Stabilizing the Proteomes of Acute Myeloid Leukemia Cells: Implications for Cancer Proteomics.

Previous work has shown that inhibition of abundant myeloid azurophil granule-associated serine proteases (ELANE [neutrophil elastase], PRTN3 [protease 3], and CTSG [Cathepsin G]) is required to stabilize some proteins in myeloid cells. We therefore hypothesized that effective inhibition of these proteases may be necessary for quantitative proteomic analysis of samples containing myeloid cells. To test this hypothesis, we thawed viably preserved acute myeloid leukemia cells from cryovials in the presence or the absence of diisopropyl fluorophosphate (DFP), a cell-permeable and irreversible serine protease inhibitor. Global proteomic analysis was performed, using label-free and isobaric peptide-labeling quantitation. The presence of DFP resulted in an increase of tryptic peptides (14-57%) and proteins (9-31%). In the absence of DFP, 11 to 31% of peptide intensity came from nontryptic peptides; 52 to 75% had cleavage specificity consistent with activities of ELANE-PRTN3. Treatment with DFP reduced the intensity of nontryptic peptides to 4-8% of the total. ELANE inhibition was 95%, based on diisopropyl phosphate modification of active site serine residue. Overall, the relative abundance of 20% of proteins was significantly altered by DFP treatment. These results suggest that active myeloid serine proteases, released during sample processing, can skew quantitative proteomic measurements. Finally, significant ELANE activity was also detected in Clinical Proteomics Tumor Analysis Consortium datasets of solid tumors (many of which have known myeloid infiltration). In the pancreatic cancer dataset, the median percentage of nontryptic intensity detected across patient samples was 34%, with many patient samples having more than half of their detected peptide intensity from nontryptic cleavage events consistent with ELANE-PRTN3 cleavage specificity. Our study suggests that in vitro cleavage of proteins by myeloid serine proteases may be relevant for proteomic studies of any tumor that contains infiltrating myeloid cells.

Active Interaction Mapping Reveals the Hierarchical Organization of Autophagy.

We have developed a general progressive procedure, Active Interaction Mapping, to guide assembly of the hierarchy of functions encoding any biological system. Using this process, we assemble an ontology of functions comprising autophagy, a central recycling process implicated in numerous diseases. A first-generation model, built from existing gene networks in Saccharomyces, captures most known autophagy components in broad relation to vesicle transport, cell cycle, and stress response. Systematic analysis identifies synthetic-lethal interactions as most informative for further experiments; consequently, we saturate the model with 156,364 such measurements across autophagy-activating conditions. These targeted interactions provide more information about autophagy than all previous datasets, producing a second-generation ontology of 220 functions. Approximately half are previously unknown; we confirm roles for Gyp1 at the phagophore-assembly site, Atg24 in cargo engulfment, Atg26 in cytoplasm-to-vacuole targeting, and Ssd1, Did4, and others in selective and non-selective autophagy. The procedure and autophagy hierarchy are at http://atgo.ucsd.edu/.

Slavery, Home Ownership, and Contemporary Perinatal Outcomes in the Southeast: A Test of Mediation and Moderation.

OBJECTIVE: To estimate the effect of geographic variation in historic slavery on perinatal outcomes [chronic hypertension, hypertensive disorders of pregnancy (HDP), very preterm birth (VPTB), or very low birth weight birth (VLBW)] among Black people living in states where slavery was legal in 1860 and test mediation by Black homeownership. METHODS: We linked data from the 1860 census (the proportion of enslaved residents) to natality data on outcomes (2013-2021) using resident county. The percent of Black residents in a county who owned their home was a potential mediator. We fit log binomial models to estimate risk ratios (RRs) representing total and controlled direct effects (accounting for Black homeownership) of proportion enslaved on outcomes, accounting for potential confounding using marginal structural models. RESULTS: Among 2,443,198 included births, 8.8% (213,829) experienced HDP, 4.1% (100,549) chronic hypertension, 3.3% (81,072) VPTB, and 2.6% (62,538) VLBW. There was an increase in chronic hypertension and VPTB risk, but not HDP or VLBW, in counties with a 10% greater proportion enslaved in 1860 [adjusted RR: 1.06, 95% CI: (1.02, 1.1); 1.02 (1.00, 1.05); 1.00 (0.98, 1.02); 1.01 (1.00, 1.03)]. There was not evidence of mediation by Black homeownership. CONCLUSIONS: Historic slavery remains relevant for perinatal health.

Proteomic and phosphoproteomic landscapes of acute myeloid leukemia.

We have developed a deep-scale proteome and phosphoproteome database from 44 representative acute myeloid leukemia (AML) patients from the LAML TCGA dataset and 6 healthy bone marrow-derived controls. After confirming data quality, we orthogonally validated several previously undescribed features of AML revealed by the proteomic data. We identified examples of posttranscriptionally regulated proteins both globally (ie, in all AML samples) and also in patients with recurrent AML driver mutations. For example, samples with IDH1/2 mutations displayed elevated levels of the 2-oxoglutarate-dependent histone demethylases KDM4A/B/C, despite no changes in messenger RNA levels for these genes; we confirmed this finding in vitro. In samples with NPMc mutations, we identified several nuclear importins with posttranscriptionally increased protein abundance and showed that they interact with NPMc but not wild-type NPM1. We identified 2 cell surface proteins (CD180 and MRC1/CD206) expressed on AML blasts of many patients (but not healthy CD34+ stem/progenitor cells) that could represent novel targets for immunologic therapies and confirmed these targets via flow cytometry. Finally, we detected nearly 30 000 phosphosites in these samples; globally, AML samples were associated with the abnormal phosphorylation of specific residues in PTPN11, STAT3, AKT1, and PRKCD. FLT3-TKD samples were associated with increased phosphorylation of activating tyrosines on the cytoplasmic Src-family tyrosine kinases FGR and HCK and related signaling proteins. PML-RARA-initiated AML samples displayed a unique phosphorylation signature, and TP53-mutant samples showed abundant phosphorylation of serine-183 on TP53 itself. This publicly available database will serve as a foundation for further investigations of protein dysregulation in AML pathogenesis.

CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome.

Biallelic mutations of the CEBPA gene (CEBPAbi) define a distinct entity associated with favorable prognosis; however, the role of monoallelic mutations (CEBPAsm) is poorly understood. We retrospectively analyzed 4708 adults with acute myeloid leukemia (AML) who had been recruited into the Study Alliance Leukemia trials, to investigate the prognostic impact of CEBPAsm. CEBPA mutations were identified in 240 patients (5.1%): 131 CEBPAbi and 109 CEBPAsm (60 affecting the N-terminal transactivation domains [CEBPAsmTAD] and 49 the C-terminal DNA-binding or basic leucine zipper region [CEBPAsmbZIP]). Interestingly, patients carrying CEBPAbi or CEBPAsmbZIP shared several clinical factors: they were significantly younger (median, 46 and 50 years, respectively) and had higher white blood cell (WBC) counts at diagnosis (median, 23.7 × 109/L and 35.7 × 109/L) than patients with CEBPAsmTAD (median age, 63 years, median WBC 13.1 × 109/L; P < .001). Co-mutations were similar in both groups: GATA2 mutations (35.1% CEBPAbi; 36.7% CEBPAsmbZIP vs 6.7% CEBPAsmTAD; P < .001) or NPM1 mutations (3.1% CEBPAbi; 8.2% CEBPAsmbZIP vs 38.3% CEBPAsmTAD; P < .001). CEBPAbi and CEBPAsmbZIP, but not CEBPAsmTAD were associated with significantly improved overall (OS; median 103 and 63 vs 13 months) and event-free survival (EFS; median, 20.7 and 17.1 months vs 5.7 months), in univariate and multivariable analyses. Additional analyses revealed that the clinical and molecular features as well as the favorable survival were confined to patients with in-frame mutations in bZIP (CEBPAbZIP-inf). When patients were classified according to CEBPAbZIP-inf and CEBPAother (including CEBPAsmTAD and non-CEBPAbZIP-inf), only patients bearing CEBPAbZIP-inf showed superior complete remission rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutation.

Neighborhood deprivation and racial differences in in vitro fertilization outcomes.

BACKGROUND: There are significant racial disparities in in vitro fertilization outcomes, which are poorly explained by individual-level characteristics. Environmental factors such as neighborhood-level socioeconomic factors may contribute to these disparities. However, few studies have directly addressed this research question in a large, racially diverse cohort. OBJECTIVE: This study aimed to investigate whether neighborhood deprivation is associated with differences in in vitro fertilization outcomes. STUDY DESIGN: Our retrospective cohort study included 1110 patients who underwent 2254 autologous in vitro fertilization cycles between 2014 and 2019 at an academic fertility center in the Southeastern United States. Neighborhood deprivation was estimated using the Neighborhood Deprivation Index, a composite variable measuring community levels of material capital based on poverty, occupation, housing, and education domains. Using multivariable log-binomial generalized estimating equations with cluster weighting, risk ratios and 95% confidence intervals were estimated for cycle cancellation, miscarriage (defined as spontaneous pregnancy loss before 20 weeks after a confirmed intrauterine gestation), and live birth according to patient Neighborhood Deprivation Index. RESULTS: There were positive associations between increasing Neighborhood Deprivation Index (indicating worsening neighborhood deprivation) and body mass index, as well as increasing prevalence of tubal and uterine factor infertility diagnoses. The crude probability of live birth per cycle was lower among Black (24%) than among White patients (32%), and the crude probability of miscarriage per clinical pregnancy was higher among Black (22%) than among White patients (12%). After adjustment, the Neighborhood Deprivation Index was not significantly associated with risk of cycle cancellation or live birth. Results were consistent when analyses were stratified by race. CONCLUSION: Our research demonstrates racial disparities between Black and White women in the incidence of miscarriage and live birth following in vitro fertilization. Although the level of neighborhood deprivation was closely related to race, it did not have strong associations with in vitro fertilization outcomes in our population as a whole or within strata of race.

Referral and evaluation for kidney transplantation among patients with lupus nephritis-related end-stage kidney disease.

OBJECTIVE: For the majority of patients with lupus nephritis-related end-stage kidney disease (LN-ESKD), kidney transplant is associated with better outcomes than dialysis. Access to kidney transplant requires an initial referral to a transplant center and medical evaluation prior to waitlisting. The study's objective was to examine access to these early steps in the kidney transplant process among patients with LN-ESKD. METHODS: Adults who began treatment for ESKD in the Southeast, Northeast, New York, or Ohio River Valley U.S. regions from 1/1/2012 to 12/31/2019, followed through 6/30/2021, were identified from the United States Renal Data System. Referral and evaluation start data were collected from 28 of 48 transplant centers across these regions. The exposure was primary cause of ESKD (LN-ESKD vs other-ESKD). The outcomes were referral and evaluation start at a transplant center. Cox models quantified the association between LN-ESKD (vs other-ESKD) and referral and evaluation start. RESULTS: Among 192,318 patients initiating treatment for ESKD, 0.4% had LN-ESKD. Over half (58%) of LN-ESKD patients were referred before study end, and among those referred, 66% started the evaluation. In adjusted analyses, patients with LN-ESKD were referred (HR: 1.09, 95% CI: 0.99, 1.19) and started the transplant evaluation (HR: 1.13, 95% CI: 1.00, 1.28) at a higher rate than patients with other-ESKD. Among referred patients with LN-ESKD, the median time from ESKD start to referral was 2.9 months (IQR: <1 to 11.7 months), which is similar to patients with other-ESKD (median 2.6 months, IQR: <1 to 8.8 months). CONCLUSIONS: Among incident patients with ESKD, having a primary diagnosis of LN-ESKD versus other-ESKD is associated with higher rates of early transplant access outcomes. Despite this, patients with LN-ESKD (vs other-ESKD) are less likely to be preemptively referred (i.e., referred prior to ESKD start) for kidney transplant. While providers may no longer be delaying the early steps in the kidney transplantation process among this patient population, there is still room for improvement in the rates of preemptive referral. Access to kidney transplant referral prior to ESKD could result in increased transplant rates and better transplant outcomes for patients with LN-ESKD.

The clinical performance and population health impact of birthweight-for-gestational age indices at term gestation.

BACKGROUND: The assessment of birthweight for gestational age and the identification of small- and large-for-gestational age (SGA and LGA) infants remain contentious, despite the recent creation of the Intergrowth 21st Project and World Health Organisation (WHO) birthweight-for-gestational age standards. OBJECTIVE: We carried out a study to identify birthweight-for-gestational age cut-offs, and corresponding population-based, Intergrowth 21st and WHO centiles associated with higher risks of adverse neonatal outcomes, and to evaluate their ability to predict serious neonatal morbidity and neonatal mortality (SNMM) at term gestation. METHODS: The study population was based on non-anomalous, singleton live births between 37 and 41 weeks' gestation in the United States from 2003 to 2017. SNMM included 5-min Apgar score <4, neonatal seizures, need for assisted ventilation, and neonatal death. Birthweight-specific SNMM was modelled by gestational week using penalised B-splines. The birthweights at which SNMM odds were minimised (and higher by 10%, 50% and 100%) were estimated, and the corresponding population, Intergrowth 21st, and WHO centiles were identified. The clinical performance and population impact of these cut-offs for predicting SNMM were evaluated. RESULTS: The study included 40,179,663 live births and 991,486 SNMM cases. Among female singletons at 39 weeks' gestation, SNMM odds was lowest at 3203 g birthweight, and 10% higher at 2835 g and 3685 g (population centiles 11th and 82nd, Intergrowth centiles 17th and 88th and WHO centiles 15th and 85th). Birthweight cut-offs were poor predictors of SNMM, for example, the cut-offs associated with 10% and 50% higher odds of SNMM among female singletons at 39 weeks' gestation resulted in a sensitivity, specificity, and population attributable fraction of 12.5%, 89.4%, and 2.1%, and 2.9%, 98.4% and 1.3%, respectively. CONCLUSIONS: Reference- and standard-based birthweight-for-gestational age indices and centiles perform poorly for predicting adverse neonatal outcomes in individual infants, and their associated population impact is also small.

Differences in Delirium Evaluation and Pharmacologic Management in Children With Developmental Delay: A Retrospective Case-Control Study.

Delirium is associated with increased mortality and cost, decreased neurocognition, and decreased quality of life in the pediatric intensive care unit (PICU) population. The Cornell Assessment for Pediatric Delirium (CAPD) is used in PICUs for delirium screening but lacks specificity in children with developmental delay (DD). Within a cohort of children receiving pharmacologic treatment for intensive care unit (ICU) delirium, we compared delirium scoring and medication management between children with and without DD. We hypothesized that CAPD scores and treatment decisions would differ between DD and neurotypical (NT) patients. In this retrospective case-control study, we queried the medical record of patients admitted to our PICU with respiratory failure from June 2018 to March 2022 who received antipsychotics typically used for ICU delirium. Antipsychotics prescribed for home use were excluded. Nonparametric statistics compared demographics, CAPD scores, medication choice, dosing (mg/kg), and medication continuation after discharge between those with and without DD based on the ICD-10 codes. Twenty-one DD admissions and 59 NT admissions were included. Groups did not significantly differ by demographics, LOS, drug, or initial dosage. DD patients had higher median CAPD scores at admission (17 vs 13; P = .02) and treatment initiation (18 vs 16.5; P = .05). Providers more frequently escalated doses in DD patients (13/21 vs 21/59; P = .04) and discharged them home on new antipsychotics (7/21 vs 5/59; P = .01). DD patients experience delirium screening and management differently than NT counterparts. Providers should be aware of baseline elevated scores in DD patients and carefully attend to indications for dosage escalation. Further work is needed to understand if prolonged duration, even after hospital discharge, benefits patients, or represents potential disparity in care.

"I probably have access, but I can't afford it": expanding definitions of affordability in access to contraceptive services among people with low income in Georgia, USA.

BACKGROUND: Disparities in rates of contraceptive use are frequently attributed to unequal access to and affordability of care. There is a need to better understand whether common definitions of affordability that solely relate to cost or to insurance status capture the reality of individuals' lived experiences. We sought to better understand how individuals with low incomes and the capacity for pregnancy conceptualized one domain of contraceptive access-affordability --in terms of health system and individual access and how both shaped contraceptive care-seeking in the US South. METHOD: Between January 2019 to February 2020, we conducted twenty-five life-history interviews with low-income individuals who may become pregnant living in suburban counties in Georgia, USA. Interviews covered the ways individual and health system access factors influenced care-seeking for family planning over the life course. Interview transcripts were analyzed using a thematic analysis approach to identify experiences associated with individual and health system access. RESULTS: Affordability was identified as a major determinant of access, one tied to unique combinations of individual factors (e.g., financial status) and health system characteristics (e.g., cost of methods) that fluctuated over time. Navigating the process to attain affordable care was unpredictable and had important implications for care-seeking. A "poor fit" between individual and health system factors could lead to inequities in access and gaps in, or non-use of contraception. Participants also reported high levels of shame and stigma associated with being uninsured or on publicly funded insurance. CONCLUSIONS: Affordability is one domain of contraceptive access that is shaped by the interplay between individual factors and health system characteristics as well as by larger structural factors such as health and economic policies that influence both. Assessments of the affordability of contraceptive care must account for the dynamic interplay among multilevel influences. Despite the expansion of contraceptive coverage through the Affordable Care Act, low-income individuals still struggle with affordability and disparities persist.

Unpacking Breastfeeding Disparities: Baby-Friendly Hospital Designation Associated with Reduced In-Hospital Exclusive Breastfeeding Disparity Attributed to Neighborhood Poverty.

OBJECTIVES: To examine US in-hospital exclusive breastfeeding (EBF) and the associations with Baby-Friendly designation and neighborhood sociodemographic factors. METHODS: Hospital data from the 2018 Maternity Practices in Infant Nutrition and Care survey were linked to hospital zip code tabulation area (ZCTA) sociodemographic data from the 2014-2018 American Community Survey (n = 2,024). The percentages of residents in the hospital ZCTA were dichotomized based on the relative mean percentage of the hospital's metropolitan area, which were exposure variables (high/low Black hospitals, high/low poverty hospitals, high/low educational attainment hospitals) along with Baby-Friendly designation. Using linear regression, we examined the associations and effect measure modification between Baby-Friendly designation and hospital sociodemographic factors with in-hospital EBF prevalence. RESULTS: US mean in-hospital EBF prevalence was 55.1%. Baby-Friendly designation was associated with 9.1% points higher in-hospital EBF prevalence compared to non-designated hospitals [95% confidence interval (CI): 7.0, 11.2]. High Black hospitals and high poverty hospitals were associated with lower EBF prevalence (difference= -3.3; 95% CI: -5.1, -1.4 and - 3.8; 95% CI: -5.7, -1.8). High educational attainment hospitals were associated with higher EBF prevalence (difference = 6.7; 95% CI: 4.1, 9.4). Baby-Friendly designation was associated with significant effect measure modification of the in-hospital EBF disparity attributed to neighborhood level poverty (4.0% points higher in high poverty/Baby-Friendly designated hospitals than high poverty/non-Baby-Friendly designated hospitals).

Highly public anti-Black violence is associated with poor mental health days for Black Americans.

Highly public anti-Black violence in the United States may cause widely experienced distress for Black Americans. This study identifies 49 publicized incidents of racial violence and quantifies national interest based on Google searches; incidents include police killings of Black individuals, decisions not to indict or convict the officer involved, and hate crime murders. Weekly time series of population mental health are produced for 2012 through 2017 using two sources: 1) Google Trends as national search volume for psychological distress terms and 2) the Behavioral Risk Factor Surveillance System (BRFSS) as average poor mental health days in the past 30 d among Black respondents (mean weekly sample size of 696). Autoregressive moving average (ARMA) models accounted for autocorrelation, monthly unemployment, season and year effects, 52-wk lags, news-related searches for suicide (for Google Trends), and depression prevalence and percent female (for BRFSS). National search interest varied more than 100-fold between racial violence incidents. Black BRFSS respondents reported 0.26 more poor mental health days during weeks with two or more racial incidents relative to none, and 0.13 more days with each log10 increase in national interest. Estimates were robust to sensitivity tests, including controlling for monthly number of Black homicide victims and weekly search interest in riots. As expected, racial incidents did not predict average poor mental health days among White BRFSS respondents. Results with national psychological distress from Google Trends were mixed but generally unsupportive of hypotheses. Reducing anti-Black violence may benefit Black Americans' mental health nationally.

Allogeneic Blood Transfusion and Risk of Postoperative Complications in Patients with Mild and Moderate Anemia of Any Cause? A Retrospective Cohort Study in Total Revision Hip Surgery.

Introduction: Patients undergoing revision total hip surgery (RTHS) have a high prevalence of mild and moderate preoperative anemia, associated with adverse outcomes. The aim of this study was to investigate the association of perioperative allogeneic blood transfusions (ABT) and postoperative complications in preoperatively mild compared to moderate anemic patients undergoing RTHS who did not receive a diagnostic anemia workup and treatment before surgery. Methods: We included 1,765 patients between 2007 and 2019 at a university hospital. Patients were categorized according to their severity of anemia using the WHO criteria of mild, moderate, and severe anemia in the first Hb level of the case. Patients were grouped as having received no ABT, 1-2 units of ABT, or more than 2 units of ABT. Need for intraoperative ABT was assessed in accordance with institutional standards. Primary endpoint was the compound incidence of postoperative complications. Secondary outcomes included major/minor complications and length of hospital and ICU stay. Results: Of the 1,765 patients, 31.0% were anemic of any cause before surgery. Transfusion rates were 81% in anemic patients and 41.2% in nonanemic patients. The adjusted risks for compound postoperative complication were significantly higher in patients with moderate anemia (OR 4.88, 95% CI: 1.54-13.15, p = 0.003) but not for patients with mild anemia (OR 1.93, 95% CI: 0.85-3.94, p < 0.090). Perioperative ABT was associated with significantly higher risks for complications in nonanemic patients and showed an increased risk for complications in all anemic patients. In RTHS, perioperative ABT as a treatment for moderate preoperative anemia of any cause was associated with a negative compound effect on postoperative complications, compared to anemia or ABT alone. Discussion: ABT is associated with adverse outcomes of patients with moderate preoperative anemia before RTHS. For this reason, medical treatment of moderate preoperative anemia may be considered.

Experimental high-energy physics without computer simulations.

This paper argues against the claim that high-energy physics experiments done so far could not be carried out without computer simulations. We show that it would be possible to completely dispense with computer simulations for experiments conducted to date, and that computer simulations up to now are mostly used for practical reasons. Our investigation covers all elements of experimental research in which computer simulations have been used. Dispensing with simulations would yield an advantage with regard to the complex theory dependence of experiments. We also point out that computer simulations may play a more essential role for the complex measurements foreseen at the Large Hadron Collider, where subtle dependencies between final state objects in high-energy physics experiments must be accurately described. Therefore, the conceivable complete replacement of computer simulations may have come to an end, and the theory dependence of high-energy physics experiments through computer simulations may be entering a new phase.

Understanding the roles of state demographics and state policies in epidemiologic studies of maternal-child health disparities.

Disparities in maternal-child health outcomes by race and ethnicity highlight structural differences in the opportunity for optimal health in the United States. Examples of these differences include access to state-level social policies that promote maternal-child health. States vary in their racial and ethnic composition as a result of the complex history of policies and laws related to slavery, Indigenous genocide and relocation, segregation, immigration, and settlement in the United States. States also vary in the social policies they enact. As a result, correlations exist between the demographic makeup of a state's population and the presence or absence of social policies in that state. These correlations become a mechanism by which racial and ethnic disparities in maternal-child health outcomes can operate. In this commentary, we use the example of three labor-related policies actively under consideration at state and federal levels (paid parental leave, paid sick leave, and reasonable accommodations during pregnancy) to demonstrate how correlations between state demographics and presence of these state policies could cause or exacerbate racial and ethnic disparities in maternal-child health outcomes. We conclude with a call for researchers to consider how the geographic distribution of racialized populations and state policies could contribute to maternal-child health disparities.

Impact of BMI on patient outcome in acute myeloid leukaemia patients receiving intensive induction therapy: a real-world registry experience.

BACKGROUND: Acute myeloid leukaemia (AML) is treated with intensive induction chemotherapy (IT) in medically fit patients. In general, obesity was identified as a risk factor for all-cause mortality, and there is an ongoing debate on its impact on outcome and optimal dosing strategy in obese AML patients. METHODS: We conducted a registry study screening 7632 patients and assessed the impact of obesity in 1677 equally IT treated, newly diagnosed AML patients on the outcome (OS, EFS, CR1), comorbidities, toxicities and used dosing strategies. RESULTS: Obese patients (BMI ≥ 30) displayed a significant inferior median OS (29.44 vs. 47.94 months, P = 0.015) and CR1 rate (78.7% vs. 84.3%, P = 0.015) without differences in median EFS (7.8 vs. 9.89 months, P = 0.3) compared to non-obese patients (BMI < 30). The effect was predominantly observed in older (≥60 years) patients. Obesity was identified as an independent risk factor for death, and obese patients demonstrated higher rates of cardiovascular or metabolic comorbidities. No differences for OS, EFS, CR1 or treatment-related toxicities were observed by stratification according to used dosing strategy or dose reduction. CONCLUSIONS: In conclusion, this study identifies obesity as an independent risk factor for worse OS in older AML patients undergoing curative IT most likely due to obesity-related comorbidities and not to dosing strategy.

Census Tracts Are Not Neighborhoods: Addressing Spatial Misalignment in Studies Examining the Impact of Historical Redlining on Present-day Health Outcomes.

BACKGROUND: Research examining the effects of historical redlining on present-day health outcomes is often complicated by the misalignment of contemporary census boundaries with the neighborhood boundaries drawn by the US Home Owners' Loan Corporation (HOLC) in the 1930s. Previous studies have used different approaches to assign historical HOLC grades to contemporary geographies, but how well they capture redlining exposure is unknown. METHODS: Our analysis included 7711 residences identified in the Multiple Listing Service database in Atlanta, Georgia (2017-2022). We evaluated the classification of HOLC grade assignment (A, B, C, D, or ungraded) when assigning exposure under four area-level approaches (centroid, majority land area, weighted score, and highest HOLC) compared with using complete address data (gold standard). We additionally compared approaches across three 2020 census geographies (tract, block group, and block). RESULTS: When comparing the use of census tracts to complete address data, sensitivity was highest for the weighted score approach, which correctly identified 77% of residences in truly A-D graded neighborhoods as compared with the majority land area (44%), centroid (54%), and highest HOLC (59%) approaches. Regarding specificity, the majority land area approach best-classified residences in truly ungraded neighborhoods (93%) as compared with the weighted score (65%), centroid (81%), and highest HOLC (54%) approaches. Classification improved regardless of approach when using census block compared with the census tract. CONCLUSIONS: Misclassification of historical redlining exposure is inevitable when using contemporary census geographies rather than complete address data. This study provides a framework for assessing spatial misalignment and selecting an approach for classification.

Neighborhood Deprivation and Neural Tube Defects.

BACKGROUND: Individual measures of socioeconomic status (SES) have been associated with an increased risk of neural tube defects (NTDs); however, the association between neighborhood SES and NTD risk is unknown. Using data from the National Birth Defects Prevention Study (NBDPS) from 1997 to 2011, we investigated the association between measures of census tract SES and NTD risk. METHODS: The study population included 10,028 controls and 1829 NTD cases. We linked maternal addresses to census tract SES measures and used these measures to calculate the neighborhood deprivation index. We used generalized estimating equations to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) estimating the impact of quartiles of census tract deprivation on NTDs adjusting for maternal race-ethnicity, maternal education, and maternal age at delivery. RESULTS: Quartiles of higher neighborhood deprivation were associated with NTDs when compared with the least deprived quartile (Q2: aOR = 1.2; 95% CI = 1.0, 1.4; Q3: aOR = 1.3, 95% CI = 1.1, 1.5; Q4 (highest): aOR = 1.2; 95% CI = 1.0, 1.4). Results for spina bifida were similar; however, estimates for anencephaly and encephalocele were attenuated. Associations differed by maternal race-ethnicity. CONCLUSIONS: Our findings suggest that residing in a census tract with more socioeconomic deprivation is associated with an increased risk for NTDs, specifically spina bifida.

Severe Maternal Morbidity in Georgia, 2009-2020.

BACKGROUND: The increasing focus of population surveillance and research on maternal-and not only fetal and infant-health outcomes is long overdue. The United States maternal mortality rate is higher than any other high-income country, and Georgia is among the highest rates in the country. Severe maternal morbidity (SMM) is conceived of as a "near miss" for maternal mortality, is 50 times more common than maternal death, and efforts to systematically monitor SMM rates in populations have increased in recent years. Much of the current population-based research on SMM has occurred in coastal states or large cities, despite substantial geographical variation with higher maternal and infant health burdens in the Southeast and rural regions. METHODS: This population-based study uses hospital discharge records linked to vital statistics to describe the epidemiology of SMM in Georgia between 2009 and 2020. RESULTS: Georgia had a higher SMM rate than the United States overall (189.2 vs. 144 per 10,000 deliveries in Georgia in 2014, the most recent year with US estimates). SMM was higher among racially minoritized pregnant persons and those at the extremes of age, of lower socioeconomic status, and with comorbid chronic conditions. SMM rates were 5 to 6 times greater for pregnant people delivering infants <1500 grams or <32 weeks' gestation as compared with those delivering normal weight or term infants. Since 2015, SMM has increased in Georgia. CONCLUSION: SMM represents a collection of life-threatening emergencies that are unevenly distributed in the population and require increased attention. This descriptive analysis provides initial guidance for programmatic interventions intending to reduce the burden of SMM and, subsequently, maternal mortality in the US South.

Prediction of complete remission and survival in acute myeloid leukemia using supervised machine learning.

Achievement of complete remission signifies a crucial milestone in the therapy of acute myeloid leukemia (AML) while refractory disease is associated with dismal outcomes. Hence, accurately identifying patients at risk is essential to tailor treatment concepts individually to disease biology. We used nine machine learning (ML) models to predict complete remission and 2-year overall survival in a large multicenter cohort of 1,383 AML patients who received intensive induction therapy. Clinical, laboratory, cytogenetic and molecular genetic data were incorporated and our results were validated on an external multicenter cohort. Our ML models autonomously selected predictive features including established markers of favorable or adverse risk as well as identifying markers of so-far controversial relevance. De novo AML, extramedullary AML, double-mutated CEBPA, mutations of CEBPA-bZIP, NPM1, FLT3-ITD, ASXL1, RUNX1, SF3B1, IKZF1, TP53, and U2AF1, t(8;21), inv(16)/t(16;16), del(5)/del(5q), del(17)/del(17p), normal or complex karyotypes, age and hemoglobin concentration at initial diagnosis were statistically significant markers predictive of complete remission, while t(8;21), del(5)/del(5q), inv(16)/t(16;16), del(17)/del(17p), double-mutated CEBPA, CEBPA-bZIP, NPM1, FLT3-ITD, DNMT3A, SF3B1, U2AF1, and TP53 mutations, age, white blood cell count, peripheral blast count, serum lactate dehydrogenase level and hemoglobin concentration at initial diagnosis as well as extramedullary manifestations were predictive for 2-year overall survival. For prediction of complete remission and 2-year overall survival areas under the receiver operating characteristic curves ranged between 0.77-0.86 and between 0.63-0.74, respectively in our test set, and between 0.71-0.80 and 0.65-0.75 in the external validation cohort. We demonstrated the feasibility of ML for risk stratification in AML as a model disease for hematologic neoplasms, using a scalable and reusable ML framework. Our study illustrates the clinical applicability of ML as a decision support system in hematology.