Citations

Background: Clozapine is the preferred medication for treatment-resistant schizophrenia with therapeutic drug monitoring (TDM) suggested to mediate its safe and effective use. However, clozapine TDM is not a ubiquitous element of care in clinical practice. Understanding the current state of clinicians' perceptions of and barriers to clozapine TDM is a crucial step in improving its use. Methods: A survey related to the use, perceptions, and barriers of clozapine TDM was distributed across multiple national organizations in the United States, representing several disciplines. Results: Most of the 190 respondents were consultants or attending physicians (42.5%) or pharmacists (52.3%). Nearly 80% of respondents had ordered clozapine level measurements in the year before completing the survey but identified slow turnaround time (TaT) as an important barrier; 73.5% of respondents noted that level measurements were performed at an offsite laboratory. Although 86.8% agreed that clozapine levels should be checked once an initial target dose was reached, less than half would subsequently order clozapine level measurements routinely, unless clinical factors such as nonadherence (96.5% agreement), new interaction (94.5% agreement), or change in smoking status (94.5% agreement) occurred. More pharmacists than prescribers indicated confidence in interpreting and clinically applying clozapine TDM results (84.6% versus 70.1%, P = 0.024), with a similar finding between the groups regarding faster clozapine TDM TaT, resulting in improved patient safety (89.0% versus 68.7% agreement, P = 0.003). In addition, more pharmacists would also conduct clozapine TDM in the setting of an acute inflammatory or infectious process (84.9% versus 61.2%, P = 0.002). Conclusions: These data provide insights into clozapine TDM perception, availability, TaT, and barriers. Further research is required to assess whether a faster TaT and more frequent clozapine TDM positively influence patient outcomes from a safety and effectiveness perspective.

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.

Traditional solvents face limitations in environmental friendliness, biocompatibility, and functional tunability, which restrict their use in pharmaceuticals, biocatalysis, and biosensing.

Abstract Introduction Male-factor infertility contributes to a substantial portion of infertility cases. Genetic factors are believed to play an important role, with Y chromosome microdeletions commonly identified among men with azoospermia. Due to the relatively high prevalence of these deletions, genetic testing for Y chromosome microdeletions has become a routine component of the diagnostic workup for infertile men. While deletions in the AZF (Azoospermia Factor) region are known to impair spermatogenesis, the hormonal profile in this population remains poorly characterized. Hormonal evaluation plays a key role in guiding treatment decisions, including the use of empirical medical therapy (EMT). However, there is limited data on hormonal profiles and EMT usage in men with AZF deletions. Objective We aimed to characterize preoperative hormonal profiles and evaluate the use and outcomes of EMT in men with AZF microdeletions undergoing surgical sperm retrieval. Methods We conducted a multi-institutional retrospective cohort study of men with genetically confirmed AZF micro-deletions, including AZFa, AZFb, AZFc, and combined deletions. Data were collected on preoperative serum gonadotropin levels (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]), total testosterone (TT), and semen analysis parameters. Additionally, we evaluated patterns of empirical medical therapy (EMT) prescriptions and outcomes of surgical sperm retrieval. Results 40 men with confirmed Y-chromosomal micro-deletions across three academic centers was identified. Patients with SRY translocations (n=4) were excluded from the study. The final cohort included 27 patients with AZFc deletions (75%), 2 with AZFa (6%), 1 with AZFb (3%), and 6 with multilocus deletions (17%). FSH (reference: &gt;7.6 mIU/mL) was elevated in 23 patients (64%), with a median of 19.6 IU/L (IQR: 14.4–25.8). LH (reference: &gt;9 mIU/mL) was elevated in 8 patients (22%), with a median of 14.9 IU/L (IQR: 13.7–20.1). Overall median TT was 243.5 (7.7-379.7). TT was below the lower limit of normal (&lt;300 ng/dL) in 13 patients (36%), with a median of 184 ng/dL (IQR: 133–233). Most patients were azoospermic on semen analysis (86%, n=31/36). Of the seven men treated with EMT, the majority (6/7, 86%) received clomiphene citrate. While there were differences in initial levels of TT, FSH, and LH for those treated with EMT compared to those without EMT, these were not statistically significant (Table 1). Among the 13 patients who underwent surgical sperm retrieval, 6 (46%) had successful outcomes; however, only one had received EMT. Conclusions Men with AZF deletions exhibit varying degrees of hormonal imbalance and rates of empirical medical therapy (EMT) use. Despite EMT, sperm retrieval outcomes were poor, with only 1 out of 7 EMT-treated patients achieving successful sperm retrieval. While hormonal differences were observed between those who received EMT and those who did not, these differences did not reach statistical significance. This is likely due to the limited sample size inherent to this rare patient population. Our findings underscore the variability in hormonal profiles and the unclear efficacy of EMT in promoting spermatogenesis in men with AZF deletions, highlighting the need for further research to inform standardized management strategies. Disclosure No

Abstract Introduction While most patients with Peyronie’s disease (PD) present with dorsal or lateral curvature, a significant number have ventral curvature (VC). These patients face limited treatment options, as they were excluded from initial clinical trials of collagenase clostridium histolyticum (CCH) due to safety concerns related to the proximity of the injection site to the urethra. However, urethral involvement is rare, as PD plaques develop in the tunica albuginea rather than the corpus spongiosum surrounding the urethra. Moreover, multiple prospective and retrospective studies have demonstrated favorable outcomes with CCH treatment in men with VC. Objective To evaluate the effectiveness and safety of CCH in men with PD and VC in a multicenter, real-world, retrospective study. Methods This is an ongoing phase 4, multicenter, retrospective review of medical records from 15 US physician sites. Eligible patients consisted of patients who are: age ≥18 years with a diagnosis of VC in PD with a palpable plaque that was treated with CCH from 2014 to the study start date at each site. Patients missing baseline (BL; pretreatment) or final (last measurement within 6 months of final CCH treatment) penile curvature measurements were excluded. Effectiveness endpoints included percentage change in VC from BL to last visit, mean change in VC (in degrees) from BL to last visit, and proportion of patients with ≥30% improvement in VC from BL to last visit. Safety was assessed as proportions of patients reporting treatment-related adverse events (TRAEs) throughout the study period. Results As of April 22, 2025, there were 116 patients with mean (SD) age of 58 (10.3) years who were eligible for analysis. Mean baseline VC decreased from 58 degrees to 37 degrees at last visit (37% improvement). An improvement in VC of ≥30% was seen in 73/116 (63%) of patients, with 81/116 (69.8%) experiencing ≥20% improvement. At least 1 TRAE was reported by 12 (10%) patients. TRAEs were mild-to-moderate in severity in 9 (75%) patients and unknown in 3 patients, with most events (14/17 [82%]) related to injection site reactions. As of the data cut, there were no treatment-related serious or treatment-related severe AEs, no reports of urethral involvement or injury, and no reports of corporal rupture. Conclusions Men with PD who present with ventral curvature represent an underserved patient population. Concerns about potential urethral injury pose a significant barrier to both minimally invasive and surgical treatments, thereby limiting available therapeutic options. These updated results from a multi-institutional real-world clinical cohort align with previous findings, and demonstrate that the clinical effectiveness and safety profile of CCH is consistent with the profile of CCH seen in other clinical presentations of PD. Disclosure Yes, this is sponsored by industry/sponsor: Endo USA, Inc Clarification: Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Endo USA, Inc.

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.

This practice guideline addresses perioperative pain management using local and regional anesthesia for cardiothoracic, mastectomy, and abdominal surgery in adults and children. For adults, the American Society of Anesthesiologists (Schaumburg, Illinois) Task Force on Perioperative Pain Management strongly recommends fascial plane blocks to reduce pain and/or opioid requirements in the first 24 h postoperatively for open cardiothoracic, abdominal, retroperitoneal, and pelvic surgeries and mastectomy. Fascial plane blocks are also recommended in adults to reduce pain and/or opioid requirements after minimally invasive abdominal procedures. The Task Force conditionally recommends use of fascial plane blocks for minimally invasive cardiothoracic surgeries and open hernia repair to reduce pain in the first 24 h postoperatively. For children, the Task Force strongly recommends use of fascial plane blocks to reduce pain/and or opioid use after open cardiac or thoracic surgeries. Fascial plane blocks are conditionally recommended to reduce pain the first 24 h in children undergoing open hernia repair. Overall, data analysis for this practice guideline was limited by low methodologic quality, inconsistencies in outcome measurements, and small sample sizes from individual centers. Future research in regional anesthesia and analgesia needs to address these pervasive limitations.

Introduction: Sepsis-induced cardiac dysfunction (SICD) is a reversible type of cardiac disorder, with variable reported incidence and uncertain prognostic implications that may occur in patients with sepsis. This study aimed to identify patients with SICD, characterise their clinical and paraclinical features, analyse the different patterns of cardiac dysfunction, and determine prognostic implications. Methods: Patients admitted to the intensive care unit (ICU) for sepsis or septic shock who underwent echocardiography on admission were identified retrospectively. Exclusion criteria included acute myocardial infarction, preexisting severe left heart valve disease or systolic dysfunction. Clinical, paraclinical, and echocardiography data were documented. The primary outcome was a composite of in-hospital mortality, prolonged hospital stay, and prolonged ICU stay. Results: A total of 128 septic patients were included, with a median age of 72.5 years and a 55% male proportion. Alcohol abuse, vasopressor therapy and orotracheal intubation on admission were risk factors for developing SICD. More than a third developed SICD (37%). We identified four different types of cardiac dysfunction based on echocardiography. An NT-proBNP level of over 9000 pg/mL was a predictor of SICD, composite outcome and mortality. A total of 56 patients (44%) experienced in-hospital mortality. Even though the occurrence of SICD did not predict mortality, it was a significant predictor of the composite outcome. Conclusions: This study describes the incidence and spectrum of SICD in a group of septic patients admitted to a tertiary care hospital. The occurrence of any type of cardiac dysfunction associated with sepsis and high NT-proBNP levels had strong prognostic implications.