Citations

Introduction: ASH Guidelines for diagnosis of pulmonary embolism (PE) start with risk assessment using a pretest probability tool (PTP) followed by D-dimer testing or CT pulmonary angiography (CTPA) depending on risk. We aimed to develop an electronic clinical quality measure (eCQM) to encourage broader use of a validated PTP scoring tool in emergency departments (EDs). The Centers for Medicare & Medicaid Services require reporting of eCQMs which consist of value sets or lists of standardized codes linked to patient data within the electronic health record. We sought to identify a standardized way to identify CTPA and abnormal D-dimer tests using administrative codes (i.e. CPT, LOINC, SNOMEDCT codes) across three institutions. Methods: Value sets identifying CTPA and D-dimers were reviewed from existing eCQMs. Three institutions representing 38 EDs from across the country submitted data from all ED encounters between September 12, 2022 and January 11, 2023. Imaging types were reviewed from each of the CPT codes and LOINC (Logical Observation Identifiers Names and Codes). We determined the number of ED encounters, pre-test probability tool use, and diagnosis of PE using different codes. We calculated sensitivity, specificity, positive and negative predictive value (PPV and NPV, respectively). Results: Over the 4-month study period, 270,214 encounters were identified across 38 EDs. Each institution identified CTPA with site-specific codes (Table 1). The Full CTPA Value Set identified 55% more encounters than the site-specific codes (Full set 15,054/9679 site-specific codes). LOINC code 88322-3 was only used at one site. CPT code 71275 had the best sensitivity and specificity, but still had false positives (PPV 82%) (Table 2). D-dimer values were identified as LOINC code 48065-7 and 91556-1 at Site 1 and 48067-3 at Site 2. SNOMEDCT codes were not used at any site despite being the way other eCQMs identify elevated D-dimer results. Different D-dimer tests with different normal ranges were used at each site. All sites did not have an electronically extractable positive indicator for D-dimer. Conclusion: Due to persistent false positives using CPT Code 71275 for identification of CTPA, using this code would lead to inclusion of patients for whom PTP was not required or recommended. Additionally, coding for an abnormal D-dimer test result are not standardized across institutions. Therefore, administrative codes cannot be used to develop eCQMs whose aim is to evaluate whether CTPA is ordered appropriately based on the PTP risk level and laboratory testing.

Background: Acute myeloid leukemia (AML) therapy in older patients (age ≥ 60) has undergone a transformation with the introduction of multiple targeted therapies, which has allowed more patients to receive therapy than before. The most successful has been the combination of venetoclax + azacitidine (VA) which generated higher overall complete response rates in phase 2 studies than would be expected with azacitidine alone, leading to accelerated FDA approval on 21Nov2018. The VIALE-A phase 3 study confirmed the improved overall survival (OS, median 14.7 versus 9.6 months) of VA, leading to full FDA approval for marketing. This retrospective analysis provides real world data on the impact of baseline clinical and genomic markers of individuals receiving intensive chemotherapy versus VA. Methods: The precision medicine Beat AML Master Trial (NCT03013998) assigns patients to biomarker specific sub-study treatments based on targeted DNA sequencing and cytogenetics. However, a large subset of patients did not enroll on a sub-study, but were followed for off-study treatment and OS. From this subset, patients enrolled onward from 21Nov2018, when VA received accelerated approval, were examined for differences in clinical/genetic characteristics and OS in those receiving venetoclax + hypomethylating agent (V/HMA), any form of intensive chemotherapy (IC), alternative non-intensive therapy (NIT), or no therapy. The genetic mutations identified in this study are characterized by a variant allele frequency of 20%+, as defined in the trial for determining the dominant clone. The method of Kaplan-Meier was used to estimate OS, and the Cox model was fit to associate patient characteristics with OS. Results: From 21Nov2018, a total of 468 AML patients consented to the Beat AML trial and did not enroll to a sub-study. Treatment was chosen by the investigator based upon available clinical and genomic data. Of these 468 patients, 62 did not receive treatment, 2 had treatment data missing, 226 were treated with V/HMA, 112 with IC, and 66 with NIT. Demographics for all patients include median age 71 (60-90), 40% female, performance status (PS) (0-20%; 1-55%; 2-22%; 3-3%), median white blood cell (WBC) 4.1 (range 0.3-298.6), complex karyotype (CK) 20.6%, core binding factor (CBF) 7.8%, KMT2A-rearranged 3.6%, NPM1-mutated (m) 15.6%, IDH2m 14.6%, TP53m 13.2%, FLT3-ITD/TKD 12.9%, and NRASm/ PTPN11m/ KRASm/ NF1m/ CBLm 23.6%. Demographics that were significantly different (p<0.01) among the three groups (V/HMA, IC, and NIT) include age (younger in IC), PS (worse in NIT), AST/ALT (worse in NIT), CBF (more in IC), CK and TP53m (less in IC). Of the 404 patients who underwent treatment with V/HMA, IC, or NIT, 208 have died with those surviving having a median follow-up of 22.3 months. Figure 1 summarizes the OS of each treatment group. The median OS (95% CI) from time of initiating therapy is 13.6 (10.9-16.8) for V/HMA, 33.8 (20.7-not reached) for IC, and 11.6 (5.2-21.3) months for NIT. Univariable analysis for OS was significant at p<0.05 for increased age, WBC, PS, hemoglobin, CBF, CK, NPM1m, TP53m, TET2m and IC versus V/HMA. Multivariable analysis was significant at p<0.05 (hazard ratio) for increased age (1.14), PS (1.83), WBC (1.08), hemoglobin (0.91), and select genomic aberrations including CBF (0.37), NPM1m (0.35), and TP53m (2.1). Conclusions: These results from a large cohort of older AML patients treated with V/HMA, IC, or NIT show that their outcome is best defined by pre-treatment clinical features previously identified including age, performance status, WBC and hemoglobin along with limited genomic characteristics including CBF, NPM1m, and TP53m. While univariate analysis of OS favored IC over V/HMA and NIT, multivariable analysis supports that this advantage was most likely due to the favorable clinical and genomic features. The OS of V/HMA patients in this cohort is similar to that in the VIALE-A registration study of VA, providing further justification for this treatment for older AML patients deemed ineligible for intensive chemotherapy. Additionally, this data supports use of the patient cohort in this study for ongoing work in understanding and/or validating biomarkers associated with survival with V/HMA.

Background. Acute myeloid leukemia (AML) is a heterogenous disease that occurs primarily in older adults with a median age of 69 years at diagnosis. Most studies that characterize the genomic landscape of AML include younger adults with the majority of patients being younger than 60 years of age. We aimed to study the mutational landscape of newly diagnosed AML patients aged 60 years or older. Methods.Samples were collected from the multi-center Beat AML Master Trial (Burd, Nat Med 2020). Patients were enrolled between 2016 and 2023. Informed consent was obtained according to the Declaration of Helsinki. Patients diagnosed with non-APL AML and who were aged ≥ 60 years old were included. Patients underwent bone marrow aspiration and biopsy, cytogenetic analysis, FLT3-ITD ratio assessment (LeukoStrat CDx FLT3 Mutation Assay, Invivoscribe) and next generation sequencing (NGS) using FoundationOne®Heme(Foundation Medicine) to interrogate the entire coding region of 406 genes and select introns of 31 genes involved in rearrangements, as well as RNA sequencing to interrogate 265 genes known to be somatically altered in human hematological malignancies. The presence of multiple hotspot mutations within one gene in an individual patient was counted as one gene mutation. Patterns of co-occurrence between gene mutations were calculated using the Phi correlation coefficient. Statistical analyses were performed using R statistical software. P<0.01 was considered statistically significant. Results. A total of 1088 newly diagnosed AML patients were identified, of whom 1032 were 60 years or older. Patients had a median age of 72 years at time of diagnosis (range 60-92 years). Forty-two percent of the patients were female, most patients were non-Hispanic and 79% were Caucasian. NGS data were available for 1024 patients and mutations were identified in 461 different genes. Patients had a median number of 11.0 mutations (range 3.0 to 28.0). The most frequently mutated genes were DNMT3A (n=257; 25.1%), TP53(n=255; 24.9%), TET2 (n=243; 23.7%), RUNX1 (n=225; 22.0%), SRSF2 (n=221; 21.6%), ASXL1 (n=216; 21.1%), NPM1 (n=206; 20.1%), FLT3 (n=205; 20.0%), IDH2 (n=190; 18.6%), NRAS (n=208; 16.9%), PTPN11(n=104; 10.2%), STAG2 (n=101, 9.9% and IDH1 (n=99; 9.7%) (Figure 1A). FLT3-ITD was present in 98 (12.1%) of the 810 patients who were tested. Strongest significant co-occurrence was found between FLT3and NPM1 (n=103), STAG2 and ASXL1 (n=63), ASXL1 and RUNX1 (n=92), ASXL1 and SRSF2 (n=88), RUNX1 and SRSF2 (n=94), STAG2 and SRSF2 (n=51) and DNMT3A and NPM1 (n=92) (p<0.01). Pairwise negative correlations were observed between TP53 and NPM1 (n=6), TP53 and SRSF2 (n=17), and between NPM1 and RUNX1 (n=6) (p<0.01) (Figure 1B). The cytogenetic profiles and the full genomic landscape will be presented during the ASH meeting. Discussion. This is the largest study investigating the mutational profile in older adults with AML aged 60 years and older. Due to the 7-day screening period of the Beat AML study, patient selection was biased towards less-rapidly proliferative AML. We showed that the pattern of gene mutations was markedly different from other studies in AML that mainly included younger AML patients (Papaemmanuil, NEJM 2016; TCGA, NEJM 2013 ). The frequency of mutated TP53 was substantially higher in older AML patients, as was the occurrence of myelodysplasia-related gene mutations (e.g., SRSF2, RUNX1, ASXL1, STAG2, U2AF1, and SF3B1) and gene mutations in IDH1, IDH2 and TET2. In contrast, NPM1 mutation was less frequently mutated in older AML patients. Furthermore, we demonstrated that a large proportion (46%) of the AML patients older than 60 years of age do have a mutation that is potentially targetable for treatment ( FLT3 IDH1 IDH2 and NPM1). The high incidence of mutated TP53 and MDS-related gene mutations underscores the increased incidence of high-risk AML and the need for innovative personalized therapies in this older age group. Figure 1. A. Co-occurrence of the 15 most frequently mutated genes, and B. co-correlation between the 15 most frequently mutated genes. Blue indicates positive correlation, red indicated negative correlation. Only significant correlations (p<0.01) are shown.

Introduction: During allogeneic hematopoietic cell transplantation (allo-HCT), conditioning regimens disrupt the epithelial barrier of the gastrointestinal (GI) tract and broad-spectrum antibiotics cause microbiome disruption characterized by low microbial diversity and high abundance of pathogens that can dominate gut communities. Microbiome disruption is associated with increased translocation of pathogenic bacteria leading to risk of bloodstream infections (BSIs) and acute graft-vs-host disease (aGvHD). Nonclinical studies have demonstrated that domination with pathogens leads to immune activation and subsequent GvHD following exposure to bacterial antigens in the gut-associated lymphoid tissue [ Jenq 2015 Biol Blood Marrow Transplant, Stein-Thoeringer 2019 Science, Peled 2020 NEJM]. SER-155, an oral investigational cultivated microbiome therapeutic comprised of 16 bacterial Firmicutes strains, was designed to engraft in the GI tract, improve GI barrier integrity, and restructure the GI microbiome by introducing bacteria with immunomodulatory and anti-inflammatory properties and driving a reduction in abundance of proinflammatory bacteria [ Halvorsen 2021 OFID, 2022 Bone Marrow Transplant]. Herein, we present preliminary clinical data through Day 100 from an open-label cohort of a Phase 1b study in patients undergoing allo-HCT (NCT04995653) and compare the incidence of GI pathogen domination in this cohort to a historical cohort. Methods: Study patients received two treatment courses of SER-155 (before conditioning and after neutrophil engraftment), each comprised of microbiome conditioning with 4 days oral vancomycin (to facilitate engraftment of SER-155 strains into the GI microbiome) followed by 10 days of oral SER-155. The primary endpoint was safety. Stool samples collected pre- and post-HCT were used to evaluate secondary endpoints, including engraftment of SER-155 strains (following each course of SER-155) and GI pathogen domination, defined as a relative abundance of a specific taxa at ≥30% ( Peled, 2020). Engraftment of SER-155 strains was assessed via strain-specific molecular probes (NanoString). Relative abundance of Enterobacteriaceae, Enterococcaceae, Streptococcaceae and Staphylococcaceae was assessed with whole metagenomic shotgun sequencing (WMS). A post-hoc comparison of GI domination was made with a historical cohort of 459 HCT patients with similar patient characteristics from one of the study sites (MSKCC) using stool samples profiled by 16S-amplicon sequencing. Results: Fifteen adults (median age 67 years; 54% male) were enrolled and 13 received study drug. SER-155 was generally well-tolerated. Following each course of SER-155, the majority of the 16 strains in SER-155 were detected in evaluable patients (median = 11 strains in 8 patients before conditioning; median = 12 strains in 7 patients after neutrophil engraftment).Between the day of transplant (Day 0) and Day 30, GI domination with potentially pathogenic bacteria occurred in only 1 of 9 (11%) evaluable patients (Figure 1). In contrast, in the historical comparator cohort, 64% of patients (294 of 459) had pathogen domination during the same timeframe, with domination by Enterococcus being most common. Conclusions: The observation of SER-155 strain engraftment before transplant and low incidence of GI pathogen domination after transplant through Day 30 are encouraging, although these preliminary data are limited by the small size of this open-label cohort of HCT patients. These observations are consistent with the design and preclinical evaluation of SER-155, supporting further development of this investigational cultivated microbiome therapeutic. Enrollment in the second double-blind, randomized, placebo-controlled cohort (approximately 60 participants) has initiated following a preplanned review by the Data Safety Monitoring Committee.

Introduction Pulmonary Embolism (PE) is a major cause of morbidity and mortality worldwide. Diagnosis is essential as untreated PE has a 30% mortality rate. Currently, computer tomography pulmonary angiogram (CTPA) is the standard of care to diagnose PE. However, this modality is expensive, exposes patients to radiation and increases risk of contrast induced nephropathy. Furthermore, only 5% of CTPAs performed are positive for PE signifying that many unnecessary tests are being performed. To address this gap, Pre-Test Probability (PTP) tools have been developed to safely exclude patients with low risk of PE and limit iatrogenic harm from over testing. Despite the tools being developed over 20 years ago, they are not widely available in electronic health record (EHR) systems and even when they are built in, uptake remains low. Methods Three large integrated health systems using Epic EHR systems across five states (MA, WI. MN, AZ, FL) built electronic PTP assessments into their EHR systems to safely exclude patients with low risk of PE and limit over testing. Two sites made the PTP optional, and one site made it a forced function (providers were forced to complete PTP prior to ordering CTPA unless a D-dimer result was present in the prior 48 hours). To assess the usability of these EHR tools, the team conducted a survey with ED clinicians across the three test sites. The survey was created to identify which PE risk stratification methods were employed by ED clinicians (EHR embedded PTP tool, apps on their phone, web applications like MDcalc, calculations from memory, or if they relied on clinical gestalt), and to identify barriers to using the EHR embedded PTP. Results Site 1 had 47 respondents, Site 2 had 94 respondents, and Site 3 had 16 respondents. Two key findings emerged from the survey (Figure 1). First, clinicians used a variety of risk stratification approaches and few of them documented their risk assessments in structured fields in the medical record. Second, clinical gestalt was the most used PE risk stratification approach, and this was true across all three test sites. In addition, the health system with a PTP prompt before clinicians could proceed with CTPA orders (Site 3) did not have a higher percentage of clinicians who reported using the EHR embedded tool than sites that did not prompt clinicians to fill in the PTP. Clinicians cited a variety of different barriers to using the EHR embedded PTP tool (Table 1). Conclusion While many clinicians indicated intermittent use of PTP criteria to aid in the diagnosis of PE, risk factors and scores from phone apps, web tools, and calculations from memory are unlikely to be documented in the patient's medical record, which means that they are not accessible to all members of the ED care team and cannot be used for electronic clinical quality measure. The biggest hurdles to increasing the use of structured PTP assessments in the ED setting to safely exclude PE and limit iatrogenic harm from over testing are (1) obtaining buy-in from ED clinicians that the PTP tools provide value over clinical gestalt, at least for a subset of patients who could most benefit, and (2) identifying best practices for incorporating PTP tools into EHR systems that make the tools easier to access and use 3) developing and implementing effective education and awareness programs around the PTP tools. This survey adds to the body of literature on PTP assessments in the ED setting and can help inform further research that is needed to continue to improve the diagnosis of PE. Funding: This project is funded in part by the Gordon and Betty Moore Foundation through Grant GBMF10778 to the American Society of Hematology.

Background: Menin, a protein involved in transcriptional regulation, plays a role in the genesis of multiple cancers. Preclinical data from BMF-219, an investigational, highly selective, oral small-molecule inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling. BMF-219 is the first and only covalent menin inhibitor in clinical development and is being evaluated in multiple hematologic malignancies, solid tumors, and diabetes mellitus. COVALENT-101 (NCT05153330) is a Phase I dose-escalation and -expansion study of BMF-219 in R/R AL (Cohort 1), DLBCL (Cohort 2), MM (Cohort 3), and CLL (Cohort 4). Here we report preliminary safety, PK and anticancer activity data from Cohort 1 (AL). Methods: Doses of BMF-219 are escalated independently for each indication, initially in single-subject cohorts followed by a “3 + 3” design. Eligible patients (pts) include adults with R/R AL ineligible for standard therapy. Initially pts were enrolled agnostic to molecular status. A subsequent amendment introduced quotas for KMT2Ar (MLL1r), NPM1 and other known menin-dependent mutations: CEBP/A, MLL1-PTD, MN1, NUP98, NUP214, PICALM-AF10, SETBP1. Prior exposure to reversible menin inhibitor therapy is permitted. Subjects receive BMF-219 daily for continuous 28-day cycles until progression/intolerability. There are 2 parallel dose-escalation arms: pts not taking (Arm A) or taking (Arm B) moderate or strong CYP3A4 inhibitors. The study is ongoing and accruing in the escalation. Expansion cohorts will enroll pts to obtain further safety and efficacy data at the OBD/RP2D. Results: As of data cutoff of 7/24/2023, 26 pts with R/R AL (24 AML; 2 ALL) are enrolled; 7 remain on study treatment. Baseline characteristics include 17(65%) males and 9(35%) females with a median age of 57.5 years (range 33-84). There is a median of 4 (range 1-8) prior lines of therapy and 11 (42%) with prior HSCT(s). Six pts (23%) had KMT2Ar, 3 (12%) KMT2A-PTD, 4 (15%) NPM1, and 13 (50%) WT for KMT2A and NPM1. Dosing began with single-patient cohorts at 100 mg QD (Arm A) and 25 mg QD (Arm B) and has been escalated through 4 dose levels. Thus far, pts have been dosed up to 500 mg QD (Arm A) and 125 mg QD (Arm B). BMF-219 exposures were comparable between arms, with ~2-4-fold higher exposures observed with co-administration of a moderate or strong CYP3A4 inhibitor. At the highest dose (DL4) in which PK was evaluated, Arm A (500 mg QD) and Arm B (125 mg QD), pts on average achieved ~50% of target exposure (2000 ng*hr/mL) with some pts surpassing it. Higher QD dosing or corresponding BID dosing is expected to achieve desired exposure. BMF-219 has generally been well tolerated with no DLTs observed and no discontinuations due to treatment-related toxicities. No related QTc prolongation was observed. At the time of data cutoff, 23 of 26 pts were included in the safety population. Common TRAEs (≥10%) include vomiting 13% (3) and Differentiation Syndrome (DS) 13% (3). No Grade 5 TRAEs were reported. The only common Grade ≥3 TRAE (≥5%) was DS 13% (3). The efficacy evaluable population includes AML pts who meet the following criteria: dosed at or near predicted efficacious dose (500 mg or above [Arm A]; 125 mg or above [Arm B]), had known menin-dependent mutations, and completed at least one scheduled response assessment (or had a minimum of 7 doses if discontinued prematurely). Thus far, 2 of 5 efficacy evaluable patients achieved a complete remission (1 CR; 1 CRi) and both continue BMF-219 treatment. Patient A: 39/M, NUP98-NSD1, ECOG=0, 500 mg QD, Arm A, 4 prior lines of treatment including intensive chemotherapy and allo-HSCT. At C1D27, marrow blasts were reduced to 6% from 13% at study entry. The patient achieved CR at C2D28 with 0% blasts.Patient B: 70/F, NPM1m, ECOG=1, 125 mg QD, Arm B, 1 prior line of treatment with decitabine and an investigational agent. At C1D28, marrow blasts were reduced to 34% from 52% at study entry. The patient achieved CRi with 3% blasts at C2D28. Conclusion: BMF-219 is generally well tolerated with no DLT observed (and able to be taken with and without CYP3A4 inhibitors) with no pts discontinuing therapy due to toxicity. BMF-219 dose escalation is ongoing and approaching target exposure. BMF-219 demonstrates early signs of clinical activity in different genomic subgroups. The trial is ongoing and includes enrollment for pts diagnosed with AL, DLBCL, MM and CLL.

We identified a patient with a recently described syndrome, monoclonal gammopathy of thrombotic significance (MGTS; Blood. 2023 Apr 6;141(14):1772-1776), and three additional patients with high 4Ts scores who were consistently negative in the PF4-polyanion HIT ELISA (Lifecodes PF4 IgG, Immucor). The MGTS patient, with a monoclonal IgG kappa, had recurrent thrombosis, and transient mild thrombocytopenia (nadir in the low 100s) over a period of years, and was noted to have a HIT ELISA optical density (OD) of 0.117. The three HIT patients experienced thrombocytopenia and thrombosis with ELISA ODs of 0.37, 0.18 and 0.20. All patients were positive in platelet-activation (functional) testing demonstrating PF4 dependence and inhibited with both high concentrations of heparin (100U/mL) and the FcγRIIa blocking monoclonal antibody (mAb) IV.3, consistent with the presence of anti-PF4 antibodies in the patient samples ( data not shown). Because the serologic profile of these patients suggested a novel HIT subtype characterized by negative HIT ELISA results, we undertook a functional platelet assay screen of 500 consecutive HIT ELISA-negative patients tested in our diagnostic laboratory. Research studies were approved by the Institutional Review Board of Mayo Clinic. Of the 500 patients tested, 20 (4.0%) stimulated platelet activation in the PF4-dependent P-selectin Expression Assay (PEA ≥19%; data not shown). To exclude non-specific activation that can be induced by HLA antibodies, additional testing was performed to evaluate whether platelet activation was PF4-dependent using buffer or PF4-treated platelets. Three patients demonstrated PF4-dependent activation that was inhibited by high heparin concentrations and mAb IV.3, as would be expected for HIT antibodies (ELISA-negative HIT, EN-HIT1-3; Figure 1). On retrospective review, all three patients thus identified had clinical histories and courses consistent with high clinical probability for HIT. To develop tools to study this new class of antibodies, monoclonal HIT antibodies were generated in mice after PF4/heparin immunizations and screened using a novel approach that included simultaneous testing of hybridoma supernatants in the PEA and PF4-polyanion ELISA. This strategy was designed to enabled us to identify mAbs that activated platelets (in the PEA), but that did not bind antigenic targets in the HIT ELISA. A novel mAb 431.4 that was developed using this approach, and the well-characterized HIT-like mAb KKO were evaluated for their abilities to both bind PF4-polyanion targets in ELISA, and to activate PF4-treated platelets in the PEA (Figure 2). In significant contrast to KKO, mAb 431.4 did not bind PF4/polyanion complexes, however, like KKO, strongly activated platelets in a PF4-dependent manner. Activation induced by both KKO and mAb 431.4 was inhibited by high heparin concentrations, as would be expected for HIT antibodies. In vivo murine studies using this novel mAb are pending at this time. In summary, the non-canonical diagnostic profile of HIT ELISA-negative but platelet activation-positive antibodies were found at a relatively high incidence in HIT-suspected patients (0.6%; 3 of 500 ELISA-negative patients). These findings have important diagnostic/management implications and suggest a re-evaluation of ASH's HIT management guidelines as noted in recommendations 2.7 and 2.8 of that document (“In patients with an intermediate (Recommendation 2.7) or high (Recommendation 2.8)-probability 4Ts score and a negative immunoassay, the ASH guideline panel recommends discontinuation of the non-heparin anticoagulant and resumption of heparin, if indicated ”; Blood Adv (2018) 2 (22): 3360-3392). Figure 1. A subset of ELISA-negative HIT-suspected patients harbor anti-PF4 platelet-activating antibodies. Three ELISA-negative (EN) HIT patient samples from a screen of 500 samples demonstrate PF4-dependent platelet activation and inhibition with high heparin concentration and mAb IV.3 incubation. PBS, phosphate buffered saline; IC, isotype control; HDH- high dose heparin (100U/mL). Figure 2. Murine mAb 431.4 serologically mimics pathogenic ELISA-negative HIT/MGTS antibodies. ELISA and PEA testing was performed using the “HIT-like” mAb KKO, novel mAb 431.4, or an isotype control (IC) antibody. PVS-polyvinyl sulfonate (polyanion used in the Immucor IgG ELISA assay).

Abstract Although incarcerated adults are at elevated risk of dying from cancer, little is known about cancer screening in carceral settings. This study compared stage-specific incidence of screen-detectable cancers among incarcerated and recently released people with the general population, as a reflection of screening practices. We calculated the age- and sex-standardized incidence ratios (SIR) for early- and late-stage cancers for incarcerated and recently released adults compared to the general Connecticut population between 2005 and 2016. Our sample included 143 cancer cases among those incarcerated, 406 among those recently released, and 201 360 in the general population. The SIR for early-stage screen-detectable cancers was lower among incarcerated (SIR = 0.28, 95% CI = 0.17 to 0.43) and recently released (SIR = 0.69, 95% CI = 0.51 to 0.88) individuals than the general population. Incidence of late-stage screen-detectable cancer was lower during incarceration (SIR = 0.51, 95% CI = 0.27 to 0.88) but not after release (SIR = 1.32, 95% CI = 0.93 to 1.82). Findings suggest that underscreening and underdetection of cancer may occur in carceral settings.

The purpose of this study was to query healthcare practitioners (HCPs) who treat firefighter injuries to identify risk factors and mechanisms associated with musculoskeletal injuries during exercise. A phenomenological design was utilized to understand the experiences of HCPs while treating firefighters’ musculoskeletal injuries due to exercise. Semi-structured interviews were conducted with 14 HCPs. Two interviews were pilot-tested with HCPs to ensure reliability and validity. Interviews were transcribed and uploaded to a qualitative analysis software program. Although the study inquired about injuries incurred by any exercise modality (e.g., endurance and resistance training), injuries induced during resistance training were prominent among HCPs as resistance training emerged as a primary exercise injury mechanism. HCPs indicated that the back and shoulder were prevalent anatomical exercise injury locations. Risk factors for exercise injuries included age, immobility, movement proficiency, and factors associated with fatigue. Exercise injury mechanisms included poor resistance training technique and overexertion. These findings could guide exercise program design, use of movement assessments, and the identification of other countermeasures to decrease the risk of resistance training exercise injuries among firefighters.

Abstract Polycaprolactone fumarate (PCLF) is a cross‐linkable PCL derivative extensively considered for tissue engineering applications. Although injection molding has been widely used to develop PCLF scaffolds, platforms developed using such technique lack precise control on architecture, design, and porosity required to ensure adequate cellular and tissue responses. In particular, the scaffolds should provide a suitable surface for cell attachment and proliferation, and facilitate cell–cell communication and nutrient flow. 3D printing technologies have led to new architype for biomaterial development with micro‐architecture mimicking native tissue. Here, we developed a method for 3D printing of PCLF structures using the extrusion printing technique. The crosslinking property of PCLF enabled the unique post‐processing of 3D printed scaffolds resulting in highly porous and flexible PCLF scaffolds with compressive properties imitating natural features of cancellous bone. Generated scaffolds supported excellent attachment and proliferation of mesenchymal stem cells (MSC). The high porosity of PCLF scaffolds facilitated vascularized membrane formation demonstrable with the stringency of the ex ovo chicken chorioallantoic membrane (CAM) implantation. Furthermore, upon implantation to rat calvarium defects, PCLF scaffolds enabled an exceptional new bone formation with a bone mineral density of newly formed bone mirroring native bone tissue. These studies suggest that the 3D‐printed highly porous PCLF scaffolds may serve as a suitable biomaterial platform to significantly expand the utility of the PCLF biomaterial for bone tissue engineering applications.