Similar Proportions Research Articles

Caplacizumab Treatment in Elderly Patients with iTTP: Updated Experience from the Spanish TTP Registry

Introduction Immune thrombotic thrombocytopenic purpura (iTPP) is a rare microangiopathic thrombotic disorder with severely reduced levels of ADAMTS13 due to the presence of autoantibodies. It has classically been treated with plasma exchange (PEx) therapy and steroids, with the introduction of novel therapies in recent years such as rituximab and caplacizumab. Data concerning caplacizumabs' efficacy and safety profile in elderly patients is scarce, as iTTP is rarely presented in this population. We aimed to compare response to treatment with caplacizumab as well as safety, and tolerability in patients ≥60 years compared to those aged <60. Mat&Met Data were obtained from the Spanish TTP Registry. Patients were eligible if the diagnosis of iTTP was confirmed by ADAMTS13 activity <20%, presence of anti-ADAMTS13 autoantibodies, and had received caplacizumab at any time during the acute episode. Response criteria were defined following the revised criteria published by the International Working Group (Cucker et al. 2021). Statistical analysis was performed using EzR software, based on R commander (R Commander Version 2.6-1). Results A total of 104 patients from 39 centers, diagnosed from November 2018 to April 2023 were included (93 first episodes and 11 relapses). Twenty-nine patients (28%) were ≥60 years (Group 1) and 75 were <60 years (Group 2). Main characteristics of these patients are detailed in Table 1. Front-line treatment consisted of PEx and steroids in every patient, while rituximab was administered in 84% of patients. Caplacizumab was administered at a median (range) of 3 days (0-26) after diagnosis in patients <60 years and 5 days (0-23) in patients ≥60 years ( P= n.s.). Caplacizumab was administered as front-line therapy (n=21), after an exacerbation (n=5) or due to refractoriness (n=3) in the cohort of patients ≥60 years, and this occurred in a similar proportion in patients <60 years (58, 12 and 5, respectively; P= n.s.). The duration of treatment with caplacizumab was 34 (range, 1-77) and 35 days (range, 1-188) in patients ≥60 and <60 years, respectively ( P= n.s.). Final outcomes are detailed in Table 2. One patient ≥60 years died due to refractory disease despite starting caplacizumab during the first 24h after diagnosis Three of the 21 patients receiving caplacizumab as front-line treatment in Group 2 suffered an exacerbation (two due to treatment discontinuation and one while receiving caplacizumab). In 5/29 patients in Group 2, therapy with caplacizumab was delayed due to initial hemorrhagic symptoms (n=3) or ongoing anticoagulation or antiaggregation (one each). Bleeding motivating transient caplacizumab discontinuation occurred in five patients (17%) (subarachnoideal hemorrhage [one patient], hematuria, and pericatheter hemorrhage [one patient], abdominal hematoma, gastrointestinal, and gingival hemorrhage [one each]), and this was more frequent than in younger patients (one case of rectal bleeding [1.3%], P= .006). No other side-effects were reported. Conclusion Association of caplacizumab to PEx and immunosuppressive therapy improves outcomes in elderly patients with iTTP, although relevant bleeding complications might be higher than in younger patients.

An urban drainage scheme for large-scale flood models

As flood modeling spatial resolutions get finer, physical processes normally neglected, such as urban drainage, must be accounted for. Here, we describe and evaluate an urban drainage scheme for large-scale flood models. The parameterization accounts for urban imperviousness, and water flow over streets and through a prescribed urban drainage network. A parameter sensitivity analysis is performed during three major extreme floods over Rio de Janeiro city, Brazil, at ∼200 m spatial resolution. Results show that, compared to a hypothetical case without urban drainage, representing a drainage network decreases urban flooding during selected extreme events across Rio de Janeiro by 31–53 %. Such a decrease is caused by an underground water storage of up to 2.5 billion m3 across the city during flood peaks. Underground water storage and transport smooth out and delay peak flows by a few hours over major rivers and channels draining the city. Simulations also indicate that the number of residents exposed to flooding drops by 60–80 %, from ∼5 million to 1–2 million, when an urban drainage system is considered during extreme events. Similar proportions are found for social infrastructure (i.e., schools and hospitals) exposed to flooding. Results reveal that racial minority and low-income populations could disproportionally be exposed to extreme floodings across the city. We conclude that representing urban drainage has a substantial impact on flood exposure and should be accounted for in fine resolution modeling. The proposed scheme is particularly useful in poorly monitored cities and where extreme floods are a frequent hazard yet to be tackled.

Dissecting Subtype-Specific Tumor-Time Interactions and Underlying Hidden Drivers in Pediatric Acute Myeloid Leukemia Via Single-Cell Multi-Omics

Introduction: Pediatric acute myeloid leukemia (AML) is a heterogeneous hematological malignancy characterized by various chromosomal abnormalities and somatic mutations. Investigating the origin of tumorigenesis and deciphering the complex interplay between AML cells and their surrounding tumor immune microenvironment (TIME) is crucial to understand the underlying mechanisms driving disease progression and response to therapy. Recent advancements in single-cell multi-omics technologies enabled us to characterize the transcriptional (GEX) and epigenetic (ATAC) landscapes of both tumors and TIMEs. Leveraging our in-house algorithm, scMINER (single-cell Mutual Information-based Network Engineering Ranger, Ding et al., 2023), this study aims to build a comprehensive cell type atlas in diverse pediatric AML bone marrow samples and construct intra- and inter-cellular networks, enabling the identification of hidden drivers that shape subtype-specific AML-TIME interactions. Methods: Using CD45 and CD33 as selective markers by flow cytometry, we have successfully isolated blasts and enriched for T cell and B cell populations for 10X single-cell multiome profiling across AML molecular subtypes, including UBTF-TD (n=1), NPM1 (n=1), and KMT2A rearrangement (n=1). We interrogated the GEX data using scMINER, including two key steps: (i) mutual information-based clustering analysis (MICA) and (ii) mutual information-based network inference engine (MINIE). MICA characterizes the intrinsic nonlinear similarity of gene expression distributions among cells, enabling a high resolution of clusters. MINIE reverse-engineers cluster-specific intracellular gene networks and infers protein activity of transcription factors (TF) or signaling factors (SIG) drivers based on the expression of its predicted regulon targets in the corresponding cluster. The activity profiles overcome the dropout effects of single-cell RNA-seq data and reflect protein activities across all cells. ArchR is used to analyze ATAC data. CellChat is used to construct and evaluate intercellular networks. Results: AML cells from three samples were divided into four major clusters, and we labeled them as NPM1, KMT2A, UBTF_one, and UBTF_two based on sample subtypes (Fig.1A). MICA managed to obtain distinct AML cell sub-clusters. Comparison with single-cell profiles of normal hematopoietic cells and annotation with marker genes revealed their correspondence with different myeloid developmental stages. Notably, the KMT2A cluster shared a high similarity in cell type proportion with the UBTF_two cluster, and the NPM1 cluster is closer to the UBTF_one cluster. This result demonstrated significant tumor heterogeneity within and across AML molecular subtypes. With the help of intracellular gene networks generated by MINIE, we identified multiple subtype-specific hidden drivers by differential activity analysis. For example, KMT2A and UBTF_two clusters exhibited elevated SAMHD1 levels, consistent with previous GSE data (Zhang et al., 2022). Chromatin accessibility analysis of ATAC data showed increased peaks near SAMHD1 in KMT2A and UBTF_two clusters, further supporting this observation. IRF8 showed a similar expression pattern to SAMHD1, suggesting its context-dependent role across AML subtypes. Accurate annotation of myeloid and immune cells greatly enriches the preciseness of the AML and TIME interaction patterns, which vary across AML molecular subtypes (Fig.1B). Interestingly, cells originated from KMT2A cluster exhibited similar interaction patterns to UBTF_two, while NPM1 and UBTF_one were grouped. This result indicated that different AML molecular subtypes may partially utilize the same mechanisms of tumor-TIME interaction, resulting in similar tumor phenotypes. Conclusions: Accurate clustering and well-defined annotation of myeloid and immune cells enabled us to build a comprehensive cell type atlas in AML samples. The subtype-specific network and the following analysis identified candidate hidden drivers that possibly contribute to the heterogeneity of tumor populations. AML subtypes sharing the same hidden drivers have similar cell type proportions and interaction patterns with TIMEs. This observation implies that AML subtypes share cell type-specific dependencies, which can be therapeutic targets to overcome the refractoriness posed by tumor heterogeneity.

Floral signals of the dimorphic oil-producing Byrsonima sericea (Malpighiaceae): is the eglandular morph deceptive?

ABSTRACT Background Presence of eglandular individuals (lacking floral oil glands) within populations of several neotropical Malpighiaceae is intriguing, with ecological and evolutionary implications so far unexplored. This floral dimorphism (glandular and eglandular individuals) is hypothesised to be related to energetic costs of oil production and pollinator deception. Aims To evaluate whether eglandular individuals of Byrsonima sericea deceive oil-collecting bees and obtain higher reproductive success (fruit production) compared to glandular individuals. Methods We monitored flower visitation and quantified and identified floral cues (visual and olfactory) associated with glandular and eglandular individuals, and measured fruit set. Results Both morphotypes exhibited similar visual cues and proportions of visits by oil-collecting bees and similar fruit set. Floral scent via headspace analysis indicated no between-morphotype differences in biogenic volatile organic compounds, whilst flower extract samples showed a clear difference in chemical composition. Conclusions Absence of oil production in B. sericea was not associated with changes in floral cues used in pollinator attraction at long distances. Maintenance of floral cues may be a deceptive mechanism that maintains the oil-collecting behaviour of bees on flowers that lack oil glands. Higher fruit set was not observed in eglandular individuals, suggesting that energetic costs associated with oil production do not involve fruit production.

Exposure-Response Relationships between the Complement Factor B Inhibitor Iptacopan and Lactate Dehydrogenase (LDH) and Hemoglobin (Hb) in Patients (Pts) with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Background: PNH is an ultrarare disease characterized by complement-mediated hemolysis and subsequent anemia, bone marrow failure and thrombosis. In pts not treated with complement inhibitors, intravascular hemolysis (IVH) results from unregulated progression of the complement system and membrane attack complex formation. IVH is controlled in pts treated with anti-C5 therapy, but extravascular hemolysis (EVH) may emerge and cause persistent anemia. High LDH levels are a marker of ongoing IVH, while anemia can result from both IVH and EVH. Iptacopan is the first oral proximal complement inhibitor targeting factor B to selectively inhibit the alternative pathway of the complement cascade. As shown in PNH Phase III trials (APPLY-PNH [NCT04558918] and APPOINT-PNH [NCT04820530]), iptacopan can achieve good control of hemolysis. Aim: To support the dose selection for iptacopan, this analysis characterizes the exposure-response relationships between iptacopan and efficacy measures (LDH and Hb) in pts with PNH. The effect of prior anti-C5 treatment status has also been evaluated. Methods: This analysis is based on data from 4 clinical trials enrolling pts with PNH.Final data were used from the completed Phase II trials X2201 (NCT03439839; pts with active hemolysis despite anti-C5 therapy received concomitant iptacopan) and X2204 (NCT03896152; anti-C5-naïve pts received iptacopan monotherapy), in which iptacopan was administered orally in doses ranging from 25 to 200 mg twice daily (bid). Data up to the cut-off dates of 26 September 2022 and 2 November 2022 were used from the Phase III trials, APPLY-PNH (pts previously treated with anti-C5) and APPOINT-PNH (pts not treated with complement inhibitors including anti-C5), respectively, in which oral iptacopan was administered at 200 mg bid. A longitudinal mixed-effects modeling approach was applied to LDH and Hb. To account for the delay between exposure and response, indirect response models were developed for LDH and Hb. The models were used to predict the long-term (6 months) LDH and Hb responses for various iptacopan bid dose levels and to estimate (using simulation) the proportion of pts achieving LDH ≤1.5 × upper limit of normal (ULN) and Hb ≥12 g/dL. Results: The modeling dataset contained 161 pts with PNH; 94 (58%) were female, and median (range) age was 45 (18-84) years. For modeling of LDH and Hb levels, 2812 and 2587 samples were used, respectively, as well as 1577 pharmacokinetic samples. In total, 53 (33%) pts had not received anti-C5 treatment. Of the remaining 108 pts, 16 (15%) received iptacopan as add-on therapy to anti-C5 (pts from X2201) and 92 (85%) had previously received anti-C5 (pts from APPLY-PNH). The indirect response models were considered biologically plausible and adequately described the data using a common EC 50 value to both anti-C5-naïve pts and pts currently receiving or who previously received anti-C5. The estimated concentration of iptacopan required to achieve 90% of the maximum response (EC 90) of LDH was 268 ng/mL (90% confidence interval [CI] 238, 302), irrespective of prior anti-C5 treatment status ( Figure). The estimated typical LDH value after iptacopan treatment at an exposure >EC 90 was 237 U/L (90% CI 224, 250) within the normal LDH range (<250 U/L). Iptacopan 200 mg bid was the dose at which the highest proportion of pts (86%) achieved LDH ≤1.5 × ULN. While baseline LDH levels differed between anti-C5-naïve pts and pts currently receiving or who previously received anti-C5, similar proportions of these pts achieved LDH ≤1.5 × ULN (84% and 88%, respectively). The estimated EC 90 of Hb ≥12 g/dL was 1968 ng/mL (90% CI 1661, 2333) ( Figure); 89% of all pts were expected to reach EC 90 exposure at iptacopan 200 mg bid. The estimated Hb value after treatment with iptacopan at an exposure >EC 90 was 12.7 g/dL (90% CI 12.4, 13.0). 70% of pts were expected to achieve Hb normalization (≥12 g/dL) with iptacopan 200 mg bid. Similar proportions of anti-C5-naïve pts and pts who were currently receiving or who previously received anti-C5 achieved Hb ≥12 g/dL (71% and 68%, respectively). Conclusions: Indirect response models were developed to describe the exposure-response relationships between iptacopan and efficacy measures (LDH and Hb) in pts with PNH. The analysis demonstrated that 200 mg bid is the dose of oral iptacopan that achieves LDH ≤1.5 × ULN and Hb normalization in the highest proportion of patients regardless of prior treatment status.

Understanding Patient Preferences for Intervention in Individuals with Precursor Multiple Myeloma: The Preference Study

Background: The standard of care for patients with monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) consists of watchful waiting until progression to clinically manifest multiple myeloma. While an increasing number of clinical trials are exploring the premise that early intervention in this MGUS/SMM patient population will prevent progression to multiple myeloma, little is known about how patients might balance the risks against potential benefits of early intervention. Methods: To quantify preference for attributes of intervention in individuals with MGUS and SMM, we developed an online conjoint instrument with four attributes that we identified as being salient to clinical decision making: prevention of multiple myeloma, monthly cost, inconvenience, and risk of long-term side effects. We recruited individuals from two nationwide prospective cohorts to take the online instrument. To be eligible to participate, participants had to be age 18 or older, have a diagnosis of MGUS or SMM, and have no concurrent malignancy requiring active therapy. Logistic regression models were used to investigate the attributes that drive decisions of early treatment. In addition, we used a latent profile analysis to investigate latent classes defined by patient choices and assess patient characteristics that predict class membership. Results: Participants (n=272) were 43% male, with a mean age of 64.1 (SD: 9.7) years. Logistic regression models suggest a strong preference for choosing interventions based on a higher likelihood of multiple myeloma prevention (odds ratio [OR] per 10% change:1.86, 95% confidence interval [CI]: 1.72, 2.00) and avoidance of side effects (OR: 0.10, 95%CI: 0.08, 0.13). Latent profile analysis identified three latent profiles: the first profile defines individuals who predominantly value avoidance of side effects, the second profile characterizes individuals who value keeping costs low, and the third profile of individuals values multiple myeloma prevention above other attributes. Mean age was similar across latent profiles. A higher proportion of individuals in profile two (group prioritizing cost) did not complete college and had a household income of less than $100,000. A similar proportion of individuals with SMM prioritized avoiding side effects as they did multiple myeloma risk reduction. Conclusions: Overall, we found that low side effects and prevention of multiple myeloma are desirable intervention attributes in patients with MGUS and SMM. The prioritization of myeloma prevention vs low side effect profile was not perfectly coupled with an individual's disease burden. These findings reinforce the notion that a “one size fits all” approach to prevention and interception of multiple myeloma may not be suitable for all patients, and thus a diverse interventional portfolio may be needed to reach broad populations of patients with precursor conditions to multiple myeloma.

Cardiovascular Risk Factors Are Common in Myeloproliferative Neoplasms and Portend Worse Survival and Thrombotic Outcomes

DISCUSSION Myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) are characterized by increased risk of arterial and venous thrombosis. Cardiovascular risk factors (CV RFs) including hypertension, hyperlipidemia, diabetes, smoking, and obesity likely contribute to thrombotic risk, but the exact incidence of these risk factors and the impact of CV RF modification in MPNs is less clear. The purpose of this study was to determine the prevalence of baseline CV RFs in MPN patients, investigate their association with genomic profiles, and evaluate their effect on long-term outcomes. We retrospectively analyzed patients who received targeted gene sequencing at Massachusetts General Brigham / Dana Farber Cancer Institute (N=977) from 2014-2023, and met WHO 2016 criteria for PV, ET, MF, or pre-fibrotic MF. CV RFs were identified through ICD-9 or 10 codes present prior to MPN diagnosis, and defined as hypertension, hyperlipidemia, diabetes, current smoking status, or BMI>30. Patient and treatment characteristics were described with summary statistics. Genomic profiles were compared between ET, PV, and MF patients with vs without a CV RF. Primary outcome was overall death. Secondary outcomes were venous thromboembolism, arterial thrombosis (including myocardial infarction and stroke), and transformation to MF or acute myeloid leukemia (AML). We calculated cumulative incidence functions of arterial/venous thrombosis as well as overall survival in patients with or without a CV RF. Hazard ratios (HR) were estimated for outcomes using Cox proportional hazards regression. Our cohort contained 399 (39.6%) ET, 312 (31.0%) PV, and 237 (23.5%) MF or pre-fibrotic MF patients. The median age at diagnosis was 58.5 years, and 47.9% of patients were male. The overall prevalence of hyperlipidemia, hypertension, and diabetes at MPN diagnosis was 16%, 20%, and 8%. The average BMI at diagnosis in all MPNs was 27.28, with 64% and 23% of patients having a BMI of >25 and >30. Six percent of MPN patients were current smokers at time of diagnosis, compared to 39% former smokers and 56% never smokers. ET and PV patients with ≥1 CV RF at MPN (N = 234, 32.9%) diagnosis were older (mean age 61.1 vs 52.1 years, p<0.001), and more likely to be male (50.9% vs 41.3%, p=0.02), non-White (12.4% vs 7.6%, p=0.015), and have a prior history of atherosclerotic disease (16.2% vs 4.4%, p<0.001), thrombosis (13.7% vs 5.0%, p<0.001), and heart failure (2.1% vs 0.4%, p=0.042). MF patients with ≥1 CV RF (N = 120, 50.6%) were also more likely to be older (mean age 67.5 vs 60.4 years, p<0.001), male (66.7% vs 53.9%, p=0.047), and have a prior history of atherosclerotic disease (19.2% vs 6.0%, p=0.003) (Table). Results of targeted gene sequencing closest to MPN diagnosis were analyzed. A similar proportion of driver ( JAK2, CALR, MPL) and concomitant ( TET2, ASXL1, DNMT3A, SRSF2, SF3B1, U2AF1, ZRSR2) mutations were seen in MPN patients with or without a CV RF. However, patients with ET or PV with ≥1 CV RF had a lower variant allele fraction (VAF) of their driver mutation (mean 41.0% vs 48.1%, p = 0.004), which was primarily driven by JAK2 (mean 43.5% vs 52.0%, p=0.003). In ET and PV, after adjusting for variables significant on univariate analysis, the presence of ≥1 CV RF was associated with higher risk of death from any cause (HR 1.73, 95% CI 1.08-2.76) and arterial thrombosis (HR 2.33, 95% CI 1.22-4.42). Among patients with MF, the presence of ≥1 CV RF was not associated with increased risk of death when adjusted for age, sex, and prior thrombosis (HR 1.36, 95% CI 0.84 - 2.20). MPN patients with ≥1 CV RF did not have increased rates of MF or leukemia progression (Fig). In our study, CV RFs are common among patients with MPN. CV RFs were associated with adverse outcomes, including death and thrombosis among patients with ET or PV. We found no differences in the molecular profiles in MPN patients with or without CV RFs, although a lower JAK2 VAF was seen in patients without CV RFs, which will need to be explored further. MPN patients with a CV RF had significantly worse overall survival and cumulative arterial thrombosis rates, although the presence of CV RFs does not impact MF or leukemia progression. However, our results highlight the importance of addressing CV RFs in MPN care to improve morbidity and mortality.

CPX-351 Versus FLAG-IDA with or without Venetoclax in Previously Untreated and Relapsed or Refractory Acute Myeloid Leukemia

1. Introduction A recent randomized comparison of liposomal daunorubicin and cytarabine (CPX-351) did not improve response rates or overall survival compared with FLAG-IDA in newly diagnosed acute myeloid leukemia (AML) - although subgroup analyses appeared to show some benefit with CPX-351. The real-world outcomes of these cohorts are unknown. Additionally, there is little data on the relative outcomes of these cohorts in the relapsed or refractory (RR) setting. We aimed to explore the efficacy of CPX-351 and FLAG-IDA with or without venetoclax in newly diagnosed and RR AML outside of clinical trials. 2. Methods We analyzed 142 patients from the Project ERIS database with newly diagnosed or relapsed or refractory (RR) AML treated with CPX-351 or FLAG-IDA from January 1, 2013 to April 18, 2023 at VCU Massey Comprehensive Cancer Center. We recorded baseline patient-related and disease characteristics, including age, ECOG, Charlson comorbidity index (CCI) scores, molecular profiling and ELN 2022 cytogenetic risk, dates of regimen initiation, and survival. We used the D'Agostino & Pearson method for normality testing and the t-test or Mann-Whitney (as applicable) tests for between-group comparisons. Categorical comparisons used Fischer's exact test. We applied the Bonferroni correction if multiple comparisons were made. The Wilson-Brown method was used for 95% confidence intervals. We analyzed survival by the Kaplan-Meier method with significance determined by the log-rank test. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact. 3. Results First, we analyzed 43 (30.3%) patients with newly diagnosed AML fit for intensive chemotherapy: 33 (76.7%) received CPX-351 and 10 (23.3%) received FLAG-IDA. In the FLAG-IDA cohort, three (30.0%) patients received concurrent venetoclax. There were no significant differences in baseline characteristics, including age, sex, race, or CCI scores, shown in Table A. However, patients in the CPX-351 cohort had significantly worse ECOG performance status compared with the FLAG-IDA cohort (median, 1 vs 0, p = 0.007). There were no significant differences in the proportion of patients that had ELN 2022 adverse risk cytogenetics between the CPX-351 and FLAG-IDA cohorts (65.6% vs 55.6%, p = 0.701). The composite complete response rate (CRc; CR + CRi + CRh) was 53.6% (95% CI: 35.8-70.5) in the CPX-351 cohort and 62.5% (95% CI: 30.6-86.3) for FLAG-IDA (p = 0.709). The rate of MRD negativity was 33.3% for CPX-351 (95% CI: 5.9-70.0) and 50.0% (95% CI: 2.6-97.4) for FLAG-IDA. A similar proportion of patients proceeded to allogeneic stem cell transplant (alloSCT; 39.4% vs 40.0%, p > 0.999). There was no significant difference in the median overall survival in patients treated with CPX-351 or FLAG-IDA (16.1 m. vs 11.4 m., p = 0.129, Figure B). Next, we analyzed 96 (90.7%) patients that received FLAG-IDA and ten (9.3%) that received CPX-351 for RR AML in any subsequent line; three (2.1%) patients in the overall cohort received either CPX-351 or FLAG-IDA in the first-line setting, then crossed over to the other arm at disease progression. Sixteen (16.7%) patients received venetoclax with FLAG-IDA. There were no significant baseline differences between cohorts, as shown in Table A. The CRc for CPX-351 was 33.3% (95% CI, 5.9-70.0) compared with 47.7% (95% CI, 37.6-58.0, p = 0.681) for FLAG-IDA. The rate of MRD negativity was 50.0% (95% CI, 2.6-97.4) for CPX-351 and 66.7% for FLAG-IDA (95% CI, 39.1-86.2, p > 0.999). There was no significant difference in the median overall survival in patients treated with CPX-351 or FLAG-IDA (12.7 m. vs 14.5 m., p = 0.561). 4. Discussion There was no significant difference in the rates of CRc, MRD negativity, or overall survival in patients that received CPX-351 or FLAG-IDA with or without venetoclax in the first-line setting or at the time of disease progression. Both approaches appear to be viable in carefully selected cohorts of patients. A comprehensive toxicity analysis and exploratory molecular subgroup analysis are ongoing.

Use of RT-PCR in conjunction with a respiratory pathogen assay to concurrently determine the prevalence of bacteria and SARS-CoV-2 from the nasopharynx of outpatients.

COVID-19 has emerged as a highly contagious and debilitating disease caused by the SARS-CoV-2 virus and has claimed the lives of over 7.7 million people worldwide. Bacterial co-infections are one of many co-morbidities that have been suggested to impact the outcome of COVID-19 in patients. The goals of this study are to elucidate the presence of bacteria in the nasopharynx of SARS-CoV-2 positive and negative patients and to describe demographic categories that may be associated with the detection of these organisms during one of the initial waves of the COVID-19 pandemic. To this end, we investigated SARS-CoV-2 and bacterial co-detection from outpatient RT-PCR testing in Texas. The results indicate that Staphylococcus aureus, Streptococcus pneumoniae, Klebsiella pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae were the most frequently detected bacteria in both SARS-CoV-2 positive and SARS-CoV-2 negative patients and that these bacteria were present in these two patient populations at similar proportions. We also detected Staphylococcus aureus in a significantly larger proportion of males relative to females and people under 65 years of age relative to those 65 and over. Finally, we observed that SARS-CoV-2 was more commonly detected in Hispanics compared to non-Hispanics; however, low disclosure rates make volunteer bias a concern when interpreting the effects of demographic variables. This study describes the bacteria present in the nasopharynx of SARS-CoV-2 positive and negative patients, highlights associations between patient demographics and SARS-CoV-2 as well as bacterial co-detection. In addition, this study highlights RT-PCR based molecular testing as a tool to detect bacteria simultaneously when SARS-CoV-2 tests are performed.

Abstract 051: Utilization of CT Perfusion to Optimize Selection Of Elderly Patients For Thrombectomy: A Retrospective analysis

Introduction CT perfusion (CTP) has been utilized to appropriately select patients with large vessel occlusion (LVO) for endovascular thrombectomy (EVT). Elderly patients and patients with fast‐growing ischemic cores have been shown to have worse outcomes after EVT. There is limited data on elderly patients aged ≥90 years old and ischemic core growth related to outcomes. We aimed to examine age, ischemic core growth, and outcomes in patients with LVO treated with EVT [1]. Methods This is a retrospective study using prospectively collected data from a large academic medical center. Patients with LVO and treated with EVT between December 2017 and December 2022 were included in this study. Patients without CTP completed prior to EVT, patients with missing baseline or 90‐day modified Rankin Scale scores (mRS), and patients in which CTP was completed but failed were excluded from this study. Early infarct growth rate (relative cerebral blood flow < 30% / last known well to CTP) was used to determine if ischemic core growth was fast (≥10ml/h) or slow (<10ml/h). We compared nonagenarians to younger patients (<90 years old) and examined outcomes. Primary outcome was 90‐day mRS, which we evaluated using a proportional odds ordinal regression model adjusted for baseline mRS, NIHSS, and confounding variables identified in univariate analyses. Secondary outcome was excellent reperfusion (TICI ≥2C), which was analyzed using hierarchical binomial logistic regression and adjusted for potential confounding variables. Subgroup analysis compared 90‐day mRS and reperfusion rates in octogenarians and nonagenarians [2]. Results Among 353 patients selected for EVT using CTP during the study, 325 patients were included in this study. Mean age ±SD was 74.61 ±14.49 years [133 (40.9%) ≥80 years old; 63 (19.4%) ≥90 years old] with initial NIHSS of 12 (IQR, 5 – 18) and 176 (54.2%) were female. Fewer nonagenarians selected for EVT with CTP were identified as fast progressors compared to younger patients, 7 (11.1%) compared to 65 (24.8%), respectively, Odds Ratio (OR) = 0.38 [95% Confidence Interval (CI), 0.16 – 0.87], p = 0.019. Nonagenarians who were fast progressors were more likely to experience worse 90‐day mRS (shift to next worse level) than younger patients and nonagenarians with slow progressing ischemic cores, median (IQR) mRS, 6 (5,6) versus 3 (1,6), adjusted OR (aOR) = 6.79 [95%CI, 1.14 – 40.29], p = 0.035. None of the nonagenarians with fast‐progressing ischemic cores achieved a 90‐day mRS of 0 – 2 or returned to baseline function. Patients aged ≥80 years, who were fast progressors, were more likely to shift to a worse 90‐day outcome than younger patients, aOR = 3.74 [95%CI, 1.43 – 9.75], p = .007. Comparable 90‐day mRS were found between octogenarians and nonagenarians, p = 0.55. Similar proportions of excellent reperfusion rates were seen in all patients, all p > 0.38. Conclusion Excellent reperfusion rates were not affected by age or ischemic core growth rate. Despite this, elderly patients with fast ischemic core growth were more likely to experience worse 90 day functional outcomes compared to younger patients and patients with slower core growth prior to EVT.

Efficacy and tolerability of lacosamide and controlled-release carbamazepine monotherapy in patients with newly diagnosed temporal lobe epilepsy: Post hoc analysis of a randomized, double-blind trial.

Temporal lobe epilepsy (TLE) is often associated with drug-resistant seizures. We evaluated the efficacy and tolerability of lacosamide (LCM) versus controlled-release carbamazepine (CBZ-CR) monotherapy in adults with newly diagnosed TLE. Exploratory post hoc analysis of patients with temporal focus of localization (indicated as the only localization focus) in a double-blind, noninferiority, phase 3 trial (SP0993; NCT01243177) in patients aged ≥16 years with newly diagnosed epilepsy randomized 1:1 to LCM or CBZ-CR monotherapy. Of 886 treated patients in this trial, temporal lobe focus of localization (TLE) was reported as the single focus for 287 (32.4%) patients (LCM 134, CBZ-CR 153). A similar proportion of patients with TLE on LCM (82 [61.2%]) and CBZ-CR (99 [64.7%]) completed the trial. Kaplan-Meier estimates for 6- and 12-month seizure freedom at the last evaluated dose level (stratified by number of seizures in the 3 months before screening [≤2 or >2 seizures]) were similar with LCM and CBZ-CR (6 months overall: 88.7% and 89.7%; 12 months overall: 78.3% and 81.7%). Treatment-emergent adverse events (TEAEs) were reported by fewer patients on LCM (73.9%) than CBZ-CR (81.0%). Drug-related TEAEs (assessed by the investigator) were reported in 41.8% of patients on LCM and 52.3% of patients on CBZ-CR; 11.2% of patients on LCM and 15.0% on CBZ-CR discontinued due to TEAEs. Lacosamide was efficacious and generally well tolerated as monotherapy in patients with TLE with efficacy outcomes comparable with CBZ-CR, and fewer patients on LCM reported any TEAEs, drug-related TEAEs, or discontinued due to TEAEs.

Impact of hyperuricaemia on patients with psoriatic arthritis treated with secukinumab in the FUTURE 2–5 and MAXIMISE studies

ObjectivesPatients with psoriatic arthritis (PsA) are at a significantly increased risk of hyperuricaemia and development of gout, and those with hyperuricaemia have been found to respond poorly to PsA treatment...

Using standard-of-care screening to identify inequities in cancer-related financial hardship.

196 Background: Financial hardship is known as an “adverse event” for individuals with cancer. This study used data collected as part of routine care to understand the magnitude of and potential inequities in cancer-related financial hardship for patients with cancer receiving care in the Deep South. Methods: Universal financial hardship screening was piloted among oncology patients initiating treatment at University of Alabama at Birmingham from October 2020-May 2023. Financial hardship screening questions were added to a standard-of-care treatment planning survey administered by lay navigators. Questions included measures of (1) financial distress (Comprehensive Score for financial Toxicity [COST], scored 0-44; scores <26 indicate financial distress), and (2) financial difficulties affording one or more of 10 items. Proportions of screens completed and variations in financial hardship were calculated overall and by patient race and rurality. Results: Patients who completed treatment planning surveys (N=2,741) were an average 62 years old (SD 13), 18% Black, Indigenous, or persons of color (BIPOC), and 16% rural dwelling. Financial hardship screening was completed by the majority (90%) of patients with treatment planning surveys. Patients with a breast (23%), gynecologic (16%), or gastrointestinal (14%) cancer most commonly completed screening. Completion was similar by race and rurality. Screening identified 34% of patients were experiencing financial distress (mean COST 28, SD 11). However, 49% of BIPOC patients screened positive for financial distress compared to 30% of White patients. The most commonly reported financial difficulties were insurance or medical bills (reported by 32% of patients), upfront medical payments (29%), and medications (22%). Large differences in reported financial difficulties were seen comparing patients who were BIPOC and White (Table). Rural- and non-rural-dwelling patients reported similar proportions of financial difficulties. Conclusions: Most patients completed lay navigator-led financial hardship screening, which identified racial inequities in financial hardship even before treatment initiation. Efforts to collect patient economic data should support the design, implementation, and evaluation of patient-centered interventions to improve equity and reduce adverse cancer-related economic outcomes.[Table: see text]

Digital health literacy among the ageing population: A comparative cross-sectional study between rural and urban Telangana, India

BackgroundDigital health literacy (DHL) is the confluence where health literacy meets digital literacy. DHL has been labelled as one of the digital determinants of health by the World Health Organization. The present study estimated and compared the DHL between Telangana's urban and rural ageing adults, and their potential determinants. MethodsA cross-sectional study was undertaken among 318 of the ageing individuals (≥45 years) of Hyderabad, visiting the primary health centres in the rural and urban field practice during March 2023. A Telugu version of the eHealth literacy scale (eHEALS) and health literacy scale tools were administered by the interviewers. Adjusted analysis was conducted by multiple linear regression method. ResultsOverall, 20.4% of the study participants had good DHL, with a similar proportion between rural and urban areas (rural-20.1% and urban-20.8%, p value-0.889). The median eHealth literacy score among the study participants was 8. While 36.5% and 45.9% had smartphones and standard analogue phones, respectively in urban areas, only 19.5% and 38.4% had smartphones and standard analogue phones, respectively in rural areas. Computer usage in the past month, higher educational qualification, and ownership of mobile phones were significant determinants of DHL. A mild but significant correlation between DHL and health literacy screening scores was found. ConclusionConsidering the low DHL among the ageing population, enabling environment with enhanced access to mobile phones/smartphones and familiarity with information and communication technology gadgets must be established to improve their DHL.

Strawberry fruit quality: Impacts of the harvest date with a breeding perspective

AbstractBackgroundThe sensory, nutritional, and organoleptic characterization of strawberry genotypes is a useful strategy to guide breeding efforts on filling consumer's expectations. This work was focused on evaluating the fruit quality of six strawberry genotypes. We aimed to highlight key clues for breeders regarding the relative contribution of different techniques for fruit characterization and consumer perception, with a special focus on contrasting harvest moments.ResultsResults showed that coloration resulted less variable compared with free sugars, firmness, or volatile compounds. There was an absence of correlation between external/internal color and anthocyanin content or between soluble solids and individual sugars (glucose, fructose, sucrose). Oxygen radical absorbance capacity and 1,1‐diphenyl‐2‐picrylhydrazyl methods showed to be complementary for antioxidant capacity determination. The predominance of esters and terpenes seems to contribute to typical strawberry flavor while a fine balance between aldehydes, terpenes, lactones, and esters found in similar proportions contributes to typical smell perception.ConclusionsThere is an important variability in fruit quality harvested fully ripe in different dates from the same harvest season and genotypes showed contrasting behaviors. Fruit color resulted more stable than other quality variables such as sugars or firmness while volatile profile showed significant changes. From a breeding perspective, it is crucial to consider many harvest moments throughout the reproductive cycle to assure a more representative fruit quality evaluation. Genotypes showing greater stability between harvests would be interesting for assuring a reproducible product during the season.

Atherosclerotic cardiovascular disease risk profile of patients with chronic hepatitis B treated with tenofovir alafenamide or tenofovir disoproxil fumarate for 96 weeks.

Patients with chronic hepatitis B (CHB) who switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) show changes in lipid profiles. To evaluate how these changes affect cardiovascular risk. This pooled analysis, based on two large prospective studies, evaluated fasting lipid profiles of patients with CHB who were treated with TAF 25 mg/day or TDF 300 mg/day for 96 weeks. Patients who fulfilled the American College of Cardiology criteria (age 40-79 years, high-density lipoprotein [HDL] 20-100 mg/dL, total cholesterol [TC] 130-320 mg/dL and systolic blood pressure 90-200 mmHg) required to assess 10-year atherosclerotic cardiovascular disease (ASCVD) risk with baseline lipid data and at least one post-baseline measurement were included in the ASCVD-risk population. The 10-year ASCVD risk was calculated for patients in this population, and changes from baseline to Week 96 were assessed using intermediate- (≥7.5%) and high-risk (≥20%) cut-offs. Among 1632 patients, 620 (38%) met the criteria for the ASCVD-risk population. At Week 96, fasting levels of all lipids, except TC:HDL ratio, were lower with TDF than TAF. No significant increase was observed in overall ASCVD risk or in any ASCVD-risk categories during the 96-week treatment period compared with baseline. A similar proportion of patients in the TAF and TDF treatment groups (1.3% and 2.3%, respectively; p = 0.34) reported cardiovascular events. Despite on-treatment differences in lipid profiles with TAF and TDF, predicted cardiovascular risk and clinical events were similar for both groups after 96 weeks.

Hydration and nutrition care practices in stroke: findings from the UK and Australia

BackgroundDehydration and malnutrition are common in hospitalised patients following stroke leading to poor outcomes including increased mortality. Little is known about hydration and nutrition care practices in hospital to avoid dehydration or malnutrition, and how these practices vary in different countries. This study sought to capture how the hydration and nutrition needs of patients’ post-stroke are assessed and managed in the United Kingdom (UK) and Australia (AUS).AimTo examine and compare current in-hospital hydration and nutrition care practice for patients with stroke in the UK and Australia.MethodsA cross-sectional survey was conducted between April and November 2019. Questionnaires were mailed to stroke specialist nurses in UK and Australian hospitals providing post-stroke inpatient acute care or rehabilitation. Non-respondents were contacted up to five times.ResultsWe received 150/174 (86%) completed surveys from hospitals in the UK, and 120/162 (74%) in Australia. Of the 270 responding hospitals, 96% reported undertaking assessment of hydration status during an admission, with nurses most likely to complete assessments (85%). The most common methods of admission assessment were visual assessment of the patient (UK 62%; AUS 58%), weight (UK 52%; AUS 52%), and body mass index (UK 47%; AUS 42%). Almost all (99%) sites reported that nutrition status was assessed at some point during admission, and these were mainly completed by nurses (91%). Use of standardised nutrition screening tools were more common in the UK (91%) than Australia (60%). Similar proportions of hydration management decisions were made by physicians (UK 84%; AUS 83%), and nutrition management decisions by dietitians (UK 98%; AUS 97%).ConclusionDespite broadly similar hydration and nutrition care practices after stroke in the UK and Australia, some variability was identified. Although nutrition assessment was more often informed by structured screening tools, the routine assessment of hydration was generally not. Nurses were responsible for assessment and monitoring, while dietitians and physicians undertook decision-making regarding management. Hydration care could be improved through the development of standardised assessment tools. This study highlights the need for increased implementation and use of evidence-based protocols in stroke hydration and nutrition care to improve patient outcomes.

The total mass, number, and distribution of immune cells in the human body.

The immune system is a complex network of cells with critical functions in health and disease. However, a comprehensive census of the cells comprising the immune system is lacking. Here, we estimated the abundance of the primary immune cell types throughout all tissues in the human body. We conducted a literature survey and integrated data from multiplexed imaging and methylome-based deconvolution. We also considered cellular mass to determine the distribution of immune cells in terms of both number and total mass. Our results indicate that the immune system of a reference 73 kg man consists of 1.8 × 1012 cells (95% CI 1.5-2.3 × 1012), weighing 1.2 kg (95% CI 0.8-1.9). Lymphocytes constitute 40% of the total number of immune cells and 15% of the mass and are mainly located in the lymph nodes and spleen. Neutrophils account for similar proportions of both the number and total mass of immune cells, with most neutrophils residing in the bone marrow. Macrophages, present in most tissues, account for 10% of immune cells but contribute nearly 50% of the total cellular mass due to their large size. The quantification of immune cells within the human body presented here can serve to understand the immune function better and facilitate quantitative modeling of this vital system.

Effects of light intensity and reduction of starter diet digestible lysine and metabolizable energy on broiler chicken growth performance, breast meat yield, and meat quality defects

The etiology of Wooden Breast (WB) is unknown; therefore, it is difficult to produce broiler flocks with similar proportions of WB-affected and unaffected birds. Because WB has been detected as early as 15 d posthatch, the objective of this randomized complete block experiment with a 2×2 factorial treatment arrangement was to determine whether combining the effects of light intensity (LI) and early nutrient reduction strategies could reliably produce WB-affected and normal broilers to further investigate the physiological mechanisms underlying WB. On day of hatch, male, Ross 708×Yield Plus broilers (n=384; 16 birds per pen; 3 replicate blocks) were randomly allotted to floor pens in the same facility and exposed to either 2 (LOWLI) or 30 (HIGHLI) lux of light from d 0 to 35. Birds were fed either a commercial starter diet (CON) or the CON diet with a 10% reduction in both ME and digestible lysine (dLys; RED) from d 0 to 14 and then a common grower diet from d 15 to 35. Broiler growth performance, breast yield, and incidence and severity of WB and White Striping (WS) were assessed. Data were analyzed as a 2-way ANOVA with SAS PROC GLIMMIX and means separated at P < 0.05 with PDIFF. No interaction among LI and diet was observed (P > 0.05). Broilers reared with HIGHLI were heavier on d 35 and consumed more feed in all phases compared with broilers reared under LOWLI (P ≤ 0.0096). Broilers reared under LOWLI gained less BW from d 15 to 35 and d 0 to 35 compared with broilers reared under HIGHLI (P=0.0073). Broilers fed the RED starter diet consumed more feed and had higher FCR from d 0 to 14 compared with broilers fed the CON diet (P ≤ 0.0012). In conclusion, combining reductions in LI and starter diet ME and dLys did not produce the hypothesized reductions in breast yield and incidence and severity of WB or WS.

Randomized trial of ketamine masked by surgical anesthesia in patients with depression.

Ketamine may have antidepressant properties, but its acute psychoactive effects complicate successful masking in placebo-controlled trials. We present a single-center, parallel-arm, triple-masked, randomized, placebo-controlled trial assessing the antidepressant efficacy of intravenous ketamine masked by surgical anesthesia (ClinicalTrials.gov, NCT03861988). Forty adult patients with major depressive disorder who were scheduled for routine surgery were randomized to a single infusion of ketamine (0.5 mg/kg) or placebo (saline) during usual anesthesia. All participants, investigators, and direct patient care staff were masked to treatment allocation. The primary outcome was depression severity measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at 1, 2, and 3 days post-infusion. After all follow-up visits, participants were asked to guess which intervention they received. A mixed-effects model showed no evidence of effect of treatment assignment on the primary outcome (-5.82, 95% CI -13.3 to 1.64, p=0.13). 36.8% of participants guessed their treatment assignment correctly; both groups allocated their guesses in similar proportions. In conclusion, a single dose of intravenous ketamine delivered during surgical anesthesia had no greater effect than placebo in acutely reducing the severity of depressive symptoms in adults with major depressive disorder. This trial successfully masked treatment allocation in moderate-to-severely depressed patients using surgical anesthesia. Although this masking strategy is impractical for most placebo-controlled trials, future studies of novel antidepressants with acute psychoactive effects should make efforts to fully mask treatment assignment in order to minimize subject-expectancy bias.