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Importance The choice of induction agent during rapid sequence intubation (RSI) of critically ill adults may affect clinical outcomes. Although ketamine and etomidate are frequently used for RSI, their comparative effectiveness remains controversial. Objective To compare the safety of etomidate vs ketamine for emergency RSI in critically ill adults. Design, Setting, and Participants This cohort study used a target trial emulation with observational data collected between March 1, 2022, and April 30, 2024, from 18 emergency departments across Brazil, with data from the Brazilian Airway Registry Cooperation. Adults who underwent RSI and received either etomidate or ketamine as a sole hypnotic agent were included; those with preintubation cardiac arrest or immediate postintubation transfer were excluded. Exposure Administration of etomidate or ketamine as the induction agent for RSI. Main Outcomes and Measures The primary outcome was 28-day in-hospital mortality. Secondary outcomes included 7-day in-hospital mortality, first-attempt intubation success, and major adverse events (new hemodynamic instability, severe hypoxemia, and cardiac arrest) within 30 minutes after intubation. Inverse probability of treatment weighting was used to adjust for confounding. Risk ratios (RRs) and risk differences (RDs) with 95% CIs were used to compare outcomes between groups. Results Among 1810 patients (median age, 64 years [IQR, 50-74 years]; 1048 men [57.9%]), 514 received ketamine and 1296 received etomidate. The median shock index was higher in the ketamine group than the etomidate group (0.81 [IQR, 0.65-1.01] vs 0.76 [IQR, 0.59-0.99]), and preintubation vasopressor use was more common in the ketamine group than the etomidate group (191 of 514 [37.2%] vs 391 of 1296 [30.2%]). Weighted 28-day mortality was higher with etomidate than ketamine (60.5% [95% CI, 57.2%-63.8%] vs 54.4% [95% CI, 45.0%-63.9%]; RR, 1.14 [95% CI, 1.03-1.27]; RD, 7.6% [95% CI, 2.0%-13.3%]). Seven-day mortality was also higher with etomidate than ketamine (35.2% [95% CI, 32.0%-38.3%] vs 30.1% [95% CI, 23.5%-36.7%]; RR, 1.19 [95% CI, 1.04-1.35]). New hemodynamic instability within 30 minutes after intubation was more frequent with ketamine (24.2% [95% CI, 20.4%-28.0%] vs 18.9% [95% CI, 16.7%-21.0%]; RR, 0.78 [0.64-0.95]). There were no statistically significant differences in the other secondary outcomes. Conclusions and Relevance In this cohort study of critically ill adults undergoing RSI, etomidate use was associated with higher in-hospital mortality at 7 and 28 days compared with ketamine. These findings highlight the need for definitive randomized clinical trials to compare both agents.

Background: Carriers of a pathogenic variant (PV) in BRCA1 face a high risk of breast cancer. This study estimated the risk of developing breast cancer according to mutation type and location. Methods: BRCA1 carriers with no personal history of breast cancer or bilateral mastectomy were included. Detailed information on clinical and family history was collected by questionnaire. Survival analysis was used to estimate 15-year cumulative risk according to PV type and location. Results: A total of 3677 BRCA1 carriers were followed for a mean of 7.2 years (range 0.1–15.0 years); 481 incident breast cancers were documented. Overall, the 15-year cumulative incidence was 25%. Risk estimates varied by exon, ranging from 9% (exon 21) to 19% (exon 12) to 36% (exon 15); however, strata were small. Carriers of four founder mutations common in Eastern Europe (c.5263_5264insC, c.181T > G, c.66_67delAG and c.4034delA) experienced a lower-than-expected cancer risk (15.9–24.4%) compared to other PVs (28.8%) (p = 0.02). Conclusions: Although our data suggests some variability in penetrance based on specific BRCA1 PV, this was based on a large number of founder mutations. Breast cancer management strategies should continue to be based on comprehensive risk assessment.

Abstract Background Women with a pathogenic variant in BRCA1 or BRCA2 are at high risk of developing ovarian cancer, and it is often recommended that they undergo bilateral salpingo-oophorectomy at an early age, resulting in surgical menopause. Menopausal hormone replacement therapy (HRT) is an effective way to mitigate the adverse outcomes of early menopause; however, the safety of menopausal HRT on breast cancer risk in this population has not been established. Methods We conducted a prospective matched analysis of HRT use following menopause and breast cancer risk in BRCA carriers. Women who initiated HRT were matched one-to-one with women who had not initiated menopausal HRT by gene, year of birth, and age at menopause, resulting in 676 matched pairs. Menopausal HRT use collected by questionnaire included formulation and mode of administration. Results After a mean of 5.6 years, there were 87 (12.9%) incident breast cancer cases in the 676 exposed women and 128 (18.9%) cases in the 676 unexposed women (P = .002). Compared with unexposed matched control individuals, women who used estrogen alone experienced a statistically significantly decreased risk of breast cancer (hazard ratio = 0.37, 95% CI = 0.24 to 0.57). No protective or adverse effect was associated with the use of estrogen plus progestogen (hazard ratio = 0.94, 95% CI = 0.54 to 1.63). Conclusions Our findings suggest no substantial increase in the risk of breast cancer in BRCA carriers with the use of HRT and that estrogen alone might be protective.

PURPOSE Venetoclax, an oral BCL-2 inhibitor, has efficacy in t(11;14)-positive relapsed/refractory multiple myeloma (RRMM), which is enhanced by dexamethasone, which promotes BCL-2 dependency. METHODS The randomized, open-label, phase III CANOVA study (ClinicalTrials.gov identifier: NCT03539744 ) enrolled adults with t(11;14)-positive RRMM who had received ≥2 previous lines of therapy. Patients were randomly assigned (1:1) to venetoclax-dexamethasone or pomalidomide-dexamethasone until progression or intolerable toxicity. The primary end point was independent review committee assessed–progression-free survival (PFS) in the intention-to-treat population analyzed by stratified log-rank test (two-sided type I error rate, α = .05), with hazard ratio (HR) and 95% CI estimated by stratified Cox proportional hazard model. Secondary end points included response rates, overall survival (OS), minimal residual disease (MRD) negativity rate (<10 –5 ), and safety. RESULTS Overall, 263 patients were randomly assigned (venetoclax-dexamethasone, n = 133; pomalidomide-dexamethasone, n = 130). Median PFS was 9.9 months (95% CI, 6.9 to 12.6) with venetoclax-dexamethasone versus 5.8 months (95% CI, 3.8 to 9.2) with pomalidomide-dexamethasone (HR, 0.823 [95% CI, 0.596 to 1.136]; P = .24). Overall response and very good partial response or better rates were 62% and 39%, respectively, with venetoclax-dexamethasone versus 35% and 14% with pomalidomide-dexamethasone. MRD negativity rate was 8% with venetoclax-dexamethasone and 0% with pomalidomide-dexamethasone. Median OS was 32.4 months (95% CI, 26.4 to 40.7) with venetoclax-dexamethasone and 26.9 months (95% CI, 20.4 to 38.9) with pomalidomide-dexamethasone (HR, 0.856 [95% CI, 0.612 to 1.197]). Grade ≥3 treatment-emergent adverse event rates were 67% with venetoclax-dexamethasone versus 83% with pomalidomide-dexamethasone. There were 16 (12%) treatment-emergent deaths with venetoclax-dexamethasone versus 8 (6%) with pomalidomide-dexamethasone. CONCLUSION The primary end point of PFS was not met. PFS and OS were numerically longer with venetoclax-dexamethasone versus pomalidomide-dexamethasone in t(11;14)-positive RRMM. Consistent with previous studies, infections were associated with venetoclax-dexamethasone; no new safety signals were observed.

Abstract Multiple myeloma is a malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment (IME). To investigate immune correlates of treatment response and disease progression, we conducted multi-omics profiling including CD138neg single-cell RNA sequencing of 243 bone marrow samples from 102 patients (631,226 cells) and CD138pos bulk RNA and whole-genome sequencing from 209 samples. In longitudinal analyses, interferon-γ signaling associated with markers of impaired T-cell memory after autologous stem cell transplant, whereas naïve B-cell abundance and immunoglobulin diversity correlated with improved progression-free survival (HR = 0.48; P = 2.3e−4). At disease progression, multiple myeloma cells upregulated cancer–testis antigens (CTAg) and immune effector genes, with concurrent B-cell depletion, enrichment of myeloid-derived suppressor cell expression, and phenotypic T-cell exhaustion. These findings highlight dynamic immune–tumor interactions, identifying naïve B-cell reconstitution as a biomarker of durable response and CTAgs as potential targets for high-risk disease at progression. Significance: Longitudinal profiling of multiple myeloma and the IME revealed dynamic immune–tumor interactions across the disease course. Altered expression in CD8+ T cells limited memory phenotype after transplant, whereas naïve B-cell recovery associated with sustained treatment response. At progression, CTAg expression associated with immunosuppression, revealing novel mechanisms of immune dysregulation.

Abstract Introduction Device malfunction remains a serious concern for patients with inflatable penile prosthesis (IPP), with pump failure being one of leading causes of revision surgery. Complete device replacement has been the traditional approach, but partial device replacement for the pump may offer a less invasive and cost-effective alternative, with potentially lower complication risk. Objective To evaluate the safety, efficacy, and clinical outcomes of pump replacement (with or without obvious tubing leak/fracture), manipulation or fluid addition in patients undergoing IPP revision surgery. Methods A retrospective review was conducted on patients who underwent IPP pump replacement with or without additional component exchange by a single surgeon, between January 2018 and April 2025. Thirty patients met the inclusion criteria. Clinical, intraoperative and postoperative data were collected and descriptively analyzed. Outcomes included postoperative infectious and non-infectious complication rates. Results The median age at revision was 77 years, with a median time to revision of 76 months post-implantation. Most common indications were frozen or pump difficulties (67%), pump + tubing damage (30%) and fluid addition requirement (10%). No intraoperative complications occurred. Postoperative complications were reported in 3 patients (10.0%), all due to mechanical malfunction, with no infections observed. Median time to complication was 24 months (IQR 7–72). One patient progressed to IPP explanation after successive revisions for impending erosion not thought related to pump manipulation. Another underwent complete replacement at 7 months for fluid leak from reservoir. A third required non-exchange revision at 24 months. The majority (91%) received Coloplast pumps. The median operative time was 53 minutes (IQR 43–70). Conclusions Pump replacement appears to be a safe and effective option for select patients, potentially reducing surgical morbidity and preserving viable components. The absence of infection in this series is reassuring, particularly in a revision setting where infection risk is amplified. Consideration of device age and patient specific factors is important in guiding the choice between partial and complete component exchange. Disclosure No

Abstract Introduction While previous research has explored overall satisfaction following IPP surgery, the specific relationship between final implant length and perceived satisfaction in both patients and their partners remains underexplored. Objective We aim to evaluate the association between IPP cylinder length and postoperative satisfaction in both patients and their sexual partners, and to determine whether perceived adequacy of length restoration correlates with overall sexual and psychosocial outcomes. Methods We initiated a registry of patients undergoing surgery for placement of a PP. After consent, perioperative study assessments and follow-ups were conducted. After surgery, patients were directed to fulfill a survey at 6 months and 12 months. Patients who fulfilled both items were included in the analysis. Results A total of 237 patients had a PP placement and completed the first survey and 158 the 12-month survey. The median IPP length was 22 cm (20-23). At 6 months, .189 patients (79.7%) reported moderate to high satisfaction, and this positive response was sustained at 12-months (n=132; 83.5%). At 6 months, 178 patients (75.1%) reported moderate to high partner’ satisfaction, and this positive response was sustained at 12-months (n=129; 81.6%). A regression analysis at 6 months showed a correlation of r=0.148 (p=0.029) and r=0.027 (p=0.743) at 12 months, implying that while significant statistically, it is not strongly related, and other factors are likely contributing to the response. Partner satisfaction showed a correlation of r=0.184 (p=0.008) at 6 months and r=0.032 (p=0.702) at 12 months, again showing no causal relationship between length of the IPP device with perceived satisfaction. A secondary analysis was performed in patients who had prostatectomy and were using vacuum devices before IPP placement (n=51). Of these, 12 (5.1%) reported decreased penile size during pre-op counseling. The median IPP length was 22 cm (19.5-23) and 21 cm (19.6-22) among patients who reported a decrease in size before IPP placement (p=0.574). There was no correlation between this statement and IPP length (p=0.572), nor satisfaction levels in both patients r=0.180 (p=0.221) and partners r=0.015 (p=0.921) at 6 months or 12 months r=0.060 (p=0.701) & r=0.078 (p=0.636). Conclusions IPP length showed a significant correlation but a weak association with patient and partner satisfaction. Our findings underscore the need for a multimodal approach when looking for patient and partner satisfaction and not only to perceived cosmesis. Comprehensive preoperative counseling should address these multidimensional aspects to better align expectations and outcomes. Disclosure Yes, this is sponsored by industry/sponsor: Coloplast Clarification: Industry funding only - investigator initiated and executed study

Abstract Introduction The opioid epidemic has encouraged increased efforts to minimize postoperative opioid use, particularly in urologic procedures. While short-acting local anesthetics are often used in inflatable penile prosthesis (IPP) placement, their effects diminish quickly, potentially leading to higher opioid requirements. Liposomal bupivacaine (LB), a long-acting local anesthetic, may reduce opioid requirements, but its cost and limited prospective data in IPP patients warrant further investigation. Objective To compare the efficacy of long-acting liposomal bupivacaine with short-acting ropivacaine in reducing postoperative pain and opioid consumption following inflatable penile prosthesis (IPP) placement. Methods This randomized controlled trial enrolled adult males undergoing primary IPP placement via a penoscrotal approach. Participants were randomized to receive either LB (20 mL Exparel + 20 mL bupivacaine 0.25%) or ropivacaine (40 mL of 0.5%) as part of a standardized multimodal analgesia protocol. All patients received acetaminophen, gabapentin, and meloxicam perioperatively, with oxycodone prescribed as needed postoperatively (figure 1). The primary outcome was postoperative opioid consumption measured in oral morphine equivalents (OME). Secondary outcomes included pain and anxiety scores assessed on postoperative days (POD) 3, 7, and 14 using visual analog scales. Results Only 13 patients completed the study due to difficulties in recruitment (9 in the long-acting group, 4 in the short-acting group). The long-acting group demonstrated consistently lower opioid consumption at all follow-up points. On POD 3, the median cumulative OME was 7.5 vs. 41.25 in the short-acting group. By POD 14, cumulative OME was 15.0 vs. 93.75. (Figure 2) Pain scores followed a similar pattern, with the long-acting group reporting lower median scores on POD 3 (4 vs. 6) and POD 7 (4 vs. 6). Anxiety scores were also lower in the long-acting group throughout the follow-up. Use of non-opioid analgesics was similar across both groups. Conclusions Despite a limited sample size, this trial showed consistent trends favoring LB over ropivacaine for reducing opioid use and pain following IPP placement. These findings suggest potential clinical benefit but require validation in larger, multicenter studies. The trial also illustrates the difficulty of conducting randomized studies when institutional practices strongly favor one approach. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Endo pharmaceuticals.

Objectives: In the United States, training for physicians who manage critically ill adult patients (intensivists) evolved through parallel subspecialty critical care medicine (CCM) pathways with significant commonality. The Society of Critical Care Medicine Adult Critical Care Physician Core Knowledge and Skills Task Force aimed to delineate the common core knowledge and skills required of all intensivists. Design: A master list of content areas and procedural skills was compiled from all CCM subspecialty program requirements and blueprints of the certification examinations. Using a modified Delphi approach, participants were asked to categorize the knowledge items as “advanced knowledge is essential,” “general, but not advanced, knowledge is essential,” or “knowledge is not essential.” Procedures were categorized as “intensivist performs routinely,” “intensivist only performs in an emergency,” or “intensivist knows” about the procedure. Setting: Representatives from CCM stakeholder organizations, including accreditation and certification organizations, critical care societies, and program directors’ societies, were invited to participate. SUBJECTS: Members of the Adult Critical Care Physician Core Knowledge and Skills Task Force of the Society of Critical Care Medicine. Interventions: For the first two rounds of the modified Delphi process, Research Electronic Data Capture was used. For the third and fourth rounds, the process was completed through online meetings with Zoom (Zoom Video Corporations, San Jose, CA) utilizing Zoom’s polling feature. Measurements and Main Results: A total of 541 items were determined to be essential, with 145 requiring advanced knowledge and 323 requiring general knowledge. For 73 items, consensus regarding advanced vs. general could not be achieved, but they remained essential. Only eight items were felt to be nonessential. Of the 16 procedures, most were categorized as “intensivist performs.” Conclusions: The large number of items included in the list of essential knowledge and skills demonstrates the complexity of modern CCM. Utilization of a common framework across the subspecialties of CCM could lead to greater harmonization among the fellowship program requirements and certification examinations.

Delirium is a serious neuropsychiatric condition marked by acute confusion and cognitive decline, commonly affecting postoperative and critically ill patients. It is especially prevalent in older adults and those requiring intensive care, including patients undergoing major surgery or receiving mechanical ventilation. For anesthesiologists, delirium is a critical and often underrecognized postoperative complication with complex perioperative contributors. Intensive care unit patients with delirium face increased mortality, cognitive impairment, and persistent symptoms beyond discharge. Despite its clinical significance, the pathophysiology of delirium remains poorly understood, with no standardized classification or targeted therapy. In light of emerging evidence connecting blood–brain barrier (BBB) permeability to the onset of delirium, we found that BBB dysfunction may represent a key mechanism underlying its pathophysiology. Through a thorough examination of predisposing and precipitating factors that impair both BBB integrity and cognitive function, we identified many points of connection between BBB dysfunction and delirium specifically. We include here a summary of our diagnostic approach with the aim of improving therapeutic strategies based on preserving BBB function to prevent or mitigate delirium.