A scalable approach for critical care data extraction and analysis in an academic medical center.

BACKGROUND: Electronic health records are a valuable asset for research, but their use is challenging due to inconsistencies of records, heterogeneous formats and the distribution over multiple, non-integrated information systems. Hence, specialized health data engineering and data science expertise are required to enable research. To facilitate secondary use of clinical routine data collected in our intensive care wards, we developed a scalable approach, consisting of cohort generation, variable filtering and data extraction steps. OBJECTIVE: With this report we share our workflow of data request, cohort identification and data extraction. We present an algorithm for automatic data extraction from our critical care information system (CCIS) that can be adapted to other object-oriented data bases. METHODS: We introduced a data request process with functionalities for automated identification of patient cohorts and a specialized hierarchical data structure that supports filtering relevant variables from the CCIS and further systems for the specified cohorts. The data extraction algorithm takes patient pseudonyms and variable lists as inputs. Algorithms are implemented in Python, leveraging the PySpark framework running on our data lake infrastructure. RESULTS: Our data request process is in operational use since June 2022. Since then we have served 121 projects with 148 service requests in total. We discuss the hierarchical structure and the frequently used data items of our CCIS in detail and present an application example, including cohort selection, data extraction and data transformation into an analyses-ready format. CONCLUSIONS: Using clinical routine data for secondary research is challenging and requires an interdisciplinary team. We developed a scalable approach that automates steps for cohort identification, data extraction and common data pre-processing steps. Additionally, we facilitate data harmonization, integration and consult on typical data analysis scenarios, machine learning algorithms and visualizations in dashboards.

Single or Double Induction With 7 + 3 Containing Standard or High-Dose Daunorubicin for Newly Diagnosed AML: The Randomized DaunoDouble Trial by the Study Alliance Leukemia.

PURPOSE: To determine the optimal daunorubicin dose and number of 7 + 3 induction cycles in newly diagnosed AML, this randomized controlled trial compared a once daily dose of 60 mg/m2 with 90 mg/m2 daunorubicin in the first 7 + 3 induction and one versus two cycles of 7 + 3 induction. PATIENTS AND METHODS: Patients age 18-65 years with newly diagnosed AML were randomly assigned to 60 versus 90 mg/m2 daunorubicin once daily plus cytarabine. Patients with marrow blasts below 5% on day 15 after first induction were randomly assigned to receive a second induction cycle or no second induction cycle. RESULTS: Eight hundred and sixty-four patients with a median age of 52 years were randomly assigned. After a preplanned interim analysis showing no significant difference in response between 60 and 90 mg/m2, all consecutive patients received 60 mg/m2 daunorubicin once daily. The proportion of good early responders was 44% versus 48% (P = .983) with a composite complete remission (CRc) rate of 90% versus 89% after induction (P = .691); the 3-year relapse-free survival (RFS) after 60 versus 90 mg/m2 once daily was 54% versus 50% (P = .561), and the 3-year overall survival (OS) was 65% versus 58% (P = .242). Among 389 good responders, CRc rates at the end of induction were 87% after single induction and 85% after double induction. The 3-year RFS was 51% versus 60% (hazard ratio [HR], 1.3; P = .091), and the 3-year OS was 76% versus 75% after single versus double induction (HR, 1.0; P = .937). CONCLUSION: The use of 90 mg/m2 daunorubicin once daily in the context of classical 7 + 3 induction does not significantly improve early response and does not lead to higher remission rates or longer survival than 60 mg/m2 once daily. In patients with a good early response after first induction, a second induction has only a limited impact on RFS and does not result in an OS benefit.

Venetoclax-based salvage therapy as bridge-to-transplant is feasible and effective in patients with relapsed/refractory AML.

The BCL2-inhibitor Venetoclax (VEN) in combination with hypomethylating agents (HMA) has been approved for first-line treatment of acute myeloid leukemai (AML) patients ineligible for intensive treatment. Emerging Data suggest that VEN containing treatment strategies may also be effective in relapsed/refractory (R/R) AML, however, comparative studies with conventional treatment strategies for medically fit patients as a bridge-to transplant strategy are limited. Using propensity score matching (PSM) analysis, we compared 37 R/R AML patients, who received VEN-based salvage therapy as bridge to allogeneic hematopoietic cell transplantation (allo-HCT) with 90 patients from the German Study Alliance Leukemia (SAL) AML registry, who were treated with non-VEN-containing salvage therapy according to their treating physician's choice (TPC) including intensive and non-intensive protocols. The overall response rate (ORR=CR+CRi) among all VEN patients was significantly higher compared to the TPC control cohort (62% vs. 42%; p=0.049). Overall, 73% of VEN-treated patients vs. 63% of TPC patients were successfully bridged to allo-HCT (p =0.41). After a median follow-up of 34.3 months for the VEN cohort and 21.0 months for the TPC cohort, the median overall-survival (OS) was 15.8 months (95%-CI, 10.6-NE) and 10.5 months (95%-CI, 6.8-19.6) (p=0.15), respectively. PSM revealed a trend towards improved OS for VEN patients (HR 0.70; 95%-CI, 0.41-1.22; p=0.20). Median event free survival (EFS) was significantly longer in the VEN cohort (8.0 months) compared to the TPC cohort (3.7 months) (p=0.006). In summary, our data suggests that VEN-based salvage therapy is a safe and effective bridge to allo-HCT for this difficult-to-treat AML patient population.

Prevalence and incidence of pelvic organ prolapse, bowel and urinary dysfunction in the Integrated Woman's Health Program.

OBJECTIVE: Despite its high prevalence, little information is available on the natural history of pelvic floor dysfunction. We aimed to determine the prevalence, incidence and persistence of pelvic organ prolapse (POP), bowel and urinary symptoms over 6-7 years and its associated factors. STUDY DESIGN: Women from a midlife cohort in Asia completed baseline and 6-7-year follow-up assessments. Sociodemographic characteristics and health conditions were obtained at baseline using validated questionnaires. Body mass index (BMI) and physical performance were objectively measured. MAIN OUTCOME MEASURES: POP, bowel, and urinary dysfunction were measured using the Pelvic Floor Distress Inventory Short Form 20 at both timepoints. Binary logistic regression was used to analyze independent associations between baseline risk factors and prevalent, new, and persistent symptoms. RESULTS: Of the 1201 women enrolled at baseline, 62.3 % had symptoms in at least one domain of pelvic floor dysfunction. Poor sleep, poorer perceived health, and disability were associated with prevalent pelvic floor symptoms, while poor sleep doubled the adjusted risk of incident POP (adjusted odds ratio, aOR: 2.3, 95 % Confidence Interval: 1.4-3.9), bowel (aOR: 2.3, 1.4-3.7) and urinary (aOR: 1.7, 1.1-2.9) symptoms at the 6.6-year follow-up visit. Postmenopausal women had reduced risks of prevalent POP (aOR: 0.5, 0.3-0.7) and urinary symptoms (aOR: 0.4, 0.3-0.6), as well as a reduced risk of developing incident urinary symptoms (aOR: 0.4, 0.2-0.8). Good physical performance scores at baseline reduced the risk of incident bowel symptoms (aOR: 0.5, 0.2-0.9), whereas obesity increased the risks of persistent symptoms. CONCLUSION: Poor sleep quality independently predicted incident pelvic floor dysfunction, while poor physical performance was associated with incident bowel symptoms.

"So that I can trust them with my body:" How people with low incomes who may become pregnant define and prioritize quality reproductive health care.

OBJECTIVES: As part of a larger mixed-methods study to better define equity in access to sexual and reproductive health (SRH) care in Georgia, this analysis sought to understand: (1) how individuals define quality care for their SRH services; and (2) how quality of care is salient in their SRH care-seeking. STUDY DESIGN: From January 2019 to February 2020, we conducted life history interviews with individuals with the capacity to become pregnant in suburban areas in Georgia. We analyzed interviews using thematic analysis. RESULTS: SRH care quality was shaped by experiences with health center environment, with providers, and with staff. Study participants emphasized elements associated with trusted SRH care such as showing compassion, respecting and non-judging, taking time, providing information, and assuring agency. Participants also voiced a desire for holistic care that addressed the lived experiences of the individual. Participants took quality of care into account when care-seeking but sometimes had to weigh out preferences for quality with issues of affordability. CONCLUSIONS: Access to quality person-centered care is an essential component of realized access to SRH services. Measures of equitable access and quality should account for experiences of quality care that include both provider and staff interactions as well as the larger healthcare environment and ability to use quality care despite financial constraints. IMPLICATIONS: Quality family planning care should involve both clinicians and staff to incorporate showing compassion, providing respectful and non-judgmental care, taking time with patients, providing information, assuring agency in decision-making, as well as addressing the lived experiences of individuals.

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.

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).

"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.

Increasing access, equitability, and rigor in the assessment of Neighborhood Mortgage Discrimination.

Mortgage discrimination alters the distribution of investment, opportunity, and economic advantage-key contributors of health disparities. Leveraging Home Mortgage Disclosure Act data, we assessed mortgage denial risk in 380 U.S. urban areas. We estimated the risks by census tract-relative to the urban-specific average-using a Bayesian spatial model with conditionally autoregressive distributions fitted with integrated nested Laplace approximation. This approach borrows information through spatial and non-spatial smoothing, resulting in stable estimates in the presence of sparse data. The method, publicly accessible, allows researchers to apply our approach, fostering deeper insights into mortgage lending discrimination and systematic neighborhood disinvestment.

Persons in contexts: The role of social networks and social density for the dynamic regulation of face-to-face interactions in daily life.

Current psychological theories on daily social interactions emphasize individual differences yet are underspecified regarding contextual factors. We aim to extend this research by examining how two context factors shape social interactions in daily life: how many relationships people maintain and how densely people live together. In Study 1, 307 German participants (Mage = 39.44 years, SDage = 14.14) answered up to 20 experience sampling questionnaires regarding their social interactions over 2 days. In Study 2, 313 German participants (Mage = 48.96 years, SDage = 15.54) summarized their daily interactions in daily diaries for 14 days. Participants reported on their social network size and the social density (i.e., household and neighborhood density) of their living situations. Mobile sensing provided additional measures of social interactions and network size. The results showed that participants living in densely populated households transitioned faster from solitude to social interactions but slower from social interactions to solitude. Participants living in dwellings with more homes also transitioned slower from solitude to social interactions. Contrary to the hypothesis, social network size was inconsistently linked with transitions from solitude to social interactions and vice versa. Furthermore, current social desires predicted subsequent social interactions within days, but not across days-irrespective of individuals' social network size or social density. Together the results point out that people live their daily life in social contexts, which contribute to how they engage in social interactions. The findings thus call for a greater integration of contextual factors in personality theories of social interactions. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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.

A freely precessing magnetar following an X-ray outburst.

Magnetars-highly magnetized neutron stars-are thought to be the most likely progenitors for fast radio bursts (FRBs). Freely precessing magnetars are further invoked to explain the repeating FRBs. We report here on new high-cadence radio observations of the magnetar XTE J1810-197 recorded shortly after an X-ray outburst. We interpret the polarization variations of the magnetar radio emission as evidence for the magnetar undergoing free precession following the outburst while its magnetosphere slowly untwists. The observations of precession being damped on a timescale of months argue against the scenario of freely precessing magnetars as the origin of repeating FRBs. Using free-precession models based on relaxing ellipticity with a decay of the wobble angle, we find the magnetar ellipticity to be in good agreement with theoretical predictions from nuclear physics. Our precise measurement of the magnetar's geometry can also further help in refining the modelling of X-ray light curves and constrain the star's compactness.

Historical Redlining and Heart Failure Outcomes Following Hospitalization in the Southeastern United States.

BACKGROUND: Historical redlining, a discriminatory lending practice, is an understudied component of the patient risk environment following hospital discharge. We investigated associations between redlining, patient race, and outcomes following heart failure hospitalization. METHODS AND RESULTS: We followed a hospital-based cohort of Black and White patients using electronic medical records for acute heart failure hospitalizations between 2010 and 2018 (n=6800). Patient residential census tracts were geocoded according to the 1930s Home Owners' Loan Corporation map grades (A/B: best/still desirable, C: declining, D: redlined). We used Poisson regression to analyze associations between Home Owners' Loan Corporation grade and 30-day outcomes (readmissions, mortality, and their composite). One-third of patients resided in historically redlined tracts (n=2034). In race-stratified analyses, there was a positive association between historically declining neighborhoods and composite readmissions and mortality for Black patients (risk ratio [RR], 1.24 [95% CI, 1.003-1.54]) and an inverse association between redlined neighborhoods and 30-day readmissions among White patients (RR, 0.58 [95% CI, 0.39-0.86]). Examining racial disparities across Home Owners' Loan Corporation grades, Black patients had higher 30-day readmissions (RR, 1.86 [95% CI, 1.31-2.65]) and composite readmissions and mortality (RR, 1.32 [95% CI, 1.04-1.65]) only in historically redlined neighborhoods. CONCLUSIONS: Historical redlining had potentially mixed impacts on outcomes by race, such that residing in less desirable neighborhoods was associated with an elevated risk of an adverse outcome following heart failure hospitalization in Black patients and a reduced risk in White patients. Moreover, racial disparities in patient outcomes were present only in historically redlined neighborhoods. Additional research is needed to explore observed heterogeneity in outcomes.

Person-centered hospital discharge data: Essential existing infrastructure to enhance public health surveillance of maternal substance use disorders in the midst of a national maternal overdose crisis.

OBJECTIVES: As crises of drug-related maternal harms escalate, US public health surveillance capacity remains suboptimal for drug-related maternal morbidities. Most state hospital discharge databases (HDDs) are encounter-based, and thus limit ascertainment of morbidities to delivery visits and ignoring those occurring during the 21 months spanning pregnancy and postpartum year. This study analyzes data from a state that curates person-centered HDD to compare patterns of substance use disorder (SUD) diagnoses at delivery vs. the full 21 pregnancy/postpartum months, overall and by maternal social position. METHODS: Among people who experienced an in-hospital birth in New York State between 9/1/2016 and 1/1/2018 (N = 330,872), we estimated SUD diagnosis (e.g., opioids, stimulants, benzodiazepines, cannabis) prevalence at delivery; across the full 9 months of pregnancy and 12 postpartum months; and by trimester and postpartum quarter. Risk ratio and risk difference estimated disparities by race/ethnicity, age, rurality, and payor. RESULTS: The 21-month SUD prevalence rate per 100,000 was 2671 (95% CI 2616-2726), with 31% (29.5%-31.5%) missing SUD indication when ascertained at delivery only (1866; 95% CI 1820-1912). Quarterly rates followed a roughly J-shaped trajectory. Structurally marginalized individuals suffered the highest 21-month SUD prevalence (e.g., Black:White risk ratio=1.80 [CI:1.73-1.88]). CONCLUSION: By spanning the full 21 months of pregnancy/postpartum, person-centered HDD reveal than the maternal SUD crisis is far greater than encounter-based delivery estimates had revealed. Generating person-centered HDD will improve efforts to tailor interventions to help people who use drugs survive while pregnant and postpartum, and eliminate inequities.

Associations between hypertension with reproductive and menopausal factors: An integrated women's health programme (IWHP) study.

BACKGROUND: Women are less likely to have classic cardiovascular risk factors than men, and events during their reproductive and menopausal years may increase hypertension risk. The aim of this study is to examine woman-specific factors, including menstrual, reproductive and pregnancy complications, in relation to the prevalence of hypertension in mid-life Asian women. METHODS: This is a cross-sectional study of 1146 healthy women aged 45-69 years, from a multi-ethnic Asian cohort. The women completed an extensive questionnaire that included their sociodemographic details, medical history, lifestyle and physical activity, and reproductive and menopausal history. They also underwent objectively measured physical performance tests and a dual X-ray absorptiometry scan. Hypertension was defined as a systolic BP ≥140 and/or diastolic BP ≥90mm Hg, past diagnosis by a physician, or use of antihypertensive medications. Multivariable logistic regression was used to assess the independent risk factors for hypertension. RESULTS: The average age of the 1146 women analysed was 56.3 (SD 6.2) years, and 55.2 percent of them were hypertensive. The prevalence of gestational diabetes and gestational hypertension was 12.6% and 9.4%, respectively. Besides age, abnormal menstrual cycle length at 25 years of age (OR:2.35, CI:1.34-4.13), preeclampsia (OR:2.46, CI:1.06-5.74), increased visceral adiposity (OR:4.21, CI:2.28-7.79) and reduced physical performance (OR:2.83, CI:1.46-5.47) were independently associated with hypertension in Asian women. CONCLUSIONS: Our findings highlight the necessity of including features of menstrual and reproductive history as possible indicators of hypertension risk in cardiovascular disease risk assessment and prevention among Asian women. Reducing visceral adiposity and exercise to improve physical performance may help women avoid developing hypertension.

Neighborhood deprivation in relation to ovarian reserve and outcomes of ovarian stimulation among oocyte donors.

OBJECTIVE: To study the relationship between neighborhood deprivation index (NDI) and markers of ovarian reserve and outcomes of controlled ovarian stimulation among young, healthy oocyte donors. DESIGN: Retrospective cohort study. PATIENTS: A total of 547 oocyte donors who underwent 905 oocyte retrieval cycles (2008-2020) at a private fertility center in Sandy Springs, Georgia, United States. INTERVENTIONS: Neighborhood deprivation index was calculated using principal component analysis applied to census-level measures of poverty, employment, household composition, and public assistance, which was then standardized and linked to donor information on the basis of donor residence. MAIN OUTCOME MEASURES: Markers of ovarian reserve, including antral follicle count (AFC) and antimüllerian hormone (AMH) levels, and outcomes of controlled ovarian stimulation including number of total and mature oocytes retrieved and ovarian sensitivity index (OSI) (defined as the number of oocytes retrieved/total gonadotropin dose × 1,000). Multivariable generalized estimating equations with Poisson and normal distribution were used to model the relationship between NDI and outcome measures adjusting for age, body mass index, and year of retrieval. RESULTS: The mean (SD) age of donors was 25.0 (2.8) years and 29% of the donors were racial or ethnic minorities. There were no associations between donor NDI and ovarian reserve markers. For every interquartile range increase in NDI, there was a reduction of -1.5% (95% confidence interval: -5.3% to 2.4%) in total oocytes retrieved although the effect estimate was imprecise. Associations of NDI with a number of mature oocytes retrieved and OSI were in a similar direction. We observed evidence for effect modification of the NDI and OSI association by donor race. There was a suggestive positive association between NDI and OSI in Black donors but no association in White donors. CONCLUSION: In this cohort of young, healthy, racially diverse oocyte donors, we found little evidence of associations between NDI and markers of ovarian reserve or outcomes of ovarian stimulation.

Plasma Proteomic Signature Predicts Myeloid Neoplasm Risk.

PURPOSE: Clonal hematopoiesis (CH) is thought to be the origin of myeloid neoplasms (MN). Yet, our understanding of the mechanisms driving CH progression to MN and clinical risk prediction of MN remains limited. The human proteome reflects complex interactions between genetic and epigenetic regulation of biological systems. We hypothesized that the plasma proteome might predict MN risk and inform our understanding of the mechanisms promoting MN development. EXPERIMENTAL DESIGN: We jointly characterized CH and plasma proteomic profiles of 46,237 individuals in the UK Biobank at baseline study entry. During 500,036 person-years of follow-up, 115 individuals developed MN. Cox proportional hazard regression was used to test for an association between plasma protein levels and MN risk. RESULTS: We identified 115 proteins associated with MN risk, of which 30% (N = 34) were also associated with CH. These were enriched for known regulators of the innate and adaptive immune system. Plasma proteomics improved the prediction of MN risk (AUC = 0.85; P = 5×10-9) beyond clinical factors and CH (AUC = 0.80). In an independent group (N = 381,485), we used inherited polygenic risk scores (PRS) for plasma protein levels to validate the relevance of these proteins toMNdevelopment. PRS analyses suggest that most MN-associated proteins we identified are not directly causally linked toMN risk, but rather represent downstream markers of pathways regulating the progression of CH to MN. CONCLUSIONS: These data highlight the role of immune cell regulation in the progression of CH to MN and the promise of leveraging multi-omic characterization of CH to improveMN risk stratification. See related commentary by Bhalgat and Taylor, p. 3095.

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.

Prognostic impact of CEBPA mutational subgroups in adult AML.

Despite recent refinements in the diagnostic and prognostic assessment of CEBPA mutations in AML, several questions remain open, i.e. implications of different types of basic region leucin zipper (bZIP) mutations, the role of co-mutations and the allelic state. Using pooled primary data analysis on 1010 CEBPA-mutant adult AML patients, a comparison was performed taking into account the type of mutation (bZIP: either typical in-frame insertion/deletion (InDel) mutations (bZIPInDel), frameshift InDel or nonsense mutations inducing translational stop (bZIPSTOP) or single base-pair missense alterations (bZIPms), and transcription activation domain (TAD) mutations) and the allelic state (single (smCEBPA) vs. double mutant (dmCEBPA)). Only bZIPInDel patients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA-mutant subgroups. Moreover, co-mutations in bZIPInDel patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS, whereas in non-bZIPInDel patients, grouping according to ELN2022 recommendations added significant prognostic information. In conclusion, these results demonstrate bZIPInDel mutations to be the major independent determinant of outcome in CEBPA-mutant AML, thereby refining current classifications according to WHO (including all dmCEBPA and smCEBPA bZIP) as well as ELN2022 and ICC recommendations (including CEBPA bZIPms).

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.