SD 14), with 74.4% self-identifying as White and 51.7% as men. Baseline estimated sodium intake was 3089 mg (SD 1078) per day, mean step count was 7618 (SD 3778) steps per day, SBP was 132 (SD 15) mmHg, and diastolic blood pressure (DBP) was 82 (SD 10) mmHg. Change in SBP from baseline to 6 months was -5.2 (SD 15) mmHg in the intervention and -5.7 (SD 15) mmHg in the control group (Table; p=0.76). Change in DBP from baseline to 6 months was -3.0 (SD 9) mmHg in the intervention and -3.6 (SD 10) mmHg in the control group (p=0.52). From baseline to 6 months, estimated daily sodium intake decreased by 1145 mg (SD 1023) in the intervention and 860 mg (SD 1001) in the control group (p=0.002), while mean daily step count increased by 170 steps (SD 2690) in the intervention and decreased by 319 steps (SD 2612) in the control group (p=0.040). Conclusion: A mobile health intervention, myBPmyLife, promoting lifestyle modification in hypertensive patients did not change SBP over 6 months compared to the control group despite significantly improving daily sodium intake and step count over that period.

칼 사우어(Carl O. Sauer)의 문화·역사지리학에 투영된 환경관

Despite Sauer set out his coursework in 1909 in the midst of Davisian physiography and environmentalism, Salisbury at Chicago assisted him to avoid the causative man-nature relation by laying emphasis on field observations. Having witnessed the widespread soil exhaustion in Illinois and Missouri, Sauer now at Ann Arbor had to redress economic and ecological problems from the deforestration of white pines on the Great Lakes. Advising on the issues of land utilization and soil erosion for the New Deal Government, Sauer in Berlekey shaped up the landscape morphology in which culture was conceived as an agent, natural landscape a medium and cultural landscape an outcome. The intellectual encounter with Boasian anthropology resulted in cultural and historical geography or culture history of seeking out the origin, diffusion and transformation of culture and cultural landscape, bearing the brunt of environmentalism. To be noted is that Sauer resurrected Marsh’s Man and Nature by organizing the 1955 international symposium on ‘Man’s Role in Changing the Face of the Earth’. Sauer’s environmental ethics urges us to do our moral and ecological duties for the coming generation.

Low-Cost Classroom and Laboratory Exercises for Investigating Both Wave and Event-Related Electroencephalogram Potentials.

Electroencephalography (EEG) has given rise to a myriad of new discoveries over the last 90 years. EEG is a noninvasive technique that has revealed insights into the spatial and temporal processing of brain activity over many neuroscience disciplines, including sensory, motor, sleep, and memory formation. Most undergraduate students, however, lack laboratory access to EEG recording equipment or the skills to perform an experiment independently. Here, we provide easy-to-follow instructions to measure both wave and event-related EEG potentials using a portable, low-cost amplifier (Backyard Brains, Ann Arbor, MI) that connects to smartphones and PCs, independent of their operating system. Using open-source software (SpikeRecorder) and analysis tools (Python, Google Colaboratory), we demonstrate tractable and robust laboratory exercises for students to gain insights into the scientific method and discover multidisciplinary neuroscience research. We developed 2 laboratory exercises and ran them on participants within our research lab (N = 17, development group). In our first protocol, we analyzed power differences in the alpha band (8-13 Hz) when participants alternated between eyes open and eyes closed states (n = 137 transitions). We could robustly see an increase of over 50% in 59 (43%) of our sessions, suggesting this would make a reliable introductory experiment. Next, we describe an exercise that uses a SpikerBox to evoke an event-related potential (ERP) during an auditory oddball task. This experiment measures the average EEG potential elicited during an auditory presentation of either a highly predictable ("standard") or low-probability ("oddball") tone. Across all sessions in the development group (n=81), we found that 64% (n=52) showed a significant peak in the standard response window for P300 with an average peak latency of 442ms. Finally, we tested the auditory oddball task in a university classroom setting. In 66% of the sessions (n=30), a clear P300 was shown, and these signals were significantly above chance when compared to a Monte Carlo simulation. These laboratory exercises cover the two methods of analysis (frequency power and ERP), which are routinely used in neurology diagnostics, brain-machine interfaces, and neurofeedback therapy. Arming students with these methods and analysis techniques will enable them to investigate this laboratory exercise's variants or test their own hypotheses.

Association between low incidence of TP53 mutations and reduced early relapse rates in Uygur DLBCL.

Diffuse large B-cell lymphoma (DLBCL) demonstrates significant heterogeneity, investigations into the distinctions in clinical and molecular characteristics between Chinese Uygur and Han DLBCL patients remain unexplored. We retrospectively reviewed 279 DLBCL patients (105 Uygur and 174 Han patients), of which 155 patients underwent genetic profiling by NGS. Compared with Han patient, Uygur patients have better clinical prognostic indicators, including a higher proportion of patients with 0-1 extranodal involvement and I/II Ann Arbor staging. Consistently, Uygur patients were significantly associated with lower risk of relapse (P = 0.06), with a one-year relapse rate of 5% vs 17% and two-year relapse rate of 19% vs 36% compared to Han patients. At the molecular level, TP53 (21.3%) was among the top frequently altered gene in the cohort. Notably, the Uygur patients exhibited a significantly lower frequency of TP53 alterations and higher frequency of ASXL3 alterations. Logistic regression analysis showed that the lowered frequency of TP53 and enrichment of ASXL3 in the Uygur patients were independent of other factors. However, only patients with TP53 mutations had higher relapse rate than those with wild type TP53 (one-year, 20% vs 10%; two-year, 51% vs 21%). Our findings highlight the notable contribution of a low TP53 mutation frequency in Uygur patients as a pivotal factor associated with the favorable prognosis of this population.