Citations

Objectives: Consensus clinical criteria for refractory septic shock were recently developed, but the incidence and outcomes with these criteria are unknown. There were two aims: 1) to describe the incidence of refractory septic shock and 2) to assess outcomes of patients with septic shock meeting refractory septic shock criteria compared with those who did not. Design: Multicohort, retrospective study. For aim 1, a descriptive epidemiologic study was designed to ascertain the cumulative incidence of refractory septic shock in patients with septic shock. For aim 2, a cohort study was conducted to compare hospital mortality between patients meeting refractory septic shock clinical criteria compared with those who did not. Setting: Large U.S. health system from 2012 to 2024. Patients: Adults (age ≥ 18 yr) meeting both Centers for Disease Control and Prevention Adult Sepsis Event and Sepsis-3 clinical criteria for septic shock. Patients with missing hospital discharge disposition and incomplete vasopressor dosage information were excluded. Interventions: None. Measurements and Main Results: Clinical criteria for refractory septic shock were operationalized as concomitant occurrence of norepinephrine (base) equivalent greater than 0.5 µg/kg/min and lactate greater than 2 mmol/L. Risk-adjusted hospital mortality was assessed with a generalized linear mixed-effects model with a random effect for hospital and fixed effects for age, sex, Elixhauser Comorbidity Index, and Sequential Organ Failure Assessment (original description, without cardiovascular component). Of 35,914 patients assessed, 15,732 patients with septic shock were included. Refractory septic shock occurred in 3423 patients (21.8%), with a cumulative incidence of 218 cases (95% CI, 211–224) per 1000 patients with septic shock. Hospital mortality with refractory septic shock was 64.4%, and risk-adjusted hospital mortality odds were 4.87-fold higher (95% CI, 4.46–5.31) compared with patients without refractory septic shock. Conclusions: Clinical criteria for refractory septic shock were fulfilled in about one in five patients with septic shock and associated with substantially higher mortality.

Background Invasive micropapillary carcinoma (IMPC) of the breast is associated with a high propensity for lymphovascular invasion and lymph node metastasis. However, whether chemotherapy is associated with improved survival outcomes in these patients remains unclear. Methods This retrospective study analyzed IMPC patients from the SEER database (2010–2018) (n=1,150) and an external validation cohort from Nanjing Drum Tower Hospital (n=199). Propensity score matching assessed chemotherapy’s impact on overall survival (OS) and breast cancer-specific survival (BCSS) in the SEER cohort. A risk stratification model was developed and validated using the external cohort. Results In the SEER cohort, chemotherapy was associated with significantly improved OS (HR = 0.517, 95% CI 0.293-0.910, P = 0.020) but not BCSS. A risk model incorporating marital status, tumor size, subtype, and radiotherapy history identified high- and low-risk groups. Chemotherapy was associated with significantly better OS only for high-risk patients (internal training cohort: HR = 0.577, 95% CI 0.349-0.952, P = 0.029; internal validation cohort: HR = 0.213, 95% CI 0.070-0.647, P = 0.003). External validation consistently confirmed poorer prognosis for high-risk patients (HR = 2.969, 95% CI 1.028-8.571, P = 0.035) and verified the model’s ability to identify patients with differential OS associations with chemotherapy: chemotherapy was associated with better OS in high-risk patients (HR = 0.163, 95% CI 0.031-0.868, P = 0.016), but not in low-risk patients (HR = 0.793, 95% CI 0.153-4.103, P = 0.782). Conclusions Chemotherapy was associated with improved prognosis particularly in high-risk patients with IMPC. However, chemotherapy decisions should be made cautiously for low-risk patients, taking into account a comprehensive assessment of clinical and pathological factors.

BACKGROUND: The EARLY TAVR trial (Evaluation of TAVR Compared to Surveillance for Patients with Asymptomatic Severe Aortic Stenosis) demonstrated that early transcatheter aortic valve replacement (TAVR) was superior to clinical surveillance (CS) in asymptomatic severe aortic stenosis. The relative impact of early TAVR versus CS strategy by age is unknown. METHODS: The study population of the EARLY TAVR trial was stratified into 4 age groups: 65 to 69 years (n=141), 70 to 74 years (n=263), 75 to 79 years (n=250), and ≥80 years (n=247). Associations between age and the trial primary end point of death, stroke, or unplanned cardiovascular hospitalization; the composite end point of death, stroke, or heart failure hospitalization; and its individual components were examined. Interaction tests evaluated whether the treatment effect of early TAVR versus CS differed by age. RESULTS: No interaction was detected between age and the treatment effect of early TAVR versus CS for the composites or individual outcomes. We observed lower stroke rates with early TAVR compared with CS in the youngest (65–69 years, absolute risk reduction, 13%; P =0.008) and oldest (≥80 years; absolute risk reduction, 12.3%; P =0.029) age groups. The absolute difference in heart failure hospitalization rates between the early TAVR and CS arms at 2 years was greatest in the oldest patients (≥80 years, 9.1%; 75–79 years, 5.9%; 70–74 years, 5.1%; 65–69 years, 4.4%). In the CS group, time to conversion to AVR was similar across all age groups (median, 11 months; P =0.73). Approximately one-third of younger patients (65–69 years) in the CS arm presented with acute valve syndrome at the time of conversion, the frequency of which tended to increase with age ( P =0.06). CONCLUSIONS: In the EARLY TAVR trial, the relative benefit of early TAVR over CS was consistent among all age groups. The greatest absolute reduction in stroke rate with early TAVR compared with CS appeared in the youngest and oldest groups, whereas reduction in heart failure hospitalization was most pronounced in the oldest patients. These data suggest that early TAVR should be considered in all age groups above 65 years. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03042104.

Abstract Background Wide-spread mast cell (MC)-associated symptoms and MC activation syndrome (MCAS) are often reported in patients with hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). The goal of this study was to develop a novel MC score based on 11 self-reported MC-related conditions with clinical and research utility to better understand MC symptoms in hEDS and HSD patients. Methods From November 1, 2019, to June 13, 2025, patients ( n =2,141) filled out an Intake Questionnaire at the Mayo Clinic Florida EDS Clinic that included 11 self-reported questions related to categories of MC-related conditions for a MC score ranging from 0/11 to 11/11. Based on the MC score distribution in hEDS and HSD patients, a MC score of 0-1 was considered a low MC score and ≥5 was considered a high MC score. Symptoms/comorbidities were compared between patients with high vs. low MC scores. Results From the 2,141 hEDS/HSD patients, 535 (25.0%) had a MC score ≥5 (Hi MC). MCAS-specific symptoms such as nausea and vomiting were reported more often in hEDS/HSD patients with a high vs. low MC score ( p <0.0001). Random clinical blood tryptase and urinary MC markers were not elevated in patients with high MC scores ( n =50/group), although high MC scores were found to significantly reduce urinary creatinine levels indicating that the protein used to normalize data was affected by MC activity. In contrast, random blood IgE, tryptase and major basic protein (MBP) by ELISA were increased in patients with high MC scores (e.g., IgE hEDS p =0.0004, HSD p =0.003). Of note, the percentage of patients reporting abuse or post-traumatic stress disorder was nearly doubled in patients with high vs. low MC scores (Abuse and PTSD: hEDS p < 0.0001; HSD p < 0.0001). Overall, 109/135 (80.7%) in hEDS and 129/135 (95.6%) in HSD reported more symptoms/comorbidities if they had a high MC score. Conclusions We found that hEDS/HSD patients with high MC scores self-reported more widespread symptoms/comorbidities and higher MC-related blood markers than patients with low MC scores indicating the utility of this tool to evaluate the level of widespread MC activity in hEDS, HSD and other patients.

Background Marfan syndrome (MFS) is associated with progressive aortic and valvular disease requiring cardiac surgery, but contemporary data on repeat cardiac operations in adults remain limited. Methods We performed a retrospective multicentre cohort study of 783 adults with MFS evaluated across three Mayo Clinic sites. Cardiac operations, postoperative complications, echocardiographic findings and redo sternotomy events were identified by chart review. Multivariate logistic regression was used to evaluate factors associated with redo sternotomy. Results Overall, 454 patients (58.0%) underwent at least one cardiac operation, and 185 patients (23.6% of the total cohort; 41.0% of operated patients) required redo sternotomy. The most common procedures were aortic root intervention (53.4%), aortic valve intervention (39.6%), mitral valve intervention (16.1%) and tricuspid valve intervention (2.6%). Valvular abnormalities were frequent, including mitral regurgitation (51.5%), mitral valve prolapse (41.1%), tricuspid regurgitation (44.6%) and aortic regurgitation (28.5%). Major postoperative complications occurred in 15.3% of patients. On multivariate analysis, hypertension (OR 2.39, 95% CI 1.54 to 3.72), emergent initial operation (OR 3.38, 95% CI 1.97 to 5.80) and postoperative complications (OR 2.59, 95% CI 1.58 to 4.27) were independently associated with redo sternotomy, whereas repair extending beyond the aortic root was associated with lower odds (OR 0.39, 95% CI 0.29 to 0.53). Conclusion In this large multicentre cohort of adults with MFS, cardiac surgery was common, and redo sternotomy occurred frequently among operated patients. These findings provide a contemporary description of the long-term need for cardiac surgery in adults with MFS managed at tertiary referral centres.

Objective Glaucoma and cancer are debilitating diseases with increasing global prevalence and morbidity. However, current literature lacks a systematic consolidation of their relationships and interactions. This systematic review aims to (A) summarize the association between intraocular/non-ocular cancers and their treatments with the prevalence and etiology of glaucoma, (B) explore glaucoma as a risk factor for complications or poor prognosis for intraocular cancer, and (C) explore the management of glaucoma secondary to cancer therapies. Methods A systematic search was performed from inception to July 2025 across three databases with variants of ‘cancer’ and ‘glaucoma’ as search terms. Findings were narratively synthesized. Results Of 8,103 identified studies, 44 were included in this review. Eighteen studies reported increased glaucoma prevalence amongst intraocular and non-ocular cancer patients. Fifteen studies suggested increased risk of regional invasion, metastases, and high-risk histopathologies when intraocular cancers co-occurred with glaucoma. Corticosteroids in cancer therapy have been linked to intraocular pressure (IOP) elevation, while androgen deprivation therapy was associated with lowered glaucoma risk. Conclusion Given the relationship between glaucoma and intraocular/non-ocular cancers, strategies to monitor and manage glaucoma risk following cancer diagnosis and/or therapy may be considered. Glaucoma may be an early sign of complications in intraocular cancers.

Abstract Nonmyeloablative-related haploidentical allogeneic stem cell transplantation (NMAC-HID allo-HSCT) has emerged as an additional treatment to achieve durable remission in sickle cell disease (SCD), a prevalent blood disorder characterized by painful vaso-occlusive crises and chronic anemia. The standard of care (SOC) for SCD includes hydroxyurea, pain management, and blood transfusion, but patients with SCD still lose several decades of life expectancy. Gene therapy (GT) for SCD is the other treatment for lifelong disease amelioration in SCD, with accessibility limited by cost and manufacturing capacity in the United States and globally. Two recent prospective studies that evaluated NMAC-HID allo-HSCT validated haploidentical allotransplantation as an efficacious and accessible treatment option in the era of GT. Given the ongoing price negotiation across jurisdictions for GT implementation and the absence of cost-effectiveness data comparing NMAC-HID allo-HSCT and GT, we conducted a cost-effectiveness analysis of NMAC-HID allo-HSCT vs GT vs SOC for adults and children living with SCD. The primary outcomes were the incremental cost-effectiveness ratio and the net monetary benefits across these 3 strategies. The secondary outcome was the maximum cost-effective threshold price for GT compared with NMAC-HID allo-HSCT. Treatment with SOC, NMAC-HID allo-HSCT, and GT accrued 14.3, 20.1, and 22.1 quality-adjusted life-years at costs of $1.22 million, $1.15 million, and $2.75 million, respectively. NMAC-HID allo-HSCT was the cost-effective strategy compared with GT in 100% of 10 000 Monte Carlo iterations across the base case and all scenario analyses. The maximum cost-effective thresholds for GT vs SOC were $1.4 million in the United States and $4200 to $22 000 across India, Nigeria, and Tanzania, depending on willingness-to-pay thresholds.

Ziftomenib - a potent, selective, oral menin inhibitor - is approved as monotherapy for adults with relapsed/refractory (R/R) NPM1-mutated acute myeloid leukemia (NPM1-m AML). The KOMET-007 phase 1 trial investigated clinical activity and tolerability of ziftomenib in combination with standard therapies for R/R and newly diagnosed AML. Here, we report outcomes of adults with R/R NPM1-m AML treated with ziftomenib plus venetoclax/azacitidine. In phase 1a, patients received ziftomenib 200, 400, or 600 mg once daily with standard doses of venetoclax/azacitidine. In phase 1b, ziftomenib 600 mg was selected for expansion. Sixty-seven patients were treated (27 phase 1a; 40 phase 1b). Median age was 66 years, and 55% were men. Median number of prior therapies was 1 (range 1-8); 55% received prior venetoclax and 22% had prior transplantation. Most common (≥20%) grade ≥3 treatment-emergent adverse events were leukopenia (34%), thrombocytopenia (28%), febrile neutropenia and neutropenia (25% each). Six patients developed QTc prolongation (1 ziftomenib-related; grade 1), and 2 experienced differentiation syndrome (grade 3); all events were successfully managed. In patients receiving ziftomenib 600 mg, composite complete remission (CRc) rate was 46% (22/48), with 67% (12/18) achieving central measurable residual disease (MRD) negativity (&lt;0.01% threshold). In venetoclax-naïve and -exposed patients, CRc rates were 70% (16/23) and 24% (6/25), with MRD-negativity rates of 75% (9/12) and 50% (3/6), respectively. Median duration of response was 8.6 months, and median overall survival was not reached. The combination of ziftomenib 600 mg with venetoclax/azacitidine was well tolerated with deep and durable clinical activity in R/R NPM1-m AML. This trial was registered at www.ClinicalTrials.gov as #NCT05735184.

Objective The United Nations defines sustainability as meeting needs of the present without compromising future generations. While often equated to “saving the planet”, sustainability is a diverse topic. Healthcare generates &gt;5% of CO 2 emissions worldwide, yet sustainability efforts in urology are limited. The North Central Section of the American Urological Association (NCSAUA) recently convened a Sustainability Task Force to address this topic. This study queried members on sustainability in urologic practice. Methods Following literature review on sustainability in surgery/urology, a 19-item anonymous REDCap survey was developed and distributed via email to NCSAUA members (N = 1607). The survey assessed current best practice, institutional/personal sustainability, and demographics. Responses were compiled and summarized using descriptive statistics. Results Survey response rate was 4.9% (79/1607). Respondents were most commonly from metropolitan areas (82%), male (71%), and in practice for 5–14 years (29%). Sustainability topics were prioritized as: (1) financial, (2) future workforce, (3) environmental. Over half (56%) reported no institutional sustainability programs or were unaware of them. Instrument (67%), computer (68%), and paper (65%) recycling were supported by a majority of respondents. However, only 28% and 29% of respondents reported current institutional use of instrument and computer recycling, respectively. Telemedicine was infrequent, with most urologists (58%) conducting 0-5% of visits virtually. Conclusions Current institutional and urologic practice emphasis on sustainability is low. Respondents ranked highest sustainability priorities as financial and future workforce. Efforts to address environmental sustainability were also supported, namely reduction of disposables and waste. The findings support the development of targeted programs to advance sustainability priorities widely.

Abstract Background Ionizing radiation (IR) accelerates atherosclerosis through induction of cellular senescence, DNA damage, defective efferocytosis, and dysregulation of clonal hematopoiesis (CH) drivers. Although low-dose colchicine reduces ischemic cardiovascular events in coronary artery disease, the precise molecular mechanisms underlying its vasculoprotective effects remain incompletely defined, and whether it mitigates radiation-associated vascular injury is unknown. Methods Bone marrow–derived macrophages (BMDMs) were pretreated with low-dose colchicine and exposed to 2 Gy IR. Molecular effects were assessed by RNA-seq, immunoblotting, and molecular docking. In vivo effects were tested in a partial carotid ligation (PLCL) model using spatial proteomics. Human monocyte-derived macrophages (HMDMs) from thoracic malignancy patients were analyzed before and after radiation therapy (RT). Results Low-dose colchicine suppressed IR-induced macrophage senescence signaling while preserving NRF2 activity. In a cell-free assay, colchicine directly activated aldehyde dehydrogenase 2 (ALDH2) in a dose-dependent manner (EC 50 1–5 nM), identifying ALDH2 as a direct molecular target of colchicine. Following irradiation, colchicine restored ALDH2, reduced mitochondrial (mt)ROS - dependent p90 ribosomal S6 kinase ( p90RSK ) activation and lipid peroxidation, preserved TET2 and DNMT3A expression, and rescued impaired efferocytosis while preventing nicotinamide adenine dinucleotide (NAD⁺) and adenosine triphosphate (ATP) depletion. These protective effects were ALDH2-dependent, as they were lost with ALDH2 inhibition or depletion and were mimicked by pharmacologic ALDH2 activation. In vivo, colchicine attenuated radiation-induced atherosclerosis and macrophage senescence-associated stemness (SAS). Consistently, macrophages from patients after RT showed reduced ALDH2 with increased mtROS, lipid peroxidation, and senescence. Conclusion These findings identify ALDH2 as a previously unrecognized molecular target of colchicine that links mitochondrial redox control to suppression of radiation-induced macrophage senescence and atherosclerosis and may contribute to the efficacy of low-dose colchicine in cardiovascular disease.