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Introduction: Bispecific antibodies (BsAbs) epcoritamab (Epco) and glofitamab (Glofit) are approved in the US for the treatment of patients (pts) with relapsed or refractory (r/r) large B-cell lymphomas (LBCLs) based upon high response rates and manageable toxicity profiles reported in pivotal trials. However, data on outcomes for pts treated with BsAbs outside of clinical trials are limited. As such, we sought to investigate the safety and efficacy of Epco and Glofit for the treatment of pts with r/r LBCLs in real-world settings. Methods: We performed a retrospective study including 19 US centers evaluating pts with r/r LBCLs receiving commercially available Epco or Glofit between 2023 and 2024. Baseline characteristics and outcomes were extracted from medical records. Efficacy outcomes included overall response rate (ORR), complete and partial response (CR, PR) rates, progression-free survival (PFS) and overall survival (OS), analyzed using the Kaplan Meier method. Key safety outcomes included cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results: As of May 31, 2024, a total of 209 pts with r/r LBCLs were treated with Epco (n=139) or Glofit (n=70). Median age at BsAb start was 67 years (interquartile range [IQR] 58-76). Most were male (62.2%), and the most common histology was diffuse large B-cell lymphoma (n=155 [74.2%]). Of pts with molecular testing (n=168), 34 (20.2%) had double/triple hit lymphoma. Most (78.9%) had Ann Arbor stage III-IV disease and 91% had an ECOG performance status of ≤1. Median number of lines of treatment before BsAb was 3 (range 1-12). Of pts with known response assessment following front-line therapy, 54 (32.1%) had primary refractory disease, defined as failure to achieve PR or CR to front-line therapy. Most pts (n=126 [60.3%]) received prior chimeric antigen receptor (CAR) T-cell therapy and 21 (10.0%) received prior autologous hematopoietic progenitor cell transplant. CD20 expression was assessed in 106 biopsies (50.7%) prior to BsAb and was positive in 90 (84.9%). A total of 172 pts were response-evaluable. The best ORR was 50.6%, with CR in 41 (23.8%), PR in 46 (26.7%), stable disease in 10 (5.8%), and progressive disease in 75 (43.6%). The ORR and CR rates were 49% and 23% for Epco, and 53% and 25% for Glofit, respectively. With a median follow-up of 5 months, the median PFS was 2.7 months (95% CI 2.0, 3.9) and median OS was 7.2 months (95% CI 6.1, not reached [NR]). The estimated PFS and OS at six months were 35% (95% CI 29%-43%) and 59% (95% CI 52%-67%), respectively. For pts who relapsed after CAR T-cell therapy, the median PFS and OS were 2.5 (95% CI 1.8, 4.7) and 7.8 (95% CI 6.2, NR) months, respectively. Pts without detectable CD20 expression via immunohistochemistry or flow cytometry prior to BsAb therapy had significantly inferior outcomes (PFS 1.1 vs 3.4 months, P < 0.001 and OS 1.3 vs 13 months, P < 0.001) compared to pts with detectable CD20. CRS of any grade occurred in 82 pts (39.2%), corresponding to 51.1% and 28.6% of pts treated with Epco and Glofit, respectively. Grade ≥3 CRS occurred in 9 (4.3%), all of whom received Epco. CRS was treated with tocilizumab in 43 pts (53.1%). ICANS occurred in 24 (11.5%) pts; any grade ICANS occurred in 13.7% and 7.1% of pts treated with Epco and Glofit, respectively. Grade ≥3 ICANS occurred in 6 pts (2.9%), 5 of which received Epco (3.6%). Of those experiencing ICANS, 66.0% were treated with corticosteroids. Two pts had deaths attributed to ICANS and one to CRS. A total of 122 (58.4%) pts discontinued therapy after a median of 3 cycles (range 0-48), 91 (74.6%) due to disease progression and 31 (25.4%) due to adverse events (15 due to infection, 3 due to ICANS, 2 due to CRS, and 11 for other reasons). Conclusions: In this heavily pretreated group with adverse disease features and high rate of CAR T exposure, the response rates, PFS, and OS following BsAb therapy were lower compared to pivotal trials. Poor outcomes were observed for those without detectable CD20. Rates of ICANS and grade ≥3 CRS were higher than reported in pivotal trials, as was the rate of discontinuation of therapy due to adverse events. Future efforts to improve outcomes may include intensified dose escalation protocols to more rapidly achieve disease control, combination therapies, and characterization of clinicopathologic factors that predict response to BsAb to identify subgroups of pts who can derive maximal benefit from these agents.

The Neurohospitalist Core Competencies comprise a set of competency-based learning objectives that encapsulate the knowledge, skills, and attitudes of neurohospitalitists who specialize in the care of hospitalized patients with neurologic conditions. These competencies serve to characterize the rapidly expanding field of neurohospitalist medicine. The 27 chapters are divided into 3 sections entitled: neurological conditions, clinical interventions and interpretation of ancillary studies, and neurohospitalist role in the healthcare system. Each individual learning objective in the chapters describes a specific concept with an action verb to illustrate the behavior that the neurohospitalist exhibits. The individual neurohospitalist may not exhibit mastery in each of the topics included as individual practices vary in scope and practice pattern. A few examples of how the complete set of competencies may be used include in the creation of curricula for neurohospitalist fellowships, to assist in defining the scope of practice of neurohospitalists for administrative leaders of hospitals and departments, and in influencing the direction of further research and quality improvement in the field.

Abstract Ataxia Telangiectasia–mutated (ATM) inhibitors are being developed as radiosensitizers to improve the antitumor effects of radiotherapy, but ATM inhibition can also radiosensitize normal tissues. Therefore, understanding the elevated risk of normal tissue toxicities is critical for radiosensitizer development. This study focused on modeling the relationship between acute mucosal toxicity, radiation dose, fractionation schedule, and radiosensitizer exposure. The ATM inhibitor WSD0628 was combined with single or fractionated doses of radiation delivered to the oral cavity or esophagus of Friend Leukemia virus B (FVB) mice. The potentiation by WSD0628 was quantified by a sensitizer enhancement ratio (SER), which describes the changes in radiation tolerance for radiation combined with WSD0628 relative to radiation-only regimens. WSD0628 profoundly enhanced radiation-induced acute oral and esophageal toxicities. For oral mucosal toxicity, the enhancement by WSD0628 with 3 fractions of radiation resulted in an SER ranging from 1.3 (0.25 mg/kg) to 3.1 (7.5 mg/kg). For the 7.5 mg/kg combination, the SER increased with increasing number of fractions from 2.2 (1 fraction) to 4.3 (7 fractions) for oral toxicity and from 2.2 (1 fraction) to 3.6 (3 fractions) for esophageal toxicity, which reflects a loss of the normal tissue sparing benefit of fractionated radiation. These findings were used to develop a modified biologically effective dose model to determine alternative radiation schedules with or without WSD0628 that result in similar levels of toxicity. Successful radiosensitizer dose escalation to a maximally effective therapeutic dose will require careful deliberation of tumor site and reduction of radiation dose volume limits for organs at risk.

AbstractObjectiveThis study aims to document and analyze the challenges and outcomes of performing complex airway surgery in a low‐resource, post‐war setting in Mekelle, Ethiopia.MethodsThis prospective case series examines clinical data from five patients who underwent airway reconstruction surgeries and one patient who underwent total laryngectomy at Ayder Comprehensive Specialized Hospital in Mekelle. Data included patient demographics, airway stenosis etiology and severity, operative details, postoperative outcomes, complications, and hospital length of stay. Ethical approval was obtained from institutional review boards at Mayo Clinic and Mekelle University.ResultsThe study included six patients aged 9–62 years, with surgeries comprising three cricotracheal resections, two tracheal resections, and one laryngectomy. Three reconstructions were for war‐related injuries. Challenges included power outages during surgeries, limitations in medical supplies and equipment, and inadequate perioperative care. Despite these, three patients requiring tracheostomies were successfully decannulated within a year. However, complications such as restenosis, infections, and the need for reintubation were common.ConclusionAirway surgeries in a low‐resource, post‐war setting face significant hurdles, including perioperative care quality, resource limitations, and infrastructure issues. Successful outcomes require multidisciplinary training tailored to local contexts, investments in hospital infrastructure and reliable electricity, and proper perioperative nutrition. This study highlights the need for comprehensive interventions to improve surgical care in such settings.Level of evidence: IV.

Ambulatory anesthesia for same-day surgery is a fast-growing and ever-improving branch of modern anesthesia. This is primarily driven by the involvement of anesthesiologists as perioperative physicians working in multidisciplinary groups. These groups work together to improve patient safety, patient outcomes, and overall efficiency of both in-patient and out-patient surgery. Appropriate patient selection and optimization are critical to maintain and improve the foundational entities of best ambulatory anesthesia practice. In this review article, a selection of considerations in the field of ambulatory anesthesia are featured, such as the aging population, sleep apnea, obesity, diabetes, cardiac disease, substance abuse, preoperative medication management, multimodal analgesia, social determinants of health, and surgical facility resources.

Introduction: Adderall, the brand name for a combination of dextroamphetamine and amphetamine salts, is used to treat attention deficit disorder and narcolepsy, but is widely abused for improving cognitive function and alertness in absence of a medical indication. While little is known of its acute cardiovascular (CV) physiologic effects, Adderall has been linked to acute CV events (myocardial infarction, tachyarrhythmias, heart failure, Takotsubo cardiomyopathy and sudden death) and to long term CV consequences including hypertension and arterial disease. Aim: To examine the acute CV responses to Adderall in healthy subjects not on stimulant therapy in a randomized double-blind placebo-controlled crossover study. (CT.gov NCT02979327) Methods: Thirty subjects were randomized to 25 mg Adderall versus placebo. We measured supine resting blood pressure (BP), heart rate (HR), and plasma catecholamines, before and 3 hours after consuming Adderall or placebo. Results: Twenty-nine subjects (16 females; aged 25±5 yrs) completed both Adderall and placebo conditions, with a median of 10 days between visits. Systolic BP (SBP) increased from 112±10 mmHg to 127±11 mmHg after use of Adderall but was unchanged before vs after placebo drug intake (112±8 mmHg and 112±9 mmHg respectively; group by time interaction p<0.01). Diastolic BP and mean BP increased by 6.8 mmHg and 8.5 mmHg respectively and HR increased by 7.3 beats/min with Adderall, but they did not change with placebo (p<0.01). Plasma norepinephrine increased from 217±79 pg/ml before to 323±105 pg/ml after Adderall but was unchanged after placebo (p<0.05) (Figure 1). Conclusions: Healthy subjects consuming a modest dose of Adderall manifest striking increases in BP, HR and sympathetic activation, even during supine rest. These findings may have important mechanistic implications for understanding acute CV events and long-term risk of CV disease associated with stimulant medications.

Introduction: Peripheral arterial disease (PAD) is caused by a lack of blood flow to the musculature relative to its metabolism which results in pain. PAD impacts up to 20% of patients around the world. PAD involves macrovascular and microvascular dysfunction. Near-infrared spectroscopy (NIRS) measures muscle oxygenation levels and assesses microvascular function. The standard of care for diagnosing PAD is the ankle-brachial index (ABI), which assesses macrovascular disease, and the 6-minute walk test (6MWT), which measures gait speed and claudication. NIRS has the potential to monitor progression of PAD. Hypothesis: NIRS measurement of muscle oxygenation, during a standard test of vascular occlusion and post-occlusive hyperemia, the vascular occlusion test (VOT), is predictive of PAD severity as determined by ABI and 6MWT. Methods: We studied 24 patients diagnosed with PAD. The mean age of the patients was 71.3 years, including 54% (n=13) males and 46% (n=11) females. The VOT consisted of rest, occlusion, and reperfusion phases each lasting 5 min (15 min total). Muscle oxygen saturation levels were recorded at 2 hertz. For every patient, 6 features were extracted from the VOT data using computational methods. The VOT features from 15 patients were used to train function-fitting neural network models to predict ABI and 6MWT Continuous Distance. The models were then used to predict ABI and 6MWT Continuous Distance from the VOT features of 9 test patients not used in the training, Results: For patients in the test set, the ABI and 6MWT Continuous Distance predicted by the models differed from the actual measurements by 14%±13% and 15%±17%, respectively (Figure 1). For patients in the training set, the ABI and 6MWT Continuous Distance predicted by the models differed from the actual measurements by 0±0% and 12%±11%, respectively (Figure 1). Conclusion: The VOT has the potential to predict the ABI and 6MWT Continuous Distance of patients diagnosed with PAD, suggesting that the VOT can be automated and used to monitor the severity of PAD. With more data from both healthy patients and PAD patients, and improvement of the model, we anticipate that the VOT will complement ABI and 6MWT in the diagnosis and monitoring of PAD.

Introduction: Peripheral artery disease (PAD), an atherosclerotic disease of the peripheral arteries, also results in microvascular dysfunction. PAD patients are recommended to undergo supervised walking and medical management; however, compliance with supervised walking programs is limited due to inconvenience and pain, necessitating alternative non-pharmacological interventions. We have shown that daily muscle stretching improved microvascular function in aged rats. This prompted us to study the effect of daily muscle stretching on microvascular function of the calf muscles in PAD patients. Methods: A randomized, single-blinded study was conducted on 24 PAD patients. Patients were assigned to either stretching or placebo stretching using a dorsiflexion splint (Image 1) for 30 min/day, 5 days/wk for 4 wks. Calf muscle oxygen saturation (smO 2 ) was recorded using near-infrared spectroscopy during the six-minute walking test (6MWT) before (Visit 1) and after (Visit 2) stretching or placebo stretching. The percentage decrease in smO 2 (from baseline) at minute 1 (Δ1) and minute 2 (Δ2) of the 6MWT was determined. Two-way ANOVA was used to compare Δ1 and Δ2 between the stretching and placebo stretching groups. Results: The mean age of the patients was 74.1±11.4 yrs with 52% (13/23) males. There was no significant difference in the changes in smO 2 during the 6MWT at either minute 1 (Δ1: 44.1±7.3% vs 27.1±7.0%, p=0.12) or minute 2 (Δ2: 78.7±8.2% vs 58.1±7.9%, p=0.08) between the stretching group and placebo stretching group at Visit 1. In contrast, at Visit 2, there was a significantly greater change in smO 2 at minute 2 (D2: 83.1±8.2% vs 51.3±7.9%, p=0.008) in the stretching group compared to the placebo stretching group with a trend towards a statistically greater change in smO 2 at minute 1 (Δ1: 39.0±7.3% vs 20.4±7.0%, p=0.06) (Image 2). Conclusion: Daily stretching of the calf muscles for 4 weeks is associated with increased oxygen extraction by the calf muscles during walking.

Introduction: An elevated blood pressure (mean arterial pressure, MAP) response to exercise is an independent predictor of hypertension (HTN) development. HTN is highly prevalent in postmenopausal females. Postmenopausal, compared to premenopausal, females have a higher MAP at rest and during exercise primarily due to higher systemic vascular resistance (SVR). Studies using small muscle mass exercise have suggested that postmenopausal females have augmented increases in MAP from rest to exercise. However, it is unclear if postmenopausal females have augmented MAP responses from rest to exercise during whole-body exercise. Hypothesis: We hypothesized that postmenopausal females would have greater increases in MAP and smaller decreases in SVR from rest to peak exercise than premenopausal females. Methods: Normotensive premenopausal (n=16; age: 30±7 yrs; BMI: 23±4 kg/m 2 ) and postmenopausal (n=14; age: 57±7 yrs; BMI: 27±4 kg/m 2 ) female participants performed an incremental cycling test until task failure. Blood pressure was measured by manual sphygmomanometry, cardiac output (Q) via open-circuit acetylene wash-in technique, and SVR was calculated. Data are reported at rest and peak oxygen uptake (VO 2 ). Data are also reported as % change from rest to VO 2 peak. Results: Postmenopausal females had higher MAP and SVR at rest and at VO 2 peak than premenopausal females (all, p<0.05). Postmenopausal, compared to premenopausal, females had lower Q at VO 2 peak commensurate with the lower achieved VO 2 peak (p<0.01). Resting MAP was positively related to MAP at VO 2 peak in postmenopausal females (r=0.85, p<0.01), but not premenopausal females (p=0.22). % change in MAP from rest to VO 2 peak was not different between groups (Post: 18±8 vs. Pre: 18±9%) (p=0.94). However, postmenopausal females had smaller % decreases in SVR from rest to VO 2 peak (Post: -44±7 vs. Pre: -54±8%) and smaller % increases in Q compared to premenopausal females (Post: 113±31 vs. Pre: 162±50%) (both, p<0.01). Conclusion: Our findings indicate that postmenopausal and premenopausal females have similar increases in MAP from rest to VO 2 peak; however, the mechanisms contributing to the MAP response differed by menopausal status. Postmenopausal females relied on smaller decreases in SVR, whereas premenopausal females had greater increases in Q. These findings provide important insight into the mechanisms contributing to the clinically relevant higher MAP response during exercise in postmenopausal females.