Citations

Background: Cytokine release syndrome (CRS) is a life-threatening systemic inflammatory condition marked by excessive cytokine production, leading to multi-organ dysfunction. It is commonly associated with T-cell-engaging therapies such as chimeric antigen receptor (CAR) T cells, T-cell receptor bispecific molecules, and monoclonal antibodies. Carfilzomib, a proteasome inhibitor, is known to cause a range of adverse effects, primarily hematologic and cardiovascular. However, multiorgan failure grade 5 (fatal), resembling CRS has not been previously reported in association with Carfilzomib. Case Report: A 74-year-old male with relapsed multiple myeloma developed grade 5 multiorgan failure 60 min after the third dose of Carfilzomib, resulting in death within 24 h of symptom onset. The patient tolerated the first doses of Carfilzomib well with only fever and headache developing post infusion. Before the second dose, the patient developed worsening pancytopenia, prompting the discontinuation of Lenalidomide. After the second Carfilzomib infusion, he experienced fever and transient encephalopathy, which resolved with acetaminophen, corticosteroids, and supportive care. However, following the third dose, he rapidly deteriorated—developing fever, tachycardia, hypotension, hypoxia, and encephalopathy. Despite aggressive management with intravenous fluids, broad-spectrum antibiotics, corticosteroids, and tocilizumab, the patient progressed to refractory shock and multi-organ failure, culminating in death within 24 h. A comprehensive infectious workup was negative, ruling out sepsis and suggesting possible Carfilzomib-induced CRS. Conclusion: Grade 5 multiorgan failure with signs and symptoms similar with CRS following Carfilzomib administration is a rare but potentially fatal adverse drug reaction. Further research is needed to better define the risk factors and optimal management strategies for Carfilzomib-induced multiorgan failure and possible CRS.

Obstructive sleep apnea (OSA), a sleep disorder that is associated with exposure to repeated bouts of hypoxia overnight. Evidence suggests that the oxyhemoglobin dissociation curve (ODC) may be shifted rightward with OSA. Nitric oxide (NO) functions as an allosteric regulator of hemoglobin oxygen-binding properties, possibly shifting the ODC curve leftward. Nitrate/nitrite supplementation increases NO bioavailability and attenuates the physiological responses to hypoxia which may be due to changes in the ODC. Therefore, we explored the hypothesis that dietary nitrate supplementation improves oxygen re-saturation following inspiratory hypoxia in subjects with OSA. Fourteen subjects with untreated mild-moderate OSA (53 ± 10yr, 8M/6F; Apnea-hypopnea Index, 17.8 ± 8.1 events) completed two separate study visits. Each visit consisted of two hypoxic bouts separated by ~2 hours and the consumption of one of two beetroot juice beverages (Placebo [BR P ] containing 5-10 mg nitrate, no detectable nitrite, or Active [BR A ] containing 500mg nitrate and 40mg nitrite). For each hypoxia bout, subjects’ pulse oxygen saturation (%SpO 2 ) was titrated to ≤80% over 3-5min by blending a 10% FiO2 gas cylinder with room air. Once ≤80% SpO 2 was achieved, subjects inhaled normoxic room air (~21% FiO2) and oxygen saturation was monitored until SpO 2 returned to baseline (recovery). During recovery, SpO 2 was averaged into 5 sec bins from the end of hypoxia (nadir) up to +15 SpO 2 % above nadir. The ‘hypoxic load’ during recovery was calculated as ( i =1 ∑ n ∣Value i −nadir+15∣) and reflects a total sum of each 5 sec bin ( n ). BR A increased plasma nitrite (248 ± 155 to 738 ± 427nM, P < 0.05), whereas there was no change following BR P (266 ± 153 to 277 ± 164nM, P = 0.87). The level of desaturation (SpO 2 nadir) at the end of hypoxia did not differ within or between trials (BR A : Pre 78 ± 2 vs. 78 ± 3; BR P : Pre 78 ± 2 vs. 78 ± 2, condition x time interaction P = 0.21). Hypoxia load increased following BR P (162.7 ± 36.6 vs. 231.8 ± 65.7, P < 0.001), but was unchanged following BR A (174.3 ± 54.2 vs. 191.2 ± 52, P = 0.32). In summary, our study suggests that acute nitrate supplementation may cause a leftward shift in the ODC in patients with untreated OSA. This is supported by a reduced hypoxic load following a repeat bout of inspiratory hypoxia. These findings may have implications for the health of patients with OSA. Foundation for the National Institutes of Health, K12 AR084222 (Joshua Bock) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

INTRODUCTION: The increased likelihood of adverse cardiovascular events (CVE) shortly after awakening has been partially attributed to low nitric oxide (NO) production in the early morning. Thus, increasing early morning NO levels to improve vascular function could reduce adverse CVE incidence, especially among older adults as total NO production declines with aging. The increased adverse CVE among post-menopausal women (PMW) are likely due to a steeper decline in their vascular function. As inorganic nitrate increases circulating NO levels for up to 12hrs, our primary hypothesis was to determine if nocturnal inorganic nitrate supplementation improves early morning vascular function relative to a placebo in eight generally healthy adults (6F, 37±5yrs, 26.9±1.8kg/m 2 ). Our secondary hypothesis was that PMW (n=3, 27.1±4.3kg/m 2 ), identified by their age (71±2yrs) and follicle-stimulating hormone levels (72.3±8.0mIU/mL), would show greater improvements in their vascular function compared to younger participants (n=5, 3F, 28±2yrs, 26.8±2.0kg/m 2 ). METHODS: Written informed consent was obtained from all participants before data collection. Participants completed three overnight study visits: Visit 1 was for acclimation with vascular function assessments occurring during Visits 2 and 3. During the latter visits, participants consumed beetroot juice with (6.45mmol) or devoid of (0mmol) inorganic nitrate at 2200 in randomized, cross-over fashion followed by vascular function assessments post-awakening (0630-0800) while participants were supine. Vascular assessments consisted of brachial blood pressure, aortic augmentation index (AIx), carotid-femoral pulse wave velocity (cfPWV), and endothelial function (FMD). Data were compared using a paired-samples t-test (α<0.05). RESULTS: Systolic (125±4 vs. 126±6mmHg, p=0.35) and diastolic (71±2 vs. 72±2mmHg, p=0.32) blood pressure were similar the morning after nitrate and placebo. Additionally, AIx (31±5 vs. 33±6%, p=0.29) and FMD (n=7, 8.8±2.0 vs. 7.6±1.7%, p=0.25) were not different the morning after nitrate and placebo consumption. However, cfPWV was lower the morning following nitrate consumption relative to the placebo (6.3±0.5 vs. 6.9±0.6m/s, p=0.01). A sub-group analysis of PMW showed that both systolic (132±6 vs. 139±9mmHg, p=0.18) and diastolic (70±3 vs. 75±2mmHg, p=0.09) blood pressure tended to be lower following nitrate relative to the placebo whereas AIx (46±1 vs. 50±5%, p=0.31) and FMD (n=2, 8.5±2.7 vs. 6.9±1.6%, p=0.78) did not differ; however, cfPWV was lower the morning after nitrate consumption (7.4±0.9 vs. 8.4±1.1m/s, p=0.02) in PMW but not in the younger participants (5.6±0.4 vs. 6.0±0.3m/s, p=0.23). CONCLUSION: Acute nocturnal inorganic nitrate supplementation lowers aortic stiffness in the early morning, especially among PMW. Although the differences in systolic (7mmHg) and diastolic blood pressure (5mmHg) were not statistically significant, they remain clinically meaningful due to their magnitude. This may suggest a role for nocturnal nitrate supplementation in reducing early-morning adverse CVE among PMW. AHA 24POST1241616 (IMG), NIH K12 AR084222 (JMB), Sleep Research Society 038-JP-23 (JMB), and a grant from Sleep Number Corporation to Mayo Clinic for studies in Aging. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Background: In the emergency setting, many diagnostic pathways incorporate change in high-sensitivity cardiac troponin (hs-cTn) concentrations (i.e., the delta) to classify patients as low-risk (rule-out) or high-risk (rule-in) for possible myocardial infarction (MI). However, the impact of analytical variation on the delta for correct classification is unknown, especially at concentrations below and around the 99th percentile. Our objective was to assess the impact of delta variation for correct risk classification across the European Society of Cardiology (ESC 0/1 h and 0/2 h), the High-STEACS, and the common change criteria (3C) pathways. Methods: A yearlong accuracy study for hs-cTnT was performed where laboratories across Canada tested three patient-based samples (level 1 target value = 6 ng/L, level 2 target value = 9 ng/L, level 3 target value = 12 ng/L) monthly across 41 different analyzers. The assigned low-delta between levels 1 and 2 was 3 ng/L (i.e., 9 − 6 = 3 ng/L) and the assigned high-delta between levels 1 and 3 was 6 ng/L (i.e., 12 − 6 = 6 ng/L). The low- and high-deltas for each analyzer were determined monthly from the measured values, with the difference calculated from the assigned deltas. The obtained deltas were then assessed via the different pathways on correct classification (i.e., percent correct with 95% confidence intervals, CI) and using non-parametric analyses. Results: The median (interquartile range) difference between the measured versus assigned low-delta (n = 436) and high-delta (n = 439) was −1 ng/L (−1 to 0). The correct classification differed among the pathways. The ESC 0/1 h pathway yielded the lowest percentage of correct classification at 35.3% (95% CI: 30.8 to 40.0) for the low-delta and 90.0% (95% CI: 86.8 to 92.6) for the high-delta. The 3C and ESC 0/2 h pathways yielded higher and equivalent estimates on correct classification: 95.2% (95% CI: 92.7 to 97.0) for the low-delta and 98.2% (95% CI: 96.4 to 99.2) for the high-delta. The High-STEACS pathway yielded 99.5% (95% CI: 98.4 to 99.9) of correct classifications for the high-delta but only 36.2% (95% CI: 31.7 to 40.9) for the low-delta. Conclusions: Analytical variation will impact risk classification for MI when using hs-cTn deltas alone per the pathways. The 3C and ESC 0/2 h pathways have <5% misclassification when using deltas for hs-cTnT in this dataset. Additional studies with different hs-cTnI assays at concentrations below and near the 99th percentile are warranted to confirm these findings.

Abstract NF-κB signaling can be subdivided into canonical and noncanonical pathways, culminating in the transcriptional activity of RELA and RELB, respectively. However, the upstream signals that activate these transcription factors and their specific regulatory roles in pancreatic ductal adenocarcinoma (PDAC) remain incompletely understood. Here, we demonstrate that TNFα is the primary activator of canonical NF-κB signaling via RELA, while TWEAK engages noncanonical signaling through RELB in PDAC. Using transcriptome-wide gene expression, genome-wide occupancy profiling, and epigenome mapping, we delineate distinct temporal dynamics and regulatory activities of each pathway. Single-cell RNA-seq analysis and multiplex immunofluorescence staining in primary PDAC samples further reveal extensive and distinct interactions with components of the tumor microenvironment. Motif analysis of RELA- and RELB-bound regions uncovers a particularly strong association of RELB with AP1 elements. Notably, while RELA binds to both open and closed chromatin, RELB exclusively occupies regions with pre-existing chromatin accessibility and AP1 co-binding. Collectively, these findings underscore the distinct and complementary roles of TNFα and TWEAK in PDAC, with TNFα engaging a broader transcriptional program via RELA and TWEAK selectively targeting genes marked by accessible chromatin and epigenetic activity. This study provides critical insights into the regulatory dynamics of NF-κB signaling in PDAC, highlighting unique and complementary functions of RELA and RELB in modulating downstream gene expression. Significance TNFα and TWEAK selectively activate RELA and RELB in pancreatic cancer, revealing that RELB-driven noncanonical signaling depends on chromatin accessibility and AP-1, uncovering distinct, targetable epigenetic dependencies from canonical signaling. Graphical abstract

Somali Americans, originating from East Africa, are a fast-growing minority in the United States. Emerging data suggest Somali individuals exhibit increased cardiovascular (CV) risk compared to non-Hispanic White adults. Previous data from our laboratory demonstrated elevated ambulatory arterial stiffness in Somali Americans, as derived from 24-hour blood pressure monitoring. We sought to confirm these vascular stiffness findings via gold-standard applanation tonometry and examine potential sex differences, given that females of African ancestry are at elevated risk of CV disease (CVD). We therefore examined aortic hemodynamics and carotid-femoral pulse wave velocity in male and female Somali Americans. We hypothesized that female Somali Americans would present with greater aortic wave reflection and arterial stiffness compared to males. We further examined the accuracy of prediction of aortic wave reflection from a predominantly White population, when applied to the Somali American population. We utilized applanation tonometry to quantify arterial stiffness in 24 female (age: 27±10 years, BMI: 27±6 kg/m 2 ) and 19 male (age: 22±6 years, BMI: 27±5 kg/m 2 ) Somali Americans without CVD. Each participant arrived in the laboratory at Mayo Clinic, fasted for at least three hours, and did not consume caffeine or exercise for at least 12 hours prior to testing. After 15 minutes of supine rest, duplicate recordings of aortic blood pressure and augmentation index (AIx) were obtained via pulse wave analysis. Similarly, aortic stiffness was quantified via duplicate carotid-femoral pulse wave velocity recordings. Statistical analysis included independent samples t-tests to test for sex differences in aortic hemodynamics, and paired samples t-tests to determine differences between estimated and obtained AIx (α≤0.05). Aortic systolic arterial pressure (111±11 vs. 108±7 mmHg, p=0.295) was similar between female and male Somali Americans. Aortic diastolic arterial pressure (75±7 vs. 67±7 mmHg, p<0.001) and heart rate (67±9 vs. 57±7 beats/min, p<0.001) were higher in female Somali adults. Similarly, AIx (28±14 vs. 19±12%, p=0.045) and AIx normalized to 75 heart beats/minute (24±13 vs. 10±13%, p=0.001) were higher in female Somali Americans. Carotid-femoral pulse wave velocity (5.4±0.9 vs. 5.5±0.8 m/s, p=0.661) was similar between sexes. Estimated AIx (corrected for sex, age, height, and resting heart rate) was markedly lower than observed AIx in both female (13±7 vs. 28±14%, p<0.001) and male (6±5 vs. 19±12%, p<0.001) Somali Americans. These findings, obtained in young, healthy Somali adults are suggestive of elevated CVD risk, evident at an early age. These data are particularly concerning regarding vascular dysfunction in Somali females and suggest that prediction models for arterial stiffness should factor in race to optimize performance. Future work into mechanisms underlying vascular dysfunction in Somali Americans is warranted. Sleep Number Grant to Mayo Clinic and by NIH R01-HL160619, R01-HL169320, T32-DK007013, K12 AR084222, and AHA 24POST1241616. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Study Design: Single-center retrospective cohort study. Objective: To determine if the 4-rod construct (4RC) is protective against the occurrence of rod fractures when compared with the 3-rod construct (3RC) in adult spinal deformity (ASD) patients with long fusions to the sacrum. Summary of Background Data: Past studies have explored the different outcomes in subjects with dual-rod versus multirod constructs. There is a lack of literature distinguishing the ramifications of 3RC versus 4RC, particularly in the prevalence of rod fractures and rod fractures requiring subsequent revision surgery as a result of pseudarthrosis. Methods: ASD patients undergoing long instrumented fusions to the sacrum were dichotomized between the 3RC and 4RC cohorts. Outcomes of interest include the occurrence of rod fractures (RFs) and RFs requiring revision (RFR). Two-tailed independent-sample t test with Welch's correction and χ 2 /Fisher exact test were used for continuous and categorical variables, respectively. Multivariable logistic regression analysis was performed to assess whether the 4RC is protective against rod fractures when compared with the 3RC. Results: One hundred forty-five patients with a minimum 2-year follow-up were included (3RC=57, 4RC=88). Four RC had a greater body mass index (BMI) ( P =0.002), longer operating room (OR) time ( P =0.002), greater estimated blood loss (EBL) ( P =0.002), total instrumented levels (TIL) ( P =0.028), and more 3-column osteotomies (3COs) performed ( P =0.028). Four RC had greater baseline coronal vertical axis (CVA) (28.2±24.9 vs. 18.5±16.9 mm, P =0.006) and sagittal vertical axis (SVA) (55.1±64.8 vs. 30.4±41.8 mm, P =0.006). Three RC had a greater rate of RF (28.1% vs. 14.8%, P =0.0506) and RFR (14.9% vs. 10.2%, P =0.486) when compared with 4RC, but these findings were not statistically significant. After controlling for BMI, the use of 3-column osteotomies, total instrumented levels, change in coronal alignment (∆CVA), change in sagittal alignment (∆SVA), use of bone morphogenetic protein, and number of interbody fusions, 3RC was associated with 4.93× greater odds of experiencing RFs ( P =0.0078). However, significance fell short when adjusting for the occurrence of RFR [OR=2.58 (0.60–11.19), P =0.2067]. Conclusion: ASD patients having long fusions to the sacrum with 4RC across the lumbosacral junction are shown to be at lesser risk of developing rod fractures but not revision surgery as compared with 3RC at 2-year follow-up.

Background: Patient-level value analysis (PLVA) has been applied to several orthopaedic procedures but has not yet been utilized to assess the value of total knee arthroplasty (TKA). The purpose of this study was to evaluate the 1-year episode of care for TKA with use of PLVA to identify characteristics that influence value at both the patient and surgeon level. Methods: The institutional patient-reported outcome (PRO) database was queried for all patients who underwent TKA from 2020 to 2022. Patients were excluded on the basis of an index revision procedure, a pathology other than primary osteoarthritis, unicompartmental knee arthroplasty, robotic-assisted TKA, incomplete baseline or 1-year PROs, concomitant procedures (i.e., bilateral TKA or hardware removal), complications requiring readmission or reoperation, TKA without patellar resurfacing, the use of constrained implants, incomplete cost information, or other hip or knee arthroplasty procedure during the 1-year episode of care. PROs of interest included preoperative and 1-year postoperative Knee injury and Osteoarthritis Outcome Score-Joint Replacement (KOOS-JR) scores. Episode-of-care costs were calculated using time-driven activity-based costing. The 1-year value quotient (V KOOS ) was calculated for each patient as the ratio of the 1-year change in KOOS-JR score to the total episode-of-care cost. Results: A total of 684 patients (62% female; mean age, 68 ± 8 years) met the inclusion criteria. The mean KOOS-JR score significantly increased from baseline (53 ± 11) to 1 year (79 ± 14; p < 0.001), with a mean improvement of 26 ± 16. The mean total episode-of-care cost was $9,563 ± $2,370. There was no significant correlation between episode-of-care costs and the change in KOOS-JR score (r = 0.02; p = 0.581). Surgery performed at an ambulatory surgery center (p < 0.001) and as an outpatient procedure (p = 0.036) were predictive of lower costs. Patient-specific instrumentation (p < 0.001) and a tibial stem extension (p < 0.001) were predictive of higher costs. Older age (p = 0.023) and male sex (p = 0.007) were predictive of less improvement in KOOS-JR scores from baseline to 1 year. Conclusions: Our study identified patient and surgical characteristics that drive costs and PROs in TKA. PLVA can be used to identify “bright spots” in orthopaedic procedures to optimize care delivery. Level of Evidence: Prognostic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Abstract Aims Oxygen consumption at peak exercise is widely used to assess functional impairment in heart failure with preserved ejection fraction (HFpEF), but few patients exercise to this intensity in daily living. Alternative metrics that quantify submaximal fitness may provide more patient-centred evaluations, but the pathophysiology of submaximal exercise intolerance in HFpEF is unexplored. Methods and results Patients with HFpEF underwent invasive haemodynamic cardiopulmonary exercise testing with blood lactate measurement during exercise to volitional fatigue. Lactate threshold (LT) was defined as the exercise workload at which arterial lactate exceeded &gt;2.0 mmol/L, taken as a measure of submaximal fitness. Of patients with HFpEF (n = 286), 194 (68%) reached LT at a workload of 40 W or less (LT ≤40 W), while 92 (32%) reached a workload exceeding 40 W at LT (LT &gt;40 W). As compared to LT &gt;40 W, patients with LT ≤40 W were more likely to be female, anaemic, and had greater pulmonary vascular disease (all p &lt; 0.01). During 20 W exercise, participants with LT ≤40 W had higher pulmonary artery pressure, biventricular filling pressures, minute ventilation and respiratory drive, higher perceived dyspnoea and fatigue ratings, greater arterial–venous oxygen content difference, despite similar cardiac output and oxygen delivery. At peak exercise, most of these differences were no longer apparent. Findings were replicated using non-invasively-measured workload at ventilatory threshold. Conclusions Two-thirds of patients with HFpEF reach LT at workloads typical of activities of daily living. Patients with HFpEF and impaired submaximal fitness are more likely to be female, have greater pulmonary vascular disease and anaemia severity, and display greater haemodynamic, symptomatic, and ventilatory control abnormalities during low-level exercise, which are not apparent at maximal exertion. These findings have therapeutic implications and suggest a potentially important role for wider evaluation of submaximal fitness in addition to peak aerobic capacity.