US Academic Medical Centers Research Articles

Evaluation of a benzodiazepine deprescribing quality improvement initiative for older adults in primary care.

Older adults are commonly prescribed long-term benzodiazepines for anxiety and insomnia despite evidence of risks and limited evidence of long-term benefits. Recent quality measures and guidelines have recommended benzodiazepine deprescribing, yet there is little real-world data on clinic-based deprescribing programs. We developed a benzodiazepine deprescribing quality improvement program for older adults at a large US academic medical center. The program targeted adults aged 65 years and older who were prescribed chronic benzodiazepines by their primary care physician (PCP). PCPs were contacted to opt-out patients not suitable for deprescribing; then eligible patients were mailed a letter discussing patient-specific risks and advising them to discuss deprescribing with their PCP or a pharmacist who was available to support tapering. The primary outcomes were the number of patients who discussed deprescribing and who initiated a taper within 90 days of outreach. Of 504 older adults prescribed benzodiazepines, 133 (26%) were opted out by their PCPs leaving a cohort of 371 (median age 71 years [IQR 68-75], 58% female, 82% White). The median daily diazepam milligram equivalent was 5 mg (IQR 3-6 mg) and 30% were prescribed long-acting benzodiazepines. Three months following patient outreach, 97 patients (26%) had a documented discussion of benzodiazepines with their PCP or clinic pharmacist. Of these patients, 35 (36%) had documentation of a deprescribing discussion and 25 (26%) initiated a taper. At 12 months, 16 patients (64%) were tapered successfully, with nine (36%) patients taking a lower benzodiazepine dose and seven (28%) discontinuing benzodiazepines completely. A low-intensity benzodiazepine deprescribing outreach program led to deprescribing conversations for a minority of patients, but one-quarter of older adults who engaged in a conversation chose to taper and nearly two-thirds sustained reduced use. Incorporating benzodiazepine deprescribing into routine care may require more intensive population-health efforts to engage patients and clinicians.

Final Results of a Phase I/II Trial of Carfilzomib + R-CHOP for Frontline Treatment of Patients with Non-Germinal Center Diffuse Large B-Cell Lymphoma (DLBCL)

INTRODUCTION: Recent data from the REMoDL-B trial show that addition of the proteasome inhibitor bortezomib to R-CHOP improves progression free survival (PFS) of patients (Pts) with activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) compared to R-CHOP, but peripheral neuropathy limited dose intensity. Relative to bortezomib, carfilzomib (K) displays comparable clinical activity in plasma cell neoplasms but does not cause neurotoxicity. K has preferential clinical activity in relapsed non-germinal center (non-GC) DLBCL treated with chemotherapy (Torka, et al. Blood Adv. 2023). To explore the safety and efficacy of K in combination with R-CHOP (KR-CHOP), we performed a phase I trial to identify the recommended phase 2 dose (RP2D) in all DLBCL Pts followed by a phase II extension exclusively in non-GC DLBCL. METHODS: Between 2015-2020, Pts with untreated de novo or transformed DLBCL, adequate organ function and ECOG PS ≤ 3 were enrolled at 3 US academic medical centers. As previously reported [Hill, et al, Blood (2018), 132 (Supl.1):1692], during phase I dose escalation, the RP2D of K was 20 mg/m 2 on days (D) 1 & 2 of cycle 1 and 56 mg/m 2 on D1 & 2 of cycles 2-6. Rituximab was given on D2 and CHOP was given on D3. All Pts received pegfilgrastim and zoster prophylaxis. To assess the cardiac safety of combining K with anthracycline, we compared echocardiogram data at baseline and conclusion of therapy from study Pts and control NHL Pts treated with CHOP. To gauge for differential clinical activity of KR-CHOP vs R-CHOP, we compared PFS and overall survival (OS) rates for study Pts with non-GC DLBCL vs. Pts with non-GC DLBCL receiving standard of-care (SOC) R-CHOP at the Cleveland Clinic during the same period. The outcomes were also compared between propensity score (PS)-matched pairs, to account for differences in baseline demographics and clinical risk. RESULTS: 48 Pts were enrolled, and 47 treated; 18 in dose levels < RP2D and 29 at RP2D.Baseline demographics and treatment outcomes are shown in the Table. All-grade (G) hematologic adverse events (AEs) were: anemia, 35% (22% ≤ G2, 13% G3); thrombocytopenia, 24% (15% ≤ G2, 2% G3, 7% G4); febrile neutropenia, 9% (all G3/G4). Non-hematologic AEs included: nausea, 49% (47% ≤ G2, 2% G3); vomiting, 23% (21% ≤ G2, 2% G3), peripheral sensory neuropathy, 27% (all ≤ G2); dyspnea, 24% (all ≤G2). There was one case of G3 congestive heart failure. Echocardiograms from 42 study Pts who completed 6 cycles of KR-CHOP showed no statistically significant difference in change in ejection fraction from baseline compared to 39 control Pts [95% vs. 94%, respectively (P = 0.59)]. The overall response rate was 89% (70% CR, 19% PR). At a median follow-up of 31 months, 3-year Kaplan-Meier estimates of PFS and OS for the study population were 79% and 87%, respectively. There were 8 deaths in the study: 4 due to lymphoma; 2 due to infection; 2 due to other causes. Comparing outcomes of the 36 study Pts with non-GC DLBCL to 172 control Pts receiving R-CHOP as SOC, more control Pts had stage IV disease (54% vs 34%, p=0.03) and older age (median 67 vs 66 years old, p=0.03), but less frequently >1 extranodal site of disease (23% vs. 42%, P = 0.02). PS matching using logistic regression identified 25 case-control pairs of Pts with non-GC DLBCL according to gender, age, and other International Prognostic Index (IPI) elements (see Table). In analysis of PS-matched pairs of Pts with non-GC DLBCL, Pts treated with KR-CHOP had better 3-year PFS and OS relative to Pts treated with R-CHOP as SOC [96% vs. 50% (p=0.002) (see Figure) and 67% vs. 96% (p = 0.02), respectively]. In Cox univariate analysis, treatment with R-CHOP vs. KR-CHOP was associated with an increased risk of PFS and OS with hazard ratios (HR) of 6.15 [95% confidence interval (CI) 1.71 - 22.05, P = 0.002] and 3.19 [(95% CI, 1.01 -10.11), P = 0.02], respectively. CONCLUSION: KR-CHOP can be delivered safely, without excess cardiac toxicity or peripheral neuropathy. The superior PFS and OS rates for Pts with non-GC DLBCL vs. controls receiving R-CHOP are encouraging but should be interpreted with caution due to inherent selection bias in clinical trial populations. These data suggest that, like bortezomib, carfilzomib (K) may have preferential clinical activity in ABC DLBCL. Future randomized trials are justified using advanced molecular profiling to further investigate which Pts with DLBCL may benefit from addition of a proteasome inhibitor as part of frontline treatment.

Patterns of Use and Impact of Post-Referral and Bridging Therapy on Outcomes in Patients Undergoing CAR T-Cell Therapy for B-Cell Lymphoma: A Single-Center Analysis

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has changed the treatment landscape for B-cell non-Hodgkin lymphoma (B-NHL) . Treatment is often given after patients have been referred for CAR T-cell therapy while evaluation is underway but prior to leukapheresis, subsequently referred to as post-referral therapy (PRT). Bridging therapy (BT) may be used while CAR T cells are being manufactured. Little has been previously reported on patterns of use of various regimens, optimal choice of treatment, and how use of these treatments impacts patient outcomes when undergoing CAR T-cell treatment. METHODS: Patients aged ≥18 years with B-NHL who underwent apheresis between November 2017 and March 2023 for commercial CAR T-cell therapy at Vanderbilt University Medical Center were identified from an internal database. Patients received axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), or brexucabtagene autoleucel (brexu-cel). The primary endpoint was complete remission (CR) at 30 days post CAR-T. Patients who died prior to that time point were not censored and considered to not have achieved CR. Tumor response after CAR T-cell infusion was assessed per Lugano criteria by the treating clinician. PRT and BT regimens were defined as follows: platinum-based included cisplatin, carboplatin, or oxaliplatin; polatuzumab-based included rituximab with or without bendamustine; non-platinum based included: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), R-hyper CVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone and/or high-dose methotrexate and cytarabine), or R-mini CVD (rituximab, cyclophosphamide, vincristine, dexamethasone); oral targeted agents included: ibrutinib, venetoclax, or lenalidomide based treatments. Differences in baseline characteristics were assessed with chi squared analysis and two sample t-test. Predictors of 30-day CR were identified with logistic regression analysis. RESULTS: This study included 60 patients who were treated with commercial CAR-T with median follow up of 280 days. A total of 9 did not receive any PRT while 51 received one or more lines of PRT. There were no statistically significant differences between those who did or did not receive PRT in median age, sex, diagnosis, disease stage, or product type (Table 1). Elevated LDH (44% vs. 80%, p=0.022) and private insurance (33% vs. 69%, p=0.043) were more common in those who received PRT compared to those who did not. There were no significant differences in the receipt of BT. A detailed summary of types of regimens used in PRT and BT is included in Table 1. For those who received PRT, the median total number of cycles of treatment received including bridging therapy was 3 (range 1-7). The median time from referral to leukapheresis was longer in those who received PRT compared to those who did not (68.5 days vs. 36 days). Fewer patients who received PRT underwent leukapheresis within 45 days (22% vs. 56%, p=0.037). There was no difference in 30-day CR after CAR-T infusion. Figure 1 shows 30-day CR stratified by type of PRT given in the first line. Amongst patients who received platinum-based therapy, 12 (60.0%) achieved a CR at 30 days, while 8 (40.0%) did not. Amongst patients who received polatuzumab-based therapy, 4 (26.7%) achieved a CR at 30 days, while 11 (77.3%) did not. In univariate logistic regression analysis, predictors of achieving CR at 30 days included age (OR 1.04, CI: 1.00-1.09, p=0.033), elevated LDH (OR 0.19, CI: 0.051-0.69, p=0.012), and receipt of platinum-based therapy as first line PRT (OR 4.13, CI: 1.23-13.78, p=0.021). Multivariate analysis showed receipt of platinum-based therapy as first line PRT (OR 5.11, CI: 1.23-21.22, p=0.025) and elevated LDH (OR 0.08, CI: 0.013-0.53, p=0.09) were significant predictors. CONCLUSION: In this retrospective analysis, we provide a detailed overview of the number of lines and types of PRT and BT used in patients undergoing CAR-T cell therapy at a single US academic medical center. While 30-day CR was not impacted by the receipt of PRT, patients who received platinum-based chemotherapy as their first PRT had significantly higher odds of achieving of 30-day CR than those who received other therapies in multivariate analysis. This trend will be important to explore in larger analyses and may provide insight into optimal post-referral treatment choices.

An artificial intelligence algorithm for detection of severe aortic stenosis: a clinical cohort study

Abstract Background/Introduction Despite guideline based indications, nearly 1/3 of patients with symptomatic severe aortic stenosis (AS) are not referred for intervention. Artificial Intelligence Decision-Support Algorithms (AI-DSAs) may be helpful to identify individuals with AS at risk for premature mortality but few have been validated for use. Purpose To evaluate an AI-DSA based on echocardiogram report data to augment the detection of severe AS within a well-resourced health care setting. Methods Blinded to clinical information, an AI-DSA trained to identify an aortic valve area (AVA) <1cm2 using minimal input data was applied to routine transthoracic echocardiogram reports from 31,141 US Medicare beneficiaries (≥ 65 years old) at a large US academic medical center (2003-2017) (Figure). Results Performance of the AI-DSA to detect an AVA <1cm2 was excellent (sensitivity 95.2%, specificity 94.8%, negative predictive value 99.8%). The AI-DSA identified 1,549 (5.0%) individuals with guideline-defined severe AS plus 463 (1.5%), 979 (3.1%), and 28,150 (90.4%) individuals with a severe AS (not meeting guidelines), moderate AS, and low-probability AS phenotypes. Five-year mortality was 73.9%, 77.1%, 71.2%, and 43.6% respectively (adjusted HR compared to low-probability AS, HR 1.40, 95% CI 1.31-1.50 [guideline severe], HR 1.31, 1.17-1.46 [non-guideline severe], HR 1.21, 1.12-1.23 [moderate], p < 0.001 for all). Overall, rates of aortic valve replacement (AVR) remained low, even in those with an AVA <1cm2 (21.9%), despite it being associated with improved survival. Findings remained consistent among outpatients, those investigated in the past decade and those with left ventricular systolic dysfunction. Conclusions Without relying on left ventricular outflow tract measurements, an AI-DSA used echocardiographic reports to reliably identify those with severe AS. These results suggest possible utility for this AI-DSA to enhance detection of individuals with the phenotype of severe AS, at risk for adverse outcomes.Figure:Graphical Abstract

Abstract 13950: Real-World Effectiveness and Safety of Evinacumab in Pediatric and Adult Patients With Homozygous Familial Hypercholesterolemia: A Multi-Site US Perspective

Introduction: Homozygous familial hypercholesterolemia (HoFH) is an autosomal co-dominant disorder characterized by extreme elevations in LDL-C and early onset ASCVD. Unfortunately, patients with HoFH generally experience poor LDL-C lowering with standard lipid-lowering therapy and rarely achieve LDL-C goals. Evinacumab is a monoclonal antibody administered by monthly IV infusion that binds angiopoietin-like 3 and when added to standard lipid-lowering therapies lowers LDL-C by ~50% in clinical trials involving patients with HoFH. Real-world effectiveness and safety of evinacumab is unknown. Methods: We performed retrospective chart review to assess effectiveness and safety of evinacumab in patients with HoFH in clinical practice at six US academic medical centers. The primary efficacy endpoint was the percent change in LDL-C from baseline to first follow-up and to most recent follow-up after evinacumab initiation. Secondary efficacy endpoints were percent change in non-HDL-C, triglycerides, total cholesterol, HDL-C, and achievement of an LDL-C <70 mg/dL. Adverse events were recorded. Results: Twenty-four patients (mean age 38 yrs; range 5-75) with HoFH were followed for a median of 63 weeks. Fifty percent were female, 66.7% had ASCVD, 87.5% were on a statin, 83.3% on ezetimibe, 66.7% on a PCSK9i, 24% on lomitapide, and 33.3% were undergoing lipoprotein apheresis. Significant reductions in LDL-C, non-HDL-C, total cholesterol, triglycerides, and HDL-C were observed both at first follow-up (4 weeks) and most recent follow-up (63 weeks) (p < 0.001 for all) (Table). Significantly more patients achieved LDL-C <70 mg/dL after evinacumab was added. No serious adverse events occurred and evinacumab was generally well-tolerated. Conclusions: Across six US academic medical centers, evinacumab was generally well-tolerated by patients with HoFH and lowered LDL-C by ~50%, consistent with results from clinical trials.

Brain Injury Outcomes after Adjuvant Erythropoietin Neuroprotection for Moderate or Severe Neonatal Hypoxic-Ischemic Encephalopathy: A Report from the HEAL Trial

Introduction: Erythropoietin (Epo) is a putative neuroprotective therapy that did not improve overall outcomes in a phase 3 randomized controlled trial for neonates with moderate or severe hypoxic-ischemic encephalopathy (HIE). However, HIE is a heterogeneous disorder, and it remains to be determined whether Epo had beneficial effects on a subset of perinatal brain injuries. Methods: This study was a secondary analysis of neuroimaging data from the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, which was conducted from 2016 to 2021 at 17 sites involving 23 US academic medical centers. Participants were neonates >36 weeks’ gestation undergoing therapeutic hypothermia for moderate or severe HIE who received 5 doses of study drug (Epoetin alpha 1,000 U/kg/dose) or placebo in the first week of life. Treatment assignment was stratified by trial site and severity of encephalopathy. The primary outcome was the locus, pattern, and acuity of brain injury as determined by three independent readers using a validated HIE Magnetic Resonance Imaging (MRI) scoring system. Results: Of the 500 infants enrolled in HEAL, 470 (94%) had high quality MRI data obtained at a median of 4.9 days of age (IQR: 4.5–5.8). The incidence of injury to the deep gray nuclei, cortex, white matter, brainstem and cerebellum was similar between Epo and placebo groups. Likewise, the distribution of injury patterns was similar between groups. Among infants imaged at less than 8 days (n = 414), 94 (23%) evidenced only acute, 93 (22%) only subacute and 89 (21%) both acute and subacute injuries, with similar distribution across treatment groups. Conclusion: Adjuvant erythropoietin did not reduce the incidence of regional brain injury. Subacute brain injury was more common than previously reported, which has key implications for the development of adjuvant neuroprotective therapies for this population.

Collaboration between maternal-fetal medicine and family planning: a survey of Northeast US academic medical centers.

To explore how complex family planning (CFP) and maternal-fetal medicine (MFM) in Northeast academic medical centers work together to provide abortion care. We distributed an exploratory cross-sectional online survey to CFP and MFM faculty and fellows at academic medical centers in the Northeast between July andSeptember of 2020. The survey included demographic information, assessment of practice patterns, hospital/administration support and assessment of collaboration. Likert scale questions examined opinions about collaboration and an open-ended question solicited ideas for improvement. We performed bivariate analysis to examine the association between subspecialty and practice location regarding provision of abortion care and perceived barriers to care. The response rate was 31 % and was similar by specialty. Of the 69 respondents, 83 % were MFMs, 75 % were faculty, and 54 % practiced in New York. More than 85 % reported personal participation in some portion of abortion care. The two most common perceived barriers to care were "lack or reluctance of physicians/staff" and state laws prohibiting termination. Nearly all (95 %) stated there was a good working relationship between CFP and MFM divisions; however, almost one-third agreed with or were neutral tothe statements "MFM and CFP are siloed in terms of work/patient care." Academic MFM and CFP providers in the Northeast collaborate well in providing abortion care, though our findings highlight areas that would benefit from improvement. Optimizing collaboration in the Northeast is important given its regional role for ensuring abortion access in the current national landscape. Improved education of all members of the patient care team on the importance of abortion access may also help provide optimal patient care where abortion services still legally exist.

Sociotechnical Factors Contributing to Burnout among Radiation Oncology Medical Physicists: Survey and Focus Group Results from a Systems-Analysis Approach

While burnout and contributing factors have been studied among physicians and surgeons, there is limited understanding of the factors contributing to radiation oncology medical physicists' (MPs) burnout. Therefore, this study aims to i) explore factors associated with burnout among MPs using a systems-analysis approach, and ii) identify and prioritize key improvement efforts. We administered a survey to MPs at a US academic medical center between May 19-June 2, 2022. The survey included a 2-item Connor-Davidson Resilience Scale, a 2- item abbreviated Maslach Burnout Inventory (MBI) measuring emotional exhaustion (EE) and depersonalization (DP), and 21 general workplace stressors based on the National Academy of Medicine's systems approach to clinicians' burnout. Participants rated workplace stressor severity on a 5-item Likert scale and priorities for improvement on a 4-item Likert scale. Burnout was categorized using a 2-Question Summative Score totaling >3 for EE and DP. Focus groups were held with ∼3 participants per group via a video conferencing platform on June 8-9, 2022. Survey results from top-rated workplace stressors and priorities were summarized and presented to focus groups. Participants were asked open-ended questions to promote discussion and elicit more contextual information about workplace stressors and to rank their highest priority stressors at the end of the focus group. Of the 12 MPs the survey was sent to, 8 responses (67%) were received. Table 1 summarizes the results. The mean resilience score was 6.88, with a standard deviation (SD) of 0.63. 87.5% (n = 7) of MPs identified themselves as burned out. The key workplace stressors contributing most to MPs' burnout were inadequate staffing (mean [SD] 3.1 [1.2]), work-life integration (3.1 [1.2]), excessive workload (2.8 [1.1]), and time pressure (2.6 [1.2]). Specifically, MPs suggested following improvements: i) hire additional physicists to cover clinic responsibilities, ii) limit or compensate for work done post-work hours, iii) improve scheduling workflow, and iv) retain hybrid work model. Survey data demonstrated moderate resilience but high levels of burnout among MPs. Results indicate inadequate staffing as the most severe workplace stressor and highest priority for improvement efforts and remained the top priority even after focus groups. These results warrant further studies with larger sample sizes, assessing factors contributing to burnout among MPs and systems-focused interventions.

Finding the Potholes in Academic Career Pathways for Underrepresented Groups in Otolaryngology.

To assess inequities in representation among ranks and odds of promotion by race in academic otolaryngology. Cross-sectional study. USacademic medical centers. Demographic data was collected for medical students, residents, and faculty in the Association of American Medical Colleges and Accreditation Council for Graduate Medical Education databases for the academic year 2020 to 2021. The rank equity index (REI) was used to make pairwise comparisons between ranks to determine groups' representation between levels. Odds ratios (ORs) and 95% confidence intervals (CIs) demonstrating the likelihood that an individual of a particular rank/race would advance in their academic career were determined. Representation comparing medical students with full professors for black, Latine, and Asian otolaryngologists was below parity (REI: 0.27, 0.85, 0.85, respectively). Black (OR: 0.20, CI: 0.15, 0.26), Latine (OR: 0.61, CI: 0.50, 0.75), and Asian (OR: 0.62, CI: 0.55, 0.71) medical students all faced lower odds of becoming otolaryngology residents compared to their white counterparts. Similar findings occurred when comparing resident and assistant professor representation. American Indian/Alaskan Native (AIAN) and Native Hawaiian/Pacific Islander (NHPI) REIs and ORs could not be assessed as only 1 self-reported AIAN and no NHPI faculty are present in the studied data. Underrepresented in Medicine and Asian physicians faced worsening representation at each rung of the academic otolaryngology ladder. The greatest losses occurred when medical students transitioned to residents and residents transitioned to assistant professors. AIAN and NH faculty were absent in otolaryngology, indicating vital targets for recruitment efforts.

44092 Tuberculid reactions at a US academic medical center: A retrospective review

44092 Tuberculid reactions at a US academic medical center: A retrospective review

44261 Cutaneous tuberculosis at a US academic medical center: A retrospective review

44261 Cutaneous tuberculosis at a US academic medical center: A retrospective review

Smartphone-Based Video Antenatal Preterm Birth Education

Preterm birth is a leading cause of infant mortality and child morbidity. Preterm birth is not always unexpected, yet standard prenatal care does not offer anticipatory education to parents at risk of delivering preterm, which leaves parents unprepared to make health care choices during the pregnancy that can improve survival and decrease morbidity in case of preterm birth. To evaluate the effect of the Preemie Prep for Parents (P3) program on maternal knowledge of preterm birth, preparation for decision-making, and anxiety. Recruitment for this randomized clinical trial conducted at a US academic medical center took place from February 3, 2020, to April 12, 2021. A total of 120 pregnant persons with a risk factor for preterm birth were enrolled between 16 and 21 weeks' gestational age and followed up through pregnancy completion. Starting at 18 weeks' gestational age, P3 program participants received links delivered via text message to 51 gestational age-specific short animated videos. Control participants received links to patient education webpages from the American College of Obstetricians and Gynecologists. At 25 weeks' gestation, scores on the Parent Prematurity Knowledge Questionnaire (scored as percent correct), Preparation for Decision Making Scale (scored 0-100), and Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety computerized adaptive test. Analysis was based on an intention to treat. A total of 120 pregnant participants (mean [SD] age, 32.5 [4.9] years) were included in the study; 60 participants were randomized to each group. Participants in the P3 group scored higher than those in the control group on knowledge of long-term outcomes at 25 weeks (88.5% vs 73.2%; estimated difference, 15.3 percentage points; 95% CI, 8.3-22.5 percentage points; P < .001). Participants in the P3 group reported being significantly more prepared than did participants in the control group for neonatal resuscitation decision-making at 25 weeks (Preparation for Decision Making Scale score, 76.0 vs 52.3; difference, 23.7; 95% CI, 14.1-33.2). There was no difference between the P3 group and the control group in anxiety at 25 weeks (mean [SE] PROMIS Anxiety scores, 53.8 [1.1] vs 54.0 [1.1]; difference, -0.1; 95% CI, -3.2 to 2.9). In this randomized clinical trial, pregnant persons randomly assigned to the P3 program had more knowledge of core competencies and were more prepared to make decisions that affect maternal and infant health, without experiencing worse anxiety. Mobile antenatal preterm birth education may provide a unique benefit to parents with preterm birth risk factors. ClinicalTrials.gov Identifier: NCT04093492.

Diagnostic Performance of Ultrasonography-Based Risk Models in Differentiating Between Benign and Malignant Ovarian Tumors in a US Cohort

Ultrasonography-based risk models can help nonexpert clinicians evaluate adnexal lesions and reduce surgical interventions for benign tumors. Yet, these models have limited uptake in the US, and studies comparing their diagnostic accuracy are lacking. To evaluate, in a US cohort, the diagnostic performance of 3 ultrasonography-based risk models for differentiating between benign and malignant adnexal lesions: International Ovarian Tumor Analysis (IOTA) Simple Rules with inconclusive cases reclassified as malignant or reevaluated by an expert, IOTA Assessment of Different Neoplasias in the Adnexa (ADNEX), and Ovarian-Adnexal Reporting and Data System (O-RADS). This retrospective diagnostic study was conducted at a single US academic medical center and included consecutive patients aged 18 to 89 years with adnexal masses that were managed surgically or conservatively between January 2017 and October 2022. Evaluation of adnexal lesions using the Simple Rules, ADNEX, and O-RADS. The main outcome was diagnostic performance, including area under the receiver operating characteristic (ROC) curve (AUC), sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios. Surgery or follow-up were reference standards. Secondary analyses evaluated the models' performances stratified by menopause status and race. The cohort included 511 female patients with a 15.9% malignant tumor prevalence (81 patients). Mean (SD) ages of patients with benign and malignant adnexal lesions were 44.1 (14.4) and 52.5 (15.2) years, respectively, and 200 (39.1%) were postmenopausal. In the ROC analysis, the AUCs for discriminative performance of the ADNEX and O-RADS models were 0.96 (95% CI, 0.93-0.98) and 0.92 (95% CI, 0.90-0.95), respectively. After converting the ADNEX continuous individualized risk into the discrete ordinal categories of O-RADS, the ADNEX performance was reduced to an AUC of 0.93 (95% CI, 0.90-0.96), which was similar to that for O-RADS. The Simple Rules combined with expert reevaluation had 93.8% sensitivity (95% CI, 86.2%-98.0%) and 91.9% specificity (95% CI, 88.9%-94.3%), and the Simple Rules combined with malignant classification had 93.8% sensitivity (95% CI, 86.2%-98.0%) and 88.1% specificity (95% CI, 84.7%-91.0%). At a 10% risk threshold, ADNEX had 91.4% sensitivity (95% CI, 83.0%-96.5%) and 86.3% specificity (95% CI, 82.7%-89.4%) and O-RADS had 98.8% sensitivity (95% CI, 93.3%-100%) and 74.4% specificity (95% CI, 70.0%-78.5%). The specificities of all models were significantly lower in the postmenopausal group. Subgroup analysis revealed high performances independent of race. In this diagnostic study of a US cohort, the Simple Rules, ADNEX, and O-RADS models performed well in differentiating between benign and malignant adnexal lesions; this outcome has been previously reported primarily in European populations. Risk stratification models can lead to more accurate and consistent evaluations of adnexal masses, especially when used by nonexpert clinicians, and may reduce unnecessary surgeries.

Improvements in Physical Function and Pain Interference and Changes in Mental Health Among Patients Seeking Musculoskeletal Care

Among patients seeking care for musculoskeletal conditions, there is mixed evidence regarding whether traditional, structure-based care is associated with improvement in patients' mental health. To determine whether improvements in physical function and pain interference are associated with meaningful improvements in anxiety and depression symptoms among patients seeking musculoskeletal care. This cohort study included adult patients treated by an orthopedic department of a tertiary care US academic medical center from June 22, 2015, to February 9, 2022. Eligible participants presented between 4 and 6 times during the study period for 1 or more musculoskeletal conditions and completed Patient-Reported Outcomes Measurement Information System (PROMIS) measures as standard care at each visit. PROMIS Physical Function and Pain Interference scores. Linear mixed effects models were used to determine whether improvements in PROMIS Anxiety and PROMIS Depression scores were associated with improved PROMIS Physical Function or Pain Interference scores after controlling for age, gender, race, and PROMIS Depression (for the anxiety model) or PROMIS Anxiety (for the depression model). Clinically meaningful improvement was defined as 3.0 points or more for PROMIS Anxiety and 3.2 points or more for PROMIS Depression. Among 11 236 patients (mean [SD] age, 57 [16] years), 7218 (64.2%) were women; 120 (1.1%) were Asian, 1288 (11.5%) were Black, and 9706 (86.4%) were White. Improvements in physical function (β = -0.14; 95% CI, -0.15 to -0.13; P < .001) and pain interference (β = 0.26; 95% CI, 0.25 to 0.26; P < .001) were each associated with improved anxiety symptoms. To reach a clinically meaningful improvement in anxiety symptoms, an improvement of 21 PROMIS points or more (95% CI, 20-23 points) on Physical Function or 12 points or more (95% CI, 12-12 points) on Pain Interference would be required. Improvements in physical function (β = -0.05; 95% CI, -0.06 to -0.04; P < .001) and pain interference (β = 0.04; 95% CI, 0.04 to 0.05; P < .001) were not associated with meaningfully improved depression symptoms. In this cohort study, substantial improvements in physical function and pain interference were required for association with any clinically meaningful improvement in anxiety symptoms, and were not associated with any meaningful improvement in depression symptoms. Patients seeking musculoskeletal care clinicians providing treatment cannot assume that addressing physical health will result in improved symptoms of depression or potentially even sufficiently improved symptoms of anxiety.

Uncharacterized and lineage-specific accessory genes within the Proteus mirabilis pan-genome landscape.

Proteus mirabilis is a Gram-negative bacterium recognized for its unique swarming motility and urease activity. A previous proteomic report on four strains hypothesized that, unlike other Gram-negative bacteria, P. mirabilis may not exhibit significant intraspecies variation in gene content. However, there has not been a comprehensive analysis of large numbers of P. mirabilis genomes from various sources to support or refute this hypothesis. We performed comparative genomic analysis on 2,060 Proteus genomes. We sequenced the genomes of 893 isolates recovered from clinical specimens from three large US academic medical centers, combined with 1,006 genomes from NCBI Assembly and 161 genomes assembled from Illumina reads in the public domain. We used average nucleotide identity (ANI) to delineate species and subspecies, core genome phylogenetic analysis to identify clusters of highly related P. mirabilis genomes, and pan-genome annotation to identify genes of interest not present in the model P. mirabilis strain HI4320. Within our cohort, Proteus is composed of 10 named species and 5 uncharacterized genomospecies. P. mirabilis can be subdivided into three subspecies; subspecies 1 represented 96.7% (1,822/1,883) of all genomes. The P. mirabilis pan-genome includes 15,399 genes outside of HI4320, and 34.3% (5,282/15,399) of these genes have no putative assigned function. Subspecies 1 is composed of several highly related clonal groups. Prophages and gene clusters encoding putatively extracellular-facing proteins are associated with clonal groups. Uncharacterized genes not present in the model strain P. mirabilis HI4320 but with homology to known virulence-associated operons can be identified within the pan-genome. IMPORTANCE Gram-negative bacteria use a variety of extracellular facing factors to interact with eukaryotic hosts. Due to intraspecies genetic variability, these factors may not be present in the model strain for a given organism, potentially providing incomplete understanding of host-microbial interactions. In contrast to previous reports on P. mirabilis, but similar to other Gram-negative bacteria, P. mirabilis has a mosaic genome with a linkage between phylogenetic position and accessory genome content. P. mirabilis encodes a variety of genes that may impact host-microbe dynamics beyond what is represented in the model strain HI4320. The diverse, whole-genome characterized strain bank from this work can be used in conjunction with reverse genetic and infection models to better understand the impact of accessory genome content on bacterial physiology and pathogenesis of infection.

Safety and efficacy of standard of care (SOC) ciltacabtagene autoleucel (Cilta-cel) for relapsed/refractory multiple myeloma (RRMM).

8012 Background: Cilta-cel was FDA approved in 2022 for the treatment of RRMM. We evaluated the outcomes of patients treated with intended SOC cilta-cel. Methods: 12 US academic medical centers contributed data to this retrospective study. As of 12/31/2022, 177 patients were leukapheresed and 139 received cilta-cel. Results: The table describes the study population compared to the CARTITUDE-1 trial. More patients in our study had extramedullary disease (EMD, 35%) and high-risk cytogenetics (41%). 55% of the patients would not have met eligibility criteria for CARTITUDE-1. Common reasons for ineligibility were cytopenias (19%), prior BCMA therapy (14%), organ dysfunction (12%), oligosecretory disease (13%), and plasma cell leukemia (8%). 83% of the patients received bridging chemotherapy (overall response rate, ORR: 28%). Lymphodepletion included fludarabine (Flu) + cyclophosphamide (Cy): 81%, bendamustine: 11%, Cy: 4%, and cladribine + Cy: 4%. Median CAR-T cells infused were 0.6 million/kg (range: 0.1-0.9), and 19% of patients were treated on an expanded access protocol (EAP). Median follow-up was 2.3 months (range: 0-8). Cytokine release syndrome (CRS) was seen in 81% (≥ grade 3: 7%) and immune effector cell-associated neurotoxicity syndrome (ICANS) in 22% (≥ grade 3: 8%) of patients. Tocilizumab, steroids, and anakinra were used in 61%, 44%, and 10% of patients, respectively. Delayed neurotoxicity (NT) was seen in 9% (cranial nerve palsy: 8, Parkinsonism: 2, others: 3). Grade ≥ 3 cytopenias at day ≥ 30 were seen in 75% of patients. Infections were seen in 32% of patients. Day 30 (N=115) and best response rates (N=118) were: ≥ partial response (PR), 75/80%; ≥ very good PR, 44/62%; and ≥ complete response (CR), 26/40%, respectively. In the non-EAP FluCy population (N=88), best ORR/≥CR were 89/49%. 17 patients died by data cut-off, 4 due to disease progression and 13 (9%) due to non-relapse mortality (NRM) (grade 5 CRS: 3, infection: 6, CRS/infection: 1, grade 5 ICANS: 1, delayed NT: 2). Conclusions: Patients treated with intended SOC cilta-cel had a favorable ORR (80%) despite a larger proportion of patients having high-risk features relative to trial patients and limited follow-up. Response rates were higher in patients receiving conforming products with FluCy conditioning (89%). Delayed NT and NRM were seen in 9% of patients. Results will be updated with continued follow-up. D.K.H., K.K.P, M.J., Y.L. &amp; S.S. contributed equally. [Table: see text]

Factors Associated With Nonadherence to Lung Cancer Screening Across Multiple Screening Time Points

Screening with low-dose computed tomography (CT) has been shown to reduce mortality from lung cancer in randomized clinical trials in which the rate of adherence to follow-up recommendations was over 90%; however, adherence to Lung Computed Tomography Screening Reporting & Data System (Lung-RADS) recommendations has been low in practice. Identifying patients who are at risk of being nonadherent to screening recommendations may enable personalized outreach to improve overall screening adherence. To identify factors associated with patient nonadherence to Lung-RADS recommendations across multiple screening time points. This cohort study was conducted at a single US academic medical center across 10 geographically distributed sites where lung cancer screening is offered. The study enrolled individuals who underwent low-dose CT screening for lung cancer between July 31, 2013, and November 30, 2021. Low-dose CT screening for lung cancer. The main outcome was nonadherence to follow-up recommendations for lung cancer screening, defined as failing to complete a recommended or more invasive follow-up examination (ie, diagnostic dose CT, positron emission tomography-CT, or tissue sampling vs low-dose CT) within 15 months (Lung-RADS score, 1 or 2), 9 months (Lung-RADS score, 3), 5 months (Lung-RADS score, 4A), or 3 months (Lung-RADS score, 4B/X). Multivariable logistic regression was used to identify factors associated with patient nonadherence to baseline Lung-RADS recommendations. A generalized estimating equations model was used to assess whether the pattern of longitudinal Lung-RADS scores was associated with patient nonadherence over time. Among 1979 included patients, 1111 (56.1%) were aged 65 years or older at baseline screening (mean [SD] age, 65.3 [6.6] years), and 1176 (59.4%) were male. The odds of being nonadherent were lower among patients with a baseline Lung-RADS score of 1 or 2 vs 3 (adjusted odds ratio [AOR], 0.35; 95% CI, 0.25-0.50), 4A (AOR, 0.21; 95% CI, 0.13-0.33), or 4B/X, (AOR, 0.10; 95% CI, 0.05-0.19); with a postgraduate vs college degree (AOR, 0.70; 95% CI, 0.53-0.92); with a family history of lung cancer vs no family history (AOR, 0.74; 95% CI, 0.59-0.93); with a high age-adjusted Charlson Comorbidity Index score (≥4) vs a low score (0 or 1) (AOR, 0.67; 95% CI, 0.46-0.98); in the high vs low income category (AOR, 0.79; 95% CI, 0.65-0.98); and referred by physicians from pulmonary or thoracic-related departments vs another department (AOR, 0.56; 95% CI, 0.44-0.73). Among 830 eligible patients who had completed at least 2 screening examinations, the adjusted odds of being nonadherent to Lung-RADS recommendations at the following screening were increased in patients with consecutive Lung-RADS scores of 1 to 2 (AOR, 1.38; 95% CI, 1.12-1.69). In this retrospective cohort study, patients with consecutive negative lung cancer screening results were more likely to be nonadherent with follow-up recommendations. These individuals are potential candidates for tailored outreach to improve adherence to recommended annual lung cancer screening.

1-Year Comparative Effectiveness of Tofacitinib vs Ustekinumab for Patients With Ulcerative Colitis and Prior Antitumor Necrosis Factor Failure.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Real-world data comparing the effectiveness of tofacitinib to ustekinumab are limited. We compared 52-week outcomes of tofacitinib vs ustekinumab for UC after antitumor necrosis factor (anti-TNF) failure. In this retrospective cohort study, adults initiated tofacitinib or ustekinumab for UC after anti-TNF failure May 1, 2018 to April 1, 2021, at a US academic medical center. The primary outcome was steroid-free clinical remission (SFCR) at 12 and 52 weeks. The secondary outcome was drug survival (ie, time to drug discontinuation due to nonresponse). Adverse events (AEs) were also assessed. Sixty-nine patients initiated tofacitinib, and 97 patients initiated ustekinumab with median follow-up of 88.0 and 62.0 weeks, respectively. After inverse probability of treatment-weighted logistic and Cox regression, there was no association of tofacitinib vs ustekinumab with SFCR at 12 weeks (odds ratio, 1.65; 95% CI, 0.79-3.41), SFCR at 52 weeks (odds ratio, 1.14; 95% CI, 0.55-2.34), or drug survival (hazard ratio, 1.37; 95% CI, 0.78-2.37). Kaplan-Meier analysis demonstrated no separation in drug survival curves. Regression results were similar after excluding patients with prior tofacitinib or ustekinumab exposure. During available follow-up, 17 AEs were reported for tofacitinib (most commonly shingles, n = 4), and 10 AEs were reported for ustekinumab (most commonly arthralgia and rash, each n = 2). Two patients discontinued treatment due to AEs (1 tofacitinib for elevated liver enzymes, 1 ustekinumab for arthralgia). In a real-world UC cohort, tofacitinib and ustekinumab demonstrated similar effectiveness at 52 weeks. Adverse events were consistent with the known safety profiles of these agents.

Generalizability of the Necrotizing Enterocolitis Surgery Trial to the Target Population of Eligible Infants

The objective of this study was to evaluate whether infants randomized in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Necrotizing Enterocolitis Surgery Trial differed from eligible infants and whether differences affected the generalizability of trial results. Secondary analysis of infants enrolled in Necrotizing Enterocolitis Surgery Trial (born 2010-2017, with follow-up through 2019) at 20 US academic medical centers and an observational data set of eligible infants through 2013. Infants born ≤1000g and diagnosed with necrotizing enterocolitis or spontaneous intestinal perforation requiring surgical intervention at ≤8weeks were eligible. The target population included trial-eligible infants (randomized and nonrandomized) born during the first half of the study with available detailed preoperative data. Using model-based weighting methods, we estimated the effect of initial laparotomy vs peritoneal drain had the target population been randomized. The trial included 308 randomized infants. The target population included 382 (156 randomized and 226 eligible, non-randomized) infants. Compared with the target population, fewer randomized infants had necrotizing enterocolitis (31% vs 47%) or died before discharge (27% vs 41%). However, incidence of the primary composite outcome, death or neurodevelopmental impairment, was similar (69% vs 72%). Effect estimates for initial laparotomy vs drain weighted to the target population were largely unchanged from the original trial after accounting for preoperative diagnosis of necrotizing enterocolitis (adjusted relative risk [95% CI]: 0.85 [0.71-1.03] in target population vs 0.81 [0.64-1.04] in trial) or spontaneous intestinal perforation (1.02 [0.79-1.30] vs 1.11 [0.95-1.31]). Despite differences between randomized and eligible infants, estimated treatment effects in the trial and target population were similar, supporting the generalizability of trial results. ClinicalTrials.gov ID: NCT01029353.

Association of Weight Loss in Ambulatory Care Settings With First Diagnosis of Lung Cancer in the US

Lung cancer, the US's leading cause of cancer death, is often diagnosed following presentation to health care settings with symptoms, and many patients present with late-stage disease. To investigate the association between weight loss and subsequent diagnosis of incident lung cancer in an ambulatory care population and to assess whether recorded weight change had higher odds of lung cancer diagnosis than objective measurements. This case-control study included patients visiting a US academic medical center between January 1, 2012, and December 31, 2019. Data were derived from US ambulatory care electronic health records from the University of Washington Medical Center linked to the local Surveillance, Epidemiology, and End Results cancer registry. Cases were identified from patients who had a primary lung cancer diagnosis between 2012 and 2019; controls were matched on age, sex, smoking status, and presenting to the same type of ambulatory clinic as cases. Data were analyzed from March 2022 through January 2023. Continuous and categorical weight change were assessed. Odds ratios estimating the likelihood of a diagnosis of lung cancer were calculated using univariable and multivariable conditional logistic regression. A total of 625 patients aged 40 years or older with a first primary lung cancer diagnosis and 4606 matched controls were included (1915 [36.6%] ages 60 to 69 years; 418 [8.0%] Asian, 389 [7.4%] Black, 4092 [78.2%] White). In unadjusted analyses, participants with weight loss of 1% to 3% (odds ratio [OR], 1.12; 95% CI, 0.88-1.41), 3% to 5% (OR, 1.36; 95% CI, 0.99-1.88), or 5% to 10% (OR, 1.23; 95% CI, 0.82-1.85) over a 2-year period did not have statistically significantly increased risk of lung cancer diagnosis compared with those who maintained a steady weight. However, participants with weight loss of 10% to 50% had more than twice the odds of a lung cancer diagnosis (OR, 2.27; 95% CI, 1.27-4.05). Most categories of weight loss showed significant associations with an increased risk of lung cancer diagnosis for at least 6 months prior to diagnosis. Patients who had weight loss both recorded in clinicians' notes and measured had higher odds of lung cancer compared with patients who had only recorded (OR, 1.26; odds; 95% CI, 1.04-1.52) or measured (OR, 8.53; 95% CI, 6.99-10.40) weight loss. In this case-control study, weight loss in the prior 6 months was associated with incident lung cancer diagnosis and was present whether weight loss was recorded as a symptom by the clinician or based on changes in routinely measured weight, demonstrating a potential opportunity for early diagnosis. The association between measured and recorded weight loss by clinicians presents novel results for the US.