Citations

AbstractINTRODUCTIONPremenopausal bilateral oophorectomy (PBO) is associated with later‐life cognition, but the underlying brain changes remain unclear. We assessed the impact of PBO and PBO age on white matter integrity.METHODSFemale participants with regional diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA) and mean diffusivity (MD) were included (22 with PBO < 40 years; 43 with PBO 40‐45 years; 39 with PBO 46‐49 years; 907 referents without PBO < 50 years). Linear regression models adjusted for age and apolipoprotein E (APOE) genotype.RESULTSFemales with PBO < 40 years, compared to referents, had lower FA and higher MD in the anterior corona radiata, genu of the corpus collosum, inferior fronto‐occipital fasciculus, superior occipital, and superior temporal white matter. Females who underwent PBO between 45 and 49 also had some changes in white matter integrity.DISCUSSIONFemales who underwent PBO < 40 years had reduced white matter integrity across multiple regions in later‐life. These results are important for females considering PBO for noncancerous conditions.Highlights Females with premenopausal bilateral oophorectomy (PBO) < 40 years had lower FA versus referents. Females with PBO < 40 years had higher MD in many regions versus referents. Adjusting for estrogen replacement therapy use did not attenuate results. Females with PBO 45‐49 years also had some white matter changes versus referents.

BACKGROUND: Peripheral nerve stimulation with a train-of-four (TOF) pattern can be used intraoperatively to evaluate the depth of neuromuscular block and confirm recovery from neuromuscular blocking agents (NMBAs). Quantitative monitoring can be challenging in infants and children due to patient size, equipment technology, and limited access to monitoring sites. Although the adductor pollicis muscle is the preferred site of monitoring, the foot is an alternative when the hands are unavailable. However, there is little information on comparative evoked neuromuscular responses at those 2 sites. METHODS: Pediatric patients undergoing inpatient surgery requiring NMBA administration were studied after informed consent. Electromyographic (EMG) monitoring was performed simultaneously in each participant at the hand (ulnar nerve, adductor pollicis muscle) and the foot (posterior tibial nerve, flexor hallucis brevis muscle). RESULTS: Fifty patients with a mean age of 3.0 ± standard deviation (SD) 2.9 years were studied. The baseline first twitch amplitude (T1) of TOF at the foot (12.46 mV) was 4.47 mV higher than at the hand ( P <.0001). The baseline TOF ratio (TOFR) before NMBA administration and the maximum TOFR after antagonism with sugammadex were not different at the 2 sites. The onset time until the T1 decreased to 10% or 5% of the baseline value (T1) was delayed by approximately 90 seconds (both P =.014) at the foot compared with the hand. The TOFR at the foot recovered (TOFR ≥0.9) 191 seconds later than when this threshold was achieved at the hand ( P =.017). After antagonism, T1 did not return to its baseline value, a typical finding with EMG monitoring, but the fractional recovery (maximum T1 at recovery divided by the baseline T1) at the hand and foot was not different, 0.81 and 0.77, respectively ( P =.68). The final TOFR achieved at recovery was approximately 100% and was not different between the 2 sites. CONCLUSIONS: Although this study in young children demonstrated the feasibility of TOF monitoring, interpretation of the depth of neuromuscular block needs to consider the delayed onset and the delayed recovery of TOFR at the foot compared to the hand. The delay in achieving these end points when monitoring the foot may impact the timing of tracheal intubation and assessment of adequate recovery of neuromuscular block to allow tracheal extubation (ie, TOFR ≥0.9).

Informed by the almost unimaginable unmet need for cardiac surgery in the developing regions of the world, leading surgeons, cardiologists, editors in chief of the major cardiothoracic journals as well as representatives of medical industry and government convened in December 2017 to address this unacceptable disparity in access to care. The ensuing “Cape Town Declaration” constituted a clarion call to cardiac surgical societies to jointly advocate the strengthening of sustainable, local cardiac surgical capacity in the developing world. The Cardiac Surgery Intersociety Alliance (CSIA) was thus created, comprising The Society of Thoracic Surgeons (STS), the American Association for Thoracic Surgery (AATS), the Asian Society for Cardiovascular and Thoracic Surgery (ASCVTS), the European Association for Cardio-Thoracic Surgery (EACTS) and the World Heart Federation (WHF). The guiding principle was advocacy for sustainable cardiac surgical capacity in low-income countries. Summary Informed by the almost unimaginable unmet need for cardiac surgery in the developing regions of the world, leading surgeons, cardiologists, editors in chief of the major cardiothoracic journals as well as representatives of medical industry and government convened in December 2017 to address this unacceptable disparity in access to care. The ensuing “Cape Town Declaration” constituted a clarion call to cardiac surgical societies to jointly advocate the strengthening of sustainable, local cardiac surgical capacity in the developing world. The Cardiac Surgery Intersociety Alliance (CSIA) was thus created, comprising The Society of Thoracic Surgeons (STS), the American Association for Thoracic Surgery (AATS), the Asian Society for Cardiovascular and Thoracic Surgery (ASCVTS), the European Association for Cardio-Thoracic Surgery (EACTS) and the World Heart Federation (WHF). The guiding principle was advocacy for sustainable cardiac surgical capacity in low-income countries. As a first step, a global needs assessment confirmed rheumatic heart disease as the overwhelming pathology requiring cardiac surgery in these regions. Subsequently, CSIA published a request for proposals to support fledgling programmes that could demonstrate the backing by their governments and health care institution. Out of 11 applicants, and following an evaluation of the sites, including site visits to the 3 finalists, Mozambique and Rwanda were selected as the first Pilot Sites. Subsequently, a mentorship and training agreement was completed between Mozambique and the University of Cape Town, a middle-income country with a comparable burden of rheumatic heart disease. The agreement entails regular video calls between the heart teams, targeted training across all aspects of cardiac surgery, as well as on-site presence of mentoring teams for complex cases with the strict observance of ‘assisting only’. In Rwanda, Team Heart, a US and Rwanda-based non-governmental organization (NGO) that has been performing cardiac surgery in Rwanda and helping to train the cardiac surgery workforce since 2008, has agreed to continue providing mentorship for the local team and to assist in the establishment of independent cardiac surgery with all that entails. This involves intermittent virtual conferences between Rwandan and US cardiologists for surgical case selection. Five years after CSIA was founded, it’s ‘Seal of Approval’ for the sustainability of endorsed programmes in Mozambique and Rwanda has resulted in higher case numbers, a stronger government commitment, significant upgrades of infrastructure, the nurturing of generous consumable donations by industry and the commencement of negotiations with global donors for major grants. Extending the CSIA Seal to additional deserving programmes could further align the international cardiac surgical community with the principle of local cardiac surgery capacity-building in developing countries.

Abstract Background: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk. Methods: We conducted a genome-wide interaction analysis of single-nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than three drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies. Our analysis included 3,707 cases and 4,167 controls from case–control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed-effect meta-analyses were conducted. Results: A potential novel region of association on 10p11.22, lead SNP rs7898449 (interaction P value (Pinteraction) = 5.1 × 10−8 in the meta-analysis; Pinteraction = 2.1 × 10−9 in the case–control studies; Pinteraction = 0.91 in the cohort studies), was identified. An SNP correlated with this lead SNP is an expression quantitative trait locus for the neuropilin 1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004). Conclusions: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an expression quantitative trait locus for neuropilin 1, a protein that plays an important role in the development and progression of pancreatic cancer. Impact: This work can provide insights into the etiology of pancreatic cancer, particularly in heavy drinkers.

Abstract Background Delirium is a common complication of older people in hospitals, rehabilitation and long-term facilities. Objective To assess the worldwide use of validated delirium assessment tools and the presence of delirium management protocols. Design Secondary analysis of a worldwide one-day point prevalence study on World Delirium Awareness Day, 15 March 2023. Setting Cross-sectional online survey including hospitals, rehabilitation and long-term facilities. Methods Participating clinicians reported data on delirium, the presence of protocols, delirium assessments, delirium-awareness interventions, non-pharmacological and pharmacological interventions, and ward/unit-specific barriers. Results Data from 44 countries, 1664 wards/units and 36 048 patients were analysed. Validated delirium assessments were used in 66.7% (n = 1110) of wards/units, 18.6% (n = 310) used personal judgement or no assessment, and 10% (n = 166) used other assessment methods. A delirium management protocol was reported in 66.8% (n = 1094) of wards/units. The presence of protocols for delirium management varied across continents, ranging from 21.6% (on 21/97 wards/units) in Africa to 90.4% (235/260) in Australia, similar to the use of validated delirium assessments with 29.6% (29/98) in Africa to 93.5% (116/124) in North America. Wards/units with a delirium management protocol [n = 1094/1664, 66.8%] were more likely to use a validated delirium test than those without a protocol [odds ratio 6.97 (95% confidence interval 5.289–9.185)]. The presence of a delirium protocol increased the chances for valid delirium assessment and, likely, evidence-based interventions. Conclusion Wards/units that reported the presence of delirium management protocols had a higher probability of using validated delirium assessments tools to assess for delirium.

7529 Background: iAEs, such as cytokine release syndrome (CRS) and macrophage activation syndrome (MAS), can occur after infusion of chimeric antigen receptor T cell therapies such as ide-cel, but are typically low-grade and manageable with tocilizumab and corticosteroids. Although high-grade iAEs are rare with ide-cel, identification of patients at increased risk may improve management and remains an unmet need. Three composite biomarkers (multivariate models) of iAE risk were previously developed in a discovery cohort from the KarMMa and KarMMa-2 studies of ide-cel in RRMM (Mashadi-Hossein A, et al. J Clin Oncol 2023;41(16_suppl):e20005). Here, we validate these 3 prototype models for risk of developing high-grade iAEs after ide-cel infusion. Methods: Two models used pretreatment patient and routine clinical laboratory parameters; the third model also included change in 6 exploratory cytokines from baseline to 1 day following ide-cel infusion. To validate, each model was retrospectively applied to KarMMa-3 (NCT03651128) data in a blinded fashion, and sensitivity and specificity to identify grade ≥3 CRS and any-grade MAS were determined. Model performance thresholds used for sensitivity and specificity were 90% and 50%, respectively. Performance for identifying grade 2 CRS was also analyzed post hoc. Results: The first and simplest model comprised a manual algorithm with 7 features; it identified patients with grade ≥3 CRS or MAS with 85% sensitivity and 60% specificity. The second model comprised 19 routinely measured pretreatment features; it identified grade ≥3 CRS with 91% sensitivity and 59% specificity, and any-grade MAS with 60% sensitivity and 88% specificity. The third and most complex model comprised 7 pretreatment clinical features and 6 exploratory cytokines; it identified grade ≥3 CRS with 100% sensitivity and 51% specificity, and any-grade MAS with 100% sensitivity and 81% specificity. None of the models identified grade ≥2 CRS with passable sensitivity or specificity. Clustering analyses across all features showed that only a subset of grade 2 CRS cases was within the previously identified high-risk iAE cluster while the remaining grade 2 CRS cases were spread across other clusters. Conclusions: Two of the 3 composite biomarkers met validation criteria for grade ≥3 CRS risk. Criteria were not met for grade 2 CRS, suggesting these models are specific to higher-grade events and that grade 2 CRS represents a more heterogeneous group of patients. While high-grade iAEs are rare with ide-cel, these models may further optimize the robust benefit–risk profile that ide-cel has demonstrated by helping identify, prior to or shortly after infusion, patients most at risk for severe events. Clinical trial information: NCT03651128 .

Summary Informed by the almost unimaginable unmet need for cardiac surgery in the developing regions of the world, leading surgeons, cardiologists, editors in chief of the major cardiothoracic journals as well as representatives of medical industry and government convened in December 2017 to address this unacceptable disparity in access to care. The ensuing “Cape Town Declaration” constituted a clarion call to cardiac surgical societies to jointly advocate the strengthening of sustainable, local cardiac surgical capacity in the developing world. The Cardiac Surgery Intersociety Alliance (CSIA) was thus created, comprising The Society of Thoracic Surgeons (STS), the American Association for Thoracic Surgery (AATS), the Asian Society for Cardiovascular and Thoracic Surgery (ASCVTS), the European Association for Cardio-Thoracic Surgery (EACTS) and the World Heart Federation (WHF). The guiding principle was advocacy for sustainable cardiac surgical capacity in low-income countries. As a first step, a global needs assessment confirmed rheumatic heart disease as the overwhelming pathology requiring cardiac surgery in these regions. Subsequently, CSIA published a request for proposals to support fledgling programmes that could demonstrate the backing by their governments and health care institution. Out of 11 applicants, and following an evaluation of the sites, including site visits to the 3 finalists, Mozambique and Rwanda were selected as the first Pilot Sites. Subsequently, a mentorship and training agreement was completed between Mozambique and the University of Cape Town, a middle-income country with a comparable burden of rheumatic heart disease. The agreement entails regular video calls between the heart teams, targeted training across all aspects of cardiac surgery, as well as on-site presence of mentoring teams for complex cases with the strict observance of ‘assisting only’. In Rwanda, Team Heart, a US and Rwanda-based non-governmental organization (NGO) that has been performing cardiac surgery in Rwanda and helping to train the cardiac surgery workforce since 2008, has agreed to continue providing mentorship for the local team and to assist in the establishment of independent cardiac surgery with all that entails. This involves intermittent virtual conferences between Rwandan and US cardiologists for surgical case selection. Five years after CSIA was founded, its ‘Seal of Approval’ for the sustainability of endorsed programmes in Mozambique and Rwanda has resulted in higher case numbers, a stronger government commitment, significant upgrades of infrastructure, the nurturing of generous consumable donations by industry and the commencement of negotiations with global donors for major grants. Extending the CSIA Seal to additional deserving programmes could further align the international cardiac surgical community with the principle of local cardiac surgery capacity-building in developing countries.

Background and Objectives: Clinical practice guidelines (CPGs) have significantly influenced medical practice worldwide. Nevertheless, the authorship of CPGs produced by several medical societies has not been representative of the field and population they address, as women and individuals from racial and ethnic minority groups have been underrepresented as authors. We hypothesized that women and individuals from minoritized racial and ethnic groups would also be underrepresented as authors of CPGs produced by the American Academy of Pediatrics (AAP). Methods: In this cross-sectional study, the gender, race, and ethnic composition of authors and subcommittee participants of AAP-produced CPGs published from January 2010 through May 2023 were analyzed and compared to the 2010 and 2021 U.S. population and 2010 and 2022 U.S. medical school pediatric faculty. Results: Women (39.7%, 127/320 of all positions, and 42.5%, 85/200 of named author positions) and women physicians (35.2%, 101/287 of all positions, and 36.4%, 64/176 of named author positions) were significantly underrepresented—while men and men physicians were significantly overrepresented—from their respective composition in the U.S. Census and pediatric faculty. Women and women physicians from all racial and ethnic groups and men and men physicians from minority racial and ethnic groups were significantly underrepresented—from their respective composition in the U.S. Census and pediatric faculty. No Black man was identified as an author. Conclusions: Medical societies that produce CPGs should be cognizant of these inequities and ensure appropriate authorship diversity.

PURPOSE Phosphatidylinositol 3-kinase/AKT-serine threonine kinase/mammalian target of rapamycin (mTOR) pathway abnormalities contribute to endocrine resistance. Everolimus, an mTOR inhibitor, improved progression-free survival in hormone receptor–positive metastatic breast cancer (BC) when combined with endocrine therapy (ET). In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor–positive, human epidermal growth factor receptor 2–negative BC after adjuvant/neoadjuvant chemotherapy. METHODS Patients were randomly assigned 1:1 to physician's choice ET and 1 year of everolimus (10 mg orally once daily) or placebo stratified by risk group. The primary end point was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test with the hazard ratio (HR) estimated by Cox regression. Subset analyses included preplanned evaluation by risk group and exploratory analyses by menopausal status and age. Secondary end points included overall survival (OS) and safety. Everolimus did not improve IDFS/OS when added to ET in patients with early-stage high-risk, hormone receptor–positive BC. RESULTS One thousand and nine hundred thirty-nine patients were randomly assigned with 1,792 eligible for analysis. Overall, no benefit of everolimus was seen for IDFS (HR, 0.94 [95% CI, 0.77 to 1.14]) or OS (HR, 0.97 [95% CI, 0.75 to 1.26]). The assumption of proportional hazards was not met suggesting significant variability in the HR over time since the start of treatment. In an unplanned subgroup analysis among postmenopausal patients (N = 1,221), no difference in IDFS (HR, 1.08 [95% CI, 0.86 to 1.36]) or OS (HR, 1.19 [95% CI, 0.89 to 1.60]) was seen. In premenopausal patients (N = 571), everolimus improved both IDFS (HR, 0.64 [95% CI, 0.44 to 0.94]) and OS (HR, 0.49 [95% CI, 0.28 to 0.86]). Treatment completion rates were lower in the everolimus arm compared with placebo (48% v 73%) with higher grade 3 and 4 adverse events (35% v 7%). CONCLUSION One year of adjuvant everolimus + ET did not improve overall outcomes. Subset analysis suggests mTOR inhibition as a possible target for patients who remain premenopausal after chemotherapy.

Background: The obesity epidemic has led to an increase in the proportion of patients with chronic liver disease due to metabolic associated steatosic liver disease and in the prevalence of obesity in patients with cirrhosis. Metabolic and bariatric surgery (MBS) has been proven to determine weight loss, obesity-related medical problems remission, and liver steatosis, inflammation, and fibrosis improvement. However, cirrhosis and portal hypertension are well-known risk factors for increased morbidity and mortality after surgery. The aim of this study is to evaluate the safety of MBS in patients with compensated advanced chronic liver disease (cALCD) and clinically significant portal hypertension (CSPH). Material and methods: This is an international, multicentric, retrospective study on 63 individuals affected by obesity with cALCD and CSPH who underwent MBS in tertiary referral centers with experts hepatobiliary surgeons between January 2010 and October 2022. The primary endpoint was postoperative mortality at 90 days. The secondary endpoints included postoperative weight loss at last follow-up and postoperative complication rate. In addition, the authors performed subgroup analyses of Child-Pugh (A vs. B) score, MELD (≤9 vs. >9) score, and type of surgery. Results: One patient (1.6%) experienced gastric leakage and mortality. There were three (5%) reported cases of portal vein thrombosis, two (3%) postoperative acute renal failure, and one (1.6%) postoperative encephalopathy. Child-Pugh score A resulted to be a protective factor for intraoperative bleeding requiring transfusion at univariate analysis (OR: 0.73, 95% CI: 0.55–0.97, P=0.046) but not at multivariate analysis. MELD>9 score and the type of surgery did not result to be a risk factor for any postoperative complication. Conclusion: MBS is safe in patients with cALCD and CSPH performed in tertiary bariatric referral centers with hepatobiliary expert surgeons. Larger, prospective studies with longer follow-up periods are needed to confirm these results.