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Purpose: The purpose of this study was to analyze the quality and readability of information regarding rotator cuff repair surgery available using an online AI software. Methods: An open AI model (ChatGPT) was used to answer 24 commonly asked questions from patients on rotator cuff repair. Questions were stratified into one of three categories based on the Rothwell classification system: fact, policy, or value. The answers for each category were evaluated for reliability, quality and readability using The Journal of the American Medical Association Benchmark criteria, DISCERN score, Flesch-Kincaid Reading Ease Score and Grade Level. Results: The Journal of the American Medical Association Benchmark criteria score for all three categories was 0, which is the lowest score indicating no reliable resources cited. The DISCERN score was 51 for fact, 53 for policy, and 55 for value questions, all of which are considered good scores. Across question categories, the reliability portion of the DISCERN score was low, due to a lack of resources. The Flesch-Kincaid Reading Ease Score (and Flesch-Kincaid Grade Level) was 48.3 (10.3) for the fact class, 42.0 (10.9) for the policy class, and 38.4 (11.6) for the value class. Conclusion: The quality of information provided by the open AI chat system was generally high across all question types but had significant shortcomings in reliability due to the absence of source material citations. The DISCERN scores of the AI generated responses matched or exceeded previously published results of studies evaluating the quality of online information about rotator cuff repairs. The responses were U.S. 10th grade or higher reading level which is above the AMA and NIH recommendation of 6th grade reading level for patient materials. The AI software commonly referred the user to seek advice from orthopedic surgeons to improve their chances of a successful outcome.

Background: Chronic Spontaneous Urticaria (CSU) is an immune-mediated skin disease that may require prolonged treatments. Currently, there are no recommendations for treatment discontinuation once CSU symptoms are controlled, particularly among patients primarily diagnosed with severe CSU. Objective: In this real-life study we aimed to describe our experience of omalizumab (Oma) treatment withdrawal in CSU and define biomarkers related to these outcomes. Methods: CSU patients followed at our allergy clinic from January 2016 to December 2022 were included. Response to Oma therapy, and Oma-withdrawal outcomes among patients who reached complete remission for >6 months were analyzed. Results: During the study period 192/335(%) CSU patients were categorized as severe-CSU and entitled to receive Oma according to our country's regulations. Of them, 131/192(68%) were considered “Oma-responders”, and 95/131(72.5%) patients underwent gradual treatment withdrawal. Successful Oma-withdrawal was documented in 47/95(49.5%) whereas 48/95(50.5%) patients experienced flare and were defined as unsuccessful OMA-withdrawal. The first was associated with shorter disease duration 7.1 ± 7.4 years vs. 10.7 ± 9.4 (P = 0.042), lower baseline-IgE 81.6 ± 84.1IU/ml vs. 324.7 ± 555.9 (P = 0.005), and lower baseline-eosinophils count 131.4 ± 110.5 vs. 195.6 ± 98.4 (P = 0.043) in comparison to failure of Oma-withdrawal group. Conclusion: OMA may be successfully withdrawn in up to 50% of severe CSU patients following complete remission of disease symptoms, utilizing a gradual withdrawal protocol. Oma-withdrawal failure was linked with longer duration of disease as well as high IgE and eosinophil counts prior to initiation of Oma therapy. These parameters may enable the design of a treatment withdrawal algorithm.

There is a lack of consensus over the description and severity assignment of allergic adverse reactions to immunotherapy, although there seems to be a consensus at least in terms of using the World Allergy Organization (WAO) grading systems to describe local adverse events for Sublingual Immunotherapy (SLIT) and Systemic Allergic Reactions (SARs) to Subcutaneous Immunotherapy (SCIT) amongst the major national/regional allergy societies. In this manuscript, we propose a modification of the previous WAO Grading system for SARs, which aligns with the newly-proposed Consortium for Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions in Food Allergy (version 3.0). We hope this can facilitate a unified grading system appropriate to SARs due to allergen immunotherapy, independent of allergen and route of administration, and across clinical and research practice.

Summary:. Free functional muscle transfer is an attractive option within reconstructive surgery when seeking to restore critical muscle function. The gracilis muscle has long been utilized for this purpose due to its expendability and consistent anatomy. Historically, survival of the skin overlying the distal one-third of the myocutaneous gracilis flap has been unpredictable. To address this, the myofasciocutaneous technique was developed, with prior studies demonstrating improved distal skin paddle viability with this approach; however, the mechanism is poorly defined. This study aimed to understand what factors contribute to survival benefit in myofasciocutaneous gracilis flaps. Using cadaveric dissections followed by latex dye injections, we discuss the creation of a deep fascial sheath that contains a rich vascular network and permits adhesion-free excursion at the recipient site. This study advances our understanding of the myofasciocutaneous gracilis flap and provides wider clinical applicability in free functional muscle transfer.

Background: Chronic spontaneous urticaria (CSU) is a common condition treated by allergist/immunologists, but the only FDA-approved biologic medication, omalizumab, may be underutilized globally. Objective: This study was performed to determine the global prescription of omalizumab for treatment of CSU by allergists/immunologists. Methods: Anonymous questionnaire surveys were distributed online to World Allergy Organization (WAO) members worldwide. Categorical data were analyzed for descriptive analysis using one-way frequency tabulation in SAS 9.4. Results: There were 348 respondents (43 missing data); Average age 51 (range 28–90); M/F 48%/52%. 58% had > 15 years of clinical experience and 10%

Background: Daratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved., Methods: In this phase 3 trial, we randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring. Treatment was continued for 39 cycles, for 36 months, or until confirmation of disease progression, whichever occurred first. The primary end point was progression-free survival; progression to active multiple myeloma was assessed by an independent review committee in accordance with International Myeloma Working Group diagnostic criteria., Results: Among the 390 enrolled patients, 194 were assigned to the daratumumab group and 196 to the active-monitoring group. With a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower with daratumumab than with active monitoring (hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.67; P<0.001). Progression-free survival at 5 years was 63.1% with daratumumab and 40.8% with active monitoring. A total of 15 patients (7.7%) in the daratumumab group and 26 patients (13.3%) in the active-monitoring group died (hazard ratio, 0.52; 95% CI, 0.27 to 0.98). Overall survival at 5 years was 93.0% with daratumumab and 86.9% with active monitoring. The most common grade 3 or 4 adverse event was hypertension, which occurred in 5.7% and 4.6% of the patients in the daratumumab group and the active-monitoring group, respectively. Adverse events led to treatment discontinuation in 5.7% of the patients in the daratumumab group, and no new safety concerns were identified., Conclusions: Among patients with high-risk smoldering multiple myeloma, subcutaneous daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death and with higher overall survival than active monitoring. No unexpected safety concerns were identified. (Funded by Janssen Research and Development; AQUILA ClinicalTrials.gov number, NCT03301220.)., (Copyright © 2024 Massachusetts Medical Society.)

Williams syndrome (WS) is a multi-system condition caused by the deletion of 25-27 coding genes on human chromosome 7. Irritability, gastrointestinal (GI) reflux and slow growth are commonly reported in infants with WS, but less data exist regarding GI concerns in older children and adults with the condition. This study evaluates 62 individuals with WS (31 children aged 3-17, and 31 adults aged 18-62) as well as 36 pediatric and adult controls to assess current and historical rates of common GI symptoms. Data were evaluated using a regression model including age, sex, self-reported race, and diagnosis. Symptoms including food intolerance, reflux, dysphagia, choking/gagging, vomiting, constipation, bloating, diarrhea, hematochezia, rectal prolapse, abdominal pain, and weight loss are more common in those with WS relative to controls. In addition, people with WS utilize more GI medications, specialty care, procedures, and supplemental feeds. Among those with WS, symptoms were present at similar rates in children and adults, except for diverticular disease, which was not noted until adulthood. GI symptoms are frequent in people with WS and serve as a significant source of morbidity., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

The level of frailty, according to the IMWG frailty index, is highly dynamic during anti-myeloma treatment. Dynamic frailty assessment improved the prediction of survival and early mortality as compared to the prognostic value of static frailty level at baseline. HOVON 143: NTR6297 HOVON 123: NTR4244., (Copyright © 2024 American Society of Hematology.)

Chronic lymphocytic leukemia (CLL) manifests heterogeneously with varying outcomes. This population-based study examined causes of death (CODs), as registered by the physician who established the death, among 20,588 CLL patients diagnosed in the Netherlands between 1996 and 2020. Utilizing cause-specific flexible parametric survival models, we estimated cause-specific hazard ratios (HRs) and cumulative incidences of death due to CLL, solid malignancies, other hematological malignancies, infections, and other causes. Our findings reveal CLL as the predominant COD, contributing to around 40% of relative mortality, with a declining 5-year death probability from 16.8% in 1996-2002 to 7.6% in 2010-2020. Also, deaths attributed to solid malignancies, other hematological malignancies, and other COD diminished over time, as evidenced by respective HRs (95% confidence interval) of 0.68 (0.60%-0.77%), 0.45 (0.38%-0.53%), and 0.77 (0.66%-0.90%). In summary, our comprehensive, population-based analysis underscores a noticeable reduction in CLL-attributed deaths and other competing causes over the studied period. Nonetheless, CLL is registered as the most prevalent cause of mortality among contemporary diagnosed patients with CLL, emphasizing the continued relevance of CLL-centric clinical strategies and research., Competing Interests: Arnon P. Kater has received personal fees from AbbVie, LAVA, Genmab, Janssen, AstraZeneca, Roche/Genentech, and Bristol Myers Squibb; and research funding from AbbVie, Janssen, AstraZeneca, Roche/Genentech, and Bristol Myers Squibb. Mark‐David Levin has received personal fees from AbbVie, Janssen, and Roche; and research funding from AbbVie, Janssen, AstraZeneca, and Roche/Genentech. Anton W. Langerak has received research funding via an unrestricted grant from Roche‐Genentech and speaker fees from Janssen. The remaining authors declare no conflict of interest., (© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

Controllable installation of a single nitrogen atom is central to many major goals in skeletal editing, with progress often gated by the availability of an appropriate N-atom source. Here we introduce a novel reagent, termed DNIBX, based on dibenzoazabicycloheptadiene (dbabh), which allows the electrophilic installation of dbabh to organic substrates. When indanone β-ketoesters are aminated by DNIBX, the resulting products undergo divergent ring expansions depending on the mode of activation, producing heterocycles in differing oxidation states under thermal and photochemical conditions. The mechanism of each transformation is discussed, and the different reactivity modes of the indanone-dbabh adducts are compared to other nitrogenous precursors., (© 2024 GSK and The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Modern medicine seeks precision targeting, imaging and therapy to maximize efficacy and avoid toxicities. Nanoparticles (NPs) have tremendous yet unmet clinical potential to carry and deliver imaging and therapeutic agents systemically with tissue precision. But their size contributes to rapid scavenging by the reticuloendothelial system and poor penetration of key endothelial cell (EC) barriers, limiting target tissue uptake, safety and efficacy. Here we discover the ability of the EC caveolae pumping system to outpace scavenging and deliver NPs rapidly and specifically into the lungs. Gold and dendritic NPs are conjugated to antibodies targeting caveolae of the lung microvascular endothelium. SPECT-CT imaging and biodistribution analyses reveal that rat lungs extract most of the intravenous dose within minutes to achieve precision lung imaging and targeting with high lung concentrations exceeding peak blood levels. These results reveal how much ECs can both limit and promote tissue penetration of NPs and the power and size-dependent limitations of the caveolae pumping system. This study provides a new retargeting paradigm for NPs to avoid reticuloendothelial system uptake and achieve rapid precision nanodelivery for future diagnostic and therapeutic applications., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

In a previous pathway-based, extreme phenotype study, we identified 1064 variants associated with supravalvar aortic stenosis (SVAS) severity in people with Williams syndrome (WS) and either no SVAS or surgical SVAS. Here, we use those variants to develop and test polygenic risk scores (PRS). We used the clumping and thresholding (CT) approach on the full 1064 variants and a 427-variant subset that was part of 13 biologically relevant pathways identified in the previous study. We also used a lasso approach on the full set. We were able to achieve an area under the curve (AUC) of >0.99 for the two CT PRS methods, using only 622 and 320 variants respectively when 2/3 of the initial 217 participants data were used for training and 1/3 for testing. The lasso performed less well. We then evaluated the performance of those PRS variant sets on an additional group of 138 patients with WS with intermediate severity SVAS and found a misclassification rate of <10% between the surgical and intermediate groups, suggesting potential for clinical utility of the score., Competing Interests: Disclosures: The authors report no conflicts.

Retrosynthetic simplicity is introduced as a metric by which methods can be evaluated. An argument in favor of reactions which are retrosynthetically simple is put forward, and recent examples in the context of skeletal editing from my own laboratory as well as contributions from others are analyzed critically through this lens., Competing Interests: Conflict of Interest The authors declare no conflict of interest.

Background: CASSIOPEIA part 1 demonstrated superior depth of response and prolonged progression-free survival with daratumumab in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) alone as an induction and consolidation regimen in transplant-eligible patients newly diagnosed with myeloma. In CASSIOPEIA part 2, daratumumab maintenance significantly improved progression-free survival and increased minimal residual disease (MRD)-negativity rates versus observation. Here, we report long-term study outcomes of CASSIOPEIA., Methods: CASSIOPEIA was a two-part, open-label, phase 3 trial of patients done at 111 European academic and community-based centres. Eligible patients were aged 18-65 years with transplant-eligible newly diagnosed myeloma and an Eastern Cooperative Oncology Group performance status of 0-2. In part 1, patients were randomly assigned (1:1) to pre-transplant induction and post-transplant consolidation with D-VTd or VTd. Patients who completed consolidation and had a partial response or better were re-randomised (1:1) to intravenous daratumumab maintenance (16 mg/kg every 8 weeks) or observation for 2 years or less. An interactive web-based system was used for both randomisations, and randomisation was balanced using permuted blocks of four. Stratification factors for the first randomisation (induction and consolidation phase) were site affiliation, International Staging System disease stage, and cytogenetic risk status. Stratification factors for the second randomisation (maintenance phase) were induction treatment and depth of response in the induction and consolidation phase. The primary endpoint for the induction and consolidation phase was the proportion of patients who achieved a stringent complete response after consolidation; results for this endpoint remain unchanged from those reported previously. The primary endpoint for the maintenance phase was progression-free survival from second randomisation. Efficacy evaluations in the induction and consolidation phase were done on the intention-to-treat population, which included all patients who underwent first randomisation, and efficacy analyses in the maintenance phase were done in the maintenance-specific intention-to-treat population, which included all patients who were randomly assigned at the second randomisation. This analysis represents the final data cutoff at the end of the study. The trial is registered with ClinicalTrials.gov, NCT02541383., Findings: Between Sept 22, 2015 and Aug 1, 2017, 1085 patients were randomly assigned to D-VTd (n=543) or VTd (n=542); between May 30, 2016 and June 18, 2018, 886 were re-randomised to daratumumab maintenance (n=442) or observation (n=444). At the clinical cutoff date, Sept 1, 2023, median follow-up was 80·1 months (IQR 75·7-85·6) from first randomisation and 70·6 months (66·4-76·1) from second randomisation. Progression-free survival from second randomisation was significantly longer in the daratumumab maintenance group than the observation-alone group (median not reached [95% CI 79·9-not estimable (NE)] vs 45·8 months [41·8-49·6]; HR 0·49 [95% CI 0·40-0·59]; p<0·0001); benefit was observed with D-VTd with daratumumab maintenance versus D-VTd with observation (median not reached [74·6-NE] vs 72·1 months [52·8-NE]; 0·76 [0·58-1·00]; p=0·048) and VTd with daratumumab maintenance versus VTd with observation (median not reached [66·9-NE] vs 32·7 months [27·2-38·7]; 0·34 [0·26-0·44]; p<0·0001)., Interpretation: The long-term follow-up results of CASSIOPEIA show that including daratumumab in both the induction and consolidation phase and the maintenance phase led to superior progression-free survival outcomes. Our results confirm D-VTd induction and consolidation as a standard of care, and support the option of subsequent daratumumab monotherapy maintenance, for transplant-eligible patients with newly diagnosed multiple myeloma., Funding: Intergroupe Francophone du Myélome, Dutch-Belgian Cooperative Trial Group for Hematology Oncology, and Janssen Research & Development., Competing Interests: Declaration of interests PM served on advisory boards for and received honoraria from Janssen, Bristol Myers Squibb, Amgen, Takeda, AbbVie, Sanofi, and Pfizer. CH received honoraria from Janssen, Bristol Myers Squibb, Amgen, AbbVie, and Pfizer. AP served in a consulting or advisory role for Bristol Myers Squibb, Janssen, and Pfizer; and received research funding from Bristol Myers Squibb, Sanofi, and Takeda. BA received research funding (paid to institution) from Bristol Myers Squibb; received honoraria from Janssen, Bristol Myers Squibb, Sanofi, and GSK; received travel funding from Janssen, Bristol Myers Squibb, and Sanofi; and served on an advisory board for Janssen, Bristol Myers Squibb, and Takeda. KB has a direct financial relationship with Janssen, Bristol Myers Squibb, Amgen, Sanofi, and Pfizer. SZ received research support from Janssen and Takeda; and served on advisory boards for Janssen, Bristol Myers Squibb, Sanofi, Oncopeptides, Amgen, and Takeda. MD received honoraria from and served in a consulting or advisory role for Amgen, Bristol Myers Squibb, Janssen, Sanofi, and Stemline; and received research funding from Janssen. CS received consulting fees or honoraria from Takeda, Bristol Myers Squibb, Janssen, Amgen, Sanofi, and Pfizer. MMo received honoraria from Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Celgene, Janssen, Takeda, Novartis, and Sanofi; and received research funding from Celgene, Janssen, and Sanofi. LK received honoraria from, served on advisory boards for, or received travel funding from AbbVie, Amgen, Janssen, Celgene/Bristol Myers Squibb, Pfizer, Sanofi, and Takeda. MMa received honoraria from and served in a consulting or advisory role for Janssen, Bristol Myers Squibb/Celgene, Sanofi, and Takeda; received research funding from Janssen and Takeda; and received travel, accommodations, or expenses from Janssen and Sanofi. FO-P served on boards for Janssen, Sanofi, and Pfizer. MR served on an advisory board for Janssen and Pfizer; received research funding from Bristol Myers Squibb, Janssen, and Sanofi; gave lectures for Amgen, Bristol Myers Squibb, Janssen, and Takeda; and had travel, accommodations, or other expenses paid or reimbursed by Amgen, Bristol Myers Squibb, GSK, Janssen, Pfizer, Sanofi, and Takeda. JMSdC served on an advisory board and received honoraria from Janssen, Sanofi, GSK, and AbbVie; and received accommodations from Pfizer and Amgen. NWCJvdD received research support from Janssen, Amgen, Celgene, Novartis, Cellectis, and Bristol Myers Squibb; and serves on advisory boards for Janssen, Amgen, Celgene, Bristol Myers Squibb, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Merck, Pfizer, AbbVie, and Servier (all paid to institution). AB served on advisory boards for Janssen, Sanofi, Amgen, and Bristol Myers Squibb. CT served on an advisory board for and received honoraria from Janssen. NM served on an advisory board for Janssen. M-CV received travel support from Janssen and Sanofi. M-DL received travel expenses from Janssen. WH is an employee of Cytel and is a contractor for Johnson & Johnson. JW, CdB, MR, VV, RC, and JV are employees of Janssen and hold stock in Johnson & Johnson. AT is an employee of Janssen. JC served on advisory boards for Sanofi and Bristol Myers Squibb; served as a consultant for Janssen, Sanofi, Bristol Myers Squibb, Pfizer, and Adaptive; received research support from Sanofi and Bristol Myers Squibb; and received travel support from Janssen, Sanofi, Bristol Myers Squibb, and Pfizer. PS served on an advisory board for Amgen, Bristol Myers Squibb, Celgene, Janssen, Karyopharm, and Pfizer; and received research funding from Amgen, Bristol Myers Squibb, Celgene, Janssen, and Karyopharm. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The molecular landscape of chronic lymphocytic leukemia (CLL) has been extensively characterized, and various potent prognostic biomarkers were discovered. The genetic composition of the B-cell receptor (BCR) immunoglobulin (IG) was shown to be especially powerful for discerning indolent from aggressive disease at diagnosis. Classification based on the IG heavy chain variable gene (IGHV) somatic hypermutation status is routinely applied. Additionally, BCR IGH stereotypy has been implicated to improve risk stratification, through characterization of subsets with consistent clinical profiles. Despite these advances, it remains challenging to predict when CLL progresses to requiring first-line therapy, thus emphasizing the need for further refinement of prognostic indicators. Signaling pathways downstream of the BCR are essential in CLL pathogenesis, and dysregulated components within these pathways impact disease progression. Considering not only genomics but the entirety of factors shaping BCR signaling activity, this review offers insights in the disease for better prognostic assessment of CLL.

Williams-Beuren syndrome (WBS) is a rare genetic condition caused by a chromosomal microdeletion at 7q11.23. It is a multisystem disorder characterized by distinct facies, intellectual disability, and supravalvar aortic stenosis (SVAS). Those with WBS are at increased risk of sudden death, but mechanisms underlying this remain poorly understood. We recently demonstrated autonomic abnormalities in those with WBS that are associated with increased susceptibility to arrhythmia and sudden cardiac death (SCD). A recently introduced method for heart rate variability (HRV) analysis called "heart rate fragmentation" (HRF) correlates with adverse cardiovascular events (CVEs) and death in studies where heart rate variability (HRV) failed to identify high-risk subjects. Some argue that HRF quantifies nonautonomic cardiovascular modulators. We, therefore, sought to apply HRF analysis to a WBS cohort to determine 1 ) if those with WBS show differences in HRF compared with healthy controls and 2 ) if HRF helps characterize HRV abnormalities in those with WBS. Similar to studies of those with coronary artery disease (CAD) and atherosclerosis, we found significantly higher HRF (4 out of 7 metrics) in those with WBS compared with healthy controls. Multivariable analyses showed a weak-to-moderate association between HRF and HRV, suggesting that HRF may reflect HRV characteristics not fully captured by traditional HRV metrics (autonomic markers). We also introduce a new metric inspired by HRF methodology, significant acute rate drop (SARD), which may detect vagal activity more directly. HRF and SARD may improve on traditional HRV measures to identify those at greatest risk for SCD both in those with WBS and in other populations. NEW & NOTEWORTHY This work is the first to apply heart rate fragmentation analyses to individuals with Williams syndrome and posits that the heart rate fragmentation parameter W 3 may enable detection and investigation of phenomena underlying the proarrhythmic short-long-short RR interval sequences paradigm known to precede ventricular fibrillation and ventricular tachycardia. It also forwards a novel method for quantifying sinus arrhythmia and sinus pauses that likely correlate with parasympathetic activity.

Objective: To describe the clinical features of patients with congenital heart disease (CHD) who subsequently developed systemic juvenile idiopathic arthritis (sJIA)., Methods: We conducted a retrospective review of patients diagnosed with CHD and sJIA at our institution. Detailed clinical, laboratory, and radiographic data were collected from the medical record and reviewed with each patient's primary medical team., Results: Five patients with sJIA and CHD were identified. Each child had a unique cardiac anatomy, but all the patients required surgical repair during the first year of life. Four children had thymectomies at the time of cardiac surgery. Classic signs of sJIA such as fever (n = 5), rash (n = 5), and arthritis (n = 4) developed after surgical intervention in all the patients. The individuals in this cohort displayed risk factors associated with severe sJIA, including disease onset before 2 years of age (n = 5), elevated interleukin 18 levels (n = 5), baseline eosinophilia prior to initiation of biologic disease-modifying antirheumatic drugs (n = 4), and positivity for HLA-DRB1*15:01 alleles (n = 4). Macrophage activation syndrome (MAS) occurred in 3 patients and sJIA-associated lung disease (sJIA-LD) was identified in 4 patients. Two children died from complications of their cardiac and/or pulmonary disease., Conclusion: We identified an association between CHD and severe forms of sJIA. Although these findings will need to be confirmed in larger, multicenter cohorts, the results highlight the importance of considering a diagnosis of sJIA in children with CHD and remaining vigilant for complications such as MAS and sJIA-LD., (Copyright © 2024 by the Journal of Rheumatology.)

Background: Frailty in newly-diagnosed multiple myeloma (NDMM) patients is associated with treatment-related toxicity, which negatively affects health-related quality of life (HRQoL). Currently, data on changes in HRQoL of frail and intermediate-fit MM patients during active treatment and post-treatment follow-up are absent., Methods: The HOVON123 study (NTR4244) was a phase II trial in which NDMM patients ≥ 75 years were treated with nine dose-adjusted cycles of Melphalan-Prednisone-Bortezomib (MPV). Two HRQoL instruments (EORTC QLQ-C30 and -MY20) were obtained before start of treatment, after 3 and 9 months of treatment and 6 and 12 months after treatment for patients who did not yet start second-line treatment. HRQoL changes and/or differences in frail and intermediate-fit patients (IMWG frailty score) were reported only when both statistically significant (p < 0.005) and clinically relevant (>MID)., Results: 137 frail and 71 intermediate-fit patients were included in the analysis. Compliance was high and comparable in both groups. At baseline, frail patients reported lower global health status, lower physical functioning scores and more fatigue and pain compared to intermediate-fit patients. Both groups improved in global health status and future perspective; polyneuropathy complaints worsened over time. Frail patients improved over time in physical functioning, fatigue and pain. Improvement in global health status occurred earlier than in intermediate-fit patients., Conclusion: HRQoL improved during anti-myeloma treatment in both intermediate-fit and frail MM patients. In frail patients, improvement occurred faster and, in more domains, which was retained during follow-up. This implies that physicians should not withhold safe and effective therapies from frail patients in fear of HRQoL deterioration., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CAMS serves on advisory boards for Sanofi and Janssen and on speakers' bureaus for Sanofi, Celgene, BMS and Takeda. GJT served as advisor for Novartis. PFY has received payments for lectures from Janssen and Amgen and support for travel expenses from Janssen. RJWK has received support for travel expenses from Novartis and serves on an advisory board of Novartis. PS has received research support from Janssen, Amgen, BMS, Celgene and Karyopharm; and serves on advisory boards for Celgene, Janssen, Amgen, Karyopharm, BMS and Pfizer. NWCJD has received research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis and BMS, all paid to their institution; and serves on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Takeda, Roche, Novartis, Bayer, Adaptive, and Servier, all paid to their institution. HMB serves on an advisory board for Pfizer and has received research support from BMS-Celgene, all paid to their institution. DGJC has received payments for lectures for Takeda, and received financial support for travel expenses from Servier, all outside the submitted work. SZ has received research support from Janssen and the Dutch Cancer Society, all paid to their institution; and serves on advisory boards for Janssen, BMS, Oncopeptides, and Sanofi, all paid to their institution. Others: All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Kazimierz Groen: BMS and Beigene: speakers bureau (no personal funding). Febe Smits: No conflicts of interest. Kazem Nasserinejad: No conflicts of interest. Mark‐David Levin: Support for attending meetings and/or travel: Janssen, Takeda. Josien C. Regelink: No conflicts of interest. Gert‐Jan Timmers: Participation on an Advisory Board: Novartis; Travel, Accommodations, Expenses; Novartis, Janssen. Esther G. M. de Waal: No conflicts of interest. Matthijs Westerman: No conflicts of interest. Gerjo A. Velders: No conflicts of interest. Koen de Heer: No conflicts of interest. Rineke B. L. Leys: No conflicts of interest. Roel J. W. van Kampen: No conflicts of interest. Claudia A. M. Stege: Speaker's Bureau: Sanofi, Celgene/Bristol Myers Squibb, Takeda; Consulting or Advisory Role: Sanofi, Janssen. Maarten R. Seefat: No conflicts of interest. Inger S. Nijhof: Payment or honoraria for lectures, presentations, or educational events: Janssen, Celgene/Bristol Myers Squibb, Sanofi. Ellen van der Spek: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Janssen. Saskia K. Klein: No conflicts of interest. Niels W. C. J. van de Donk: Consulting or Advisory Role: Janssen, Celgene, Bristol Myers Squibb, Novartis, Amgen, Servier, Takeda, Bayer, Roche, Pfizer, Abbvie, Adaptive (no personal funding); Research Funding: Janssen, Celgene, Amgen, Novartis, Bristol Myers Squibb, Cellectis. Paula F. Ypma: Payment or honoraria for presentations: Janssen; Support for attending meetings and/or travel: Janssen. Sonja Zweegman: Consulting or Advisory Role: Janssen‐Cilag, Takeda, Celgene/Bristol Myers Squibb, Sanofi, Oncopeptides (no personal funding); Research Funding: Janssen, Takeda.

Selectivity in organic chemistry is generally presumed to arise from energy differences between competing selectivity-determining transition states. However, in cases where static density functional theory (DFT) fails to reproduce experimental product distributions, dynamic effects can be examined to understand the behavior of more complex reaction systems. Previously, we reported a method for nitrogen deletion of secondary amines which relies on the formation of isodiazene intermediates that subsequently extrude dinitrogen with concomitant C-C bond formation via a caged diradical. Herein, a detailed mechanistic analysis of the nitrogen deletion of 1-aryl-tetrahydroisoquinolines is presented, suggesting that in this system the previously determined diradical mechanism undergoes dynamically controlled partitioning to both the normal 1,5-coupling product and an unexpected spirocyclic dearomatized intermediate, which converges to the expected indane by an unusually facile 1,3-sigmatropic rearrangement. This mechanism is not reproduced by static DFT but is supported by quasi-classical molecular dynamics calculations and unifies several unusual observations in this system, including partial chirality transfer, nonstatistical isotopic scrambling at the ethylene bridge, the isolation of spirocyclic dearomatized species in a related heterocyclic series, and the observation that introduction of an 8-substituent dramatically improves enantiospecificity.

Background: In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available., Methods: GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0-2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m 2 , days 1-2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m 2 , days 1-3) and intravenous cyclophosphamide (250 mg/m 2 , days 1-3). Intravenous rituximab (375 mg/m 2 , day 1 of cycle 1; 500 mg/m 2 , day 1 of cycles 2-6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax-rituximab group, intravenous rituximab (375 mg/m 2 , day 1 of cycle 1; 500 mg/m 2 , day 1 of cycles 2-6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2-6: 1000 mg on day 1). In the venetoclax-obinutuzumab-ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax-rituximab and the venetoclax-obinutuzumab group and between 12 and 36 cycles in the venetoclax-obinutuzumab-ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment., Findings: Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax-rituximab group n=237; venetoclax-obinutuzumab group n=229; and venetoclax-obinutuzumab-ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6-57·9]), patients in the venetoclax-obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32-0·69], p<0·0001) and the venetoclax-rituximab group (0·57 [0·38-0·84], p=0·0011). The venetoclax-obinutuzumab-ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19-0·47]; p<0·0001) and the venetoclax-rituximab group (0·38 [0·24-0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax-obinutuzumab-ibrutinib and venetoclax-obinutuzumab groups (0·63 [0·39-1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax-rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9-91·1; 37 [16%] events) in the venetoclax-obinutuzumab-ibrutinib group, 81·8% (75·8-87·8; 55 [24%] events) in the venetoclax-obinutuzumab group, 70·1% (63·0-77·3; 84 [35%] events) in the venetoclax-rituximab group, and 62·0% (54·4-69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax-rituximab group, 127 [56%] of 228 in the venetoclax-obinutuzumab group, and 112 [48%] of 231 in the venetoclax-obinutuzumab-ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax-rituximab and venetoclax-obinutuzumab groups, and four (2%) in the venetoclax-obinutuzumab-ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy)., Interpretation: With more than 4 years of follow-up, venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax-rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination., Funding: AbbVie, Janssen, and F Hoffmann-La Roche., Competing Interests: Declaration of interests MF reports research funding from AbbVie, AstraZeneca, BeiGene, Janssen, and Roche, and honoraria from AbbVie. JvT reports honoraria from AbbVie, BeiGene, Amgen, AstraZeneca, Janssen, Lilly, and Roche; travel grants from AbbVie, AstraZeneca, BeiGene, Roche, Lilly, and Janssen; and has received consulting fees from and participated on advisory boards for AbbVe, BeiGene, Amgen, and AstraZeneca. MG has received honoraria for participation in symposia and advisory boards from AbbVie, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb (BMS)/Celgene, GSK, Novartis, Incyte, Janssen-Cilag, Jazz, Roche, Pfizer, Sanofi, and Servier; travel support from AbbVie, BeiGene, Pfizer, and Roche; all fees went to their institution. GJ has received honoraria from Astellas and AbbVie and participated on advisory boards for AbbVie and Servier. M-DL reports travel grants from AbbVie and Janssen. CdC-B reports consulting fees from Janssen, honoraria for lectures from Octapharma, support for attending meetings from AbbVie and Octapharma, and participation on advisory boards for Janssen, BeiGene, and AstraZeneca. CSchn reports speakers fees from AstraZeneca and AbbVie, travel support from AbbVie, and participation on an advisory board for Janssen. RB reports travel support from BeiGene, Janssen, and AbbVie, and honoraria for participation on an advisory board from AbbVie. TN reports honoraria for lectures or presentations and has participated at advisory boards from AbbVie, Roche, AstraZeneca, Gilead, BeiGene, and Janssen. CBP is the chairman of the Danish CLL group. HF reports research funding from Sanofi, Novartis, and Alexion and honoraria for lectures from Sanofi. NK reports research funding from AstraZeneca; honoraria from AbbVie, AstraZeneca, Kite/Gilead, BMS, and Lilly; and travel support from AbbVie, AstraZeneca, BeiGene, Lilly, and Janssen; and participation on advisory boards for AstraZeneca and Janssen. JD reports consulting fees, honoraria, and travel support from AbbVie and Janssen. SB reports honoraria from and participation on speakers bureaus for Roche, Janssen, AbbVie, AstraZeneca, and Sanofi; travel support from Janssen, BeiGene, and Roche; and research funding from Janssen and Miltenyi. FS reports speakers fees from AstraZeneca, travel support from Lilly, and research funding from AstraZeneca. A-MF reports research funding and honoraria from AstraZeneca and travel support from AbbVie. KF reports research grants from AbbVie and Roche, honoraria for advisory boards from AstraZeneca, and travel support from Roche. K-AK reports consulting fees, participation on speakers bureaus, and research funding from Roche, AbbVie, and Janssen. MR reports honoraria from Janssen, Roche, and AstraZeneca; consulting fees from Roche, Janssen, AstraZeneca, and AbbVie; research funding from AbbVie and Roche, and travel support from AstraZeneca. MBr reports research funding and consulting fees from Amgen; honoraria for speakers bureaus from Amgen, Becton Dickinson, Janssen, and Pfizer; travel support from Janssen; and participation on advisory boards for Incyte and Amgen. ET reports participation on advisory boards and honoraria from AbbVie, Janssen-Cilag, and BeiGene, AstraZeneca, and Roche; and travel support from AstraZeneca, AbbVie, BeiGene, Janssen. SS reports honoraria from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, and Sunesis; research funding from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, and Sunesis; travel support from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis; and speaker fees from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, and Sunesis. MH reports consulting fees from Roche, Gilead, Janssen, BMS, AbbVie, and AstraZeneca and honoraria from Roche, Gilead, Janssen, BMS, AbbVie, and AstraZeneca. APK reports honoraria from AbbVie, AstraZeneca, BMS, Janssen, LAVA, and Roche/Genentech; travel grants from AbbVie and Janssen; research funding from AstraZeneca, Janssen, Roche/Genentech, AbbVie, and BMS. CUN reports research funding from Octapharma and AstraZeneca; consultancy and speaker fees from AbbVie, AstraZeneca, Janssen, Genmab, BeiGene, Octapharma, CSL Behring, Takeda, Lilly, and MSD; and participation on advisory boards for AstraZeneca, MSD, Genmab, and Janssen. BE reports consulting fees fromJanssen, AbbVie, Gilead, AstraZeneca, MSD, BeiGene, and Lilly; participation on speakers bureau for Roche, AbbVie, BeiGene, AstraZeneca, and MSD; honoraria from Roche, AbbVie, AstraZeneca, BeiGene, and MSD; research funding from Janssen, Gilead, Roche, AbbVie, BeiGene, and AstraZeneca; and travel support from BeiGene. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Patients with chronic lymphocytic leukemia (CLL) have increased risk of severe infections. Although adaptive immune dysfunction is well described, clinical tools for identifying patients at risk are lacking, warranting investigation of additional immune components. In contrast to chemotherapy, targeted agents could spare or even improve innate immune function. Therefore, we investigated innate immune phenotypes and function in patients with CLL before and during targeted treatment., Experimental Design: Baseline and consecutive blood samples were collected from patients with CLL treated with acalabrutinib (n = 17) or ibrutinib+venetoclax (n = 18) in clinical trials. Innate immune function was assessed by TruCulture, a whole-blood ligand-stimulation assay quantifying cytokine release in response to standardized stimuli. Innate immune phenotypes were characterized by flow cytometry. As a proxy for infections, we mapped antimicrobial use before and during treatment., Results: At baseline, patients with CLL displayed impaired stimulated cytokine responses to the endotoxin lipopolysaccharide (LPS) along with deactivated monocytes, enrichment of myeloid-derived suppressor cells and metamyelocytes, and elevated (unstimulated) proinflammatory cytokines. Two/three cycles of acalabrutinib or ibrutinib normalized LPS-stimulated responses, in parallel with decreased duration of infections. Innate immune profiles and elevated proinflammatory cytokines further normalized during longer-term acalabrutinib or ibrutinib+venetoclax, paralleled by decreased infection frequency., Conclusions: Innate immune impairment and infection susceptibility in patients with CLL were restored in parallel during targeted therapy. Thus, targeted treatment may reduce the risk of infections in CLL, as currently under investigation in the PreVent-ACaLL phase 2 trial of acalabrutinib+venetoclax for high-risk CLL (NCT03868722)., (©2024 American Association for Cancer Research.)

Large immune complexes formed by the cross-linking of antibodies with polyvalent antigens play critical roles in modulating cell-mediated immunity. While both the size and the shape of immune complexes are important determinants in Fc receptor-mediated signaling responsible for phagocytosis, degranulation, and, in some instances, autoimmune pathologies, their characterization remains extremely challenging due to their large size and structural heterogeneity. We use native mass spectrometry (MS) supplemented with limited charge reduction in the gas phase to determine the stoichiometry of immune complexes formed by a bivalent (homodimeric) antigen, a 163 kDa aminopeptidase P2 (APP2), and a monoclonal antibody (mAb) to APP2. The observed (APP2·mAb) n complexes populate a wide range of stoichiometries ( n = 1-4) with the largest detected species exceeding 1 MDa, although the gas-phase dissociation products are also evident in the mass spectra. While frequently considering a nuisance that complicates interpretation of native MS data, limited dissociation provides an additional dimension for characterization of the immune complex quaternary structure. APP2/mAb associations with identical composition but slightly different elution times in size exclusion chromatography exhibit notable differences in their spontaneous fragmentation profiles. The latter indicates the presence of both extended linear and cyclized (APP2·mAb) n configurations. The unique ability of MS to distinguish between such isomeric structures will be invaluable for a variety of applications where the biological effects of immune complexes are determined by their ability to assemble Fc receptor clusters of certain density on cell surfaces, such as platelet activation by clustering the low-affinity receptors FcγRIIa on their surface.

Background: Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability., Methods and Results: We performed genome sequencing on 473 individuals with Williams-Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway-level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes/pathways identified here and those ascertained through larger aortic disease/trait genome-wide association studies. We show that SVAS severity in Williams-Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes ( ACAN and LTBP4 ) were uniquely expressed in the aorta. Many genes in the identified pathways were previously reported in genome-wide association studies for aneurysm, bicuspid aortic valve, or aortic size., Conclusions: Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta-focused genome-wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.

Abstract: High-risk multiple myeloma (MM) is often defined based on cytogenetic abnormalities, but patients who relapse early after initial therapy are considered a functional high-risk group. In the phase 3 CASTOR and POLLUX studies, daratumumab plus bortezomib/dexamethasone (D-Vd) or lenalidomide/dexamethasone (D-Rd) improved progression-free survival (PFS) and overall survival (OS), regardless of cytogenetic risk, and achieved higher rates of complete response or better (≥CR) and minimal residual disease (MRD) negativity vs that with Vd/Rd alone in relapsed/refractory MM. Post hoc analyses of CASTOR and POLLUX evaluated patient subgroups with 1 prior line of therapy based on timing of progression/relapse (early or late) after initiation of first line of therapy. PFS consistently favored the daratumumab-containing regimens across subgroups using both a 24- and 18-month early-relapse cutoff. In the CASTOR/POLLUX pooled data set, daratumumab reduced the risk of disease progression or death by 65% (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.26-0.48; P < .0001) in the early-relapse (<24 months) subgroup and by 65% (HR, 0.35; 95% CI, 0.26-0.47; P < .0001) in the late-relapse (≥24 months) subgroup. OS also favored the daratumumab-containing regimens in both the early-relapse (HR, 0.62; 95% CI, 0.45-0.86; P = .0036) and late-relapse (HR, 0.67; 95% CI, 0.48-0.93; P = .0183) subgroups in the pooled population using a 24-month cutoff. Rates of ≥CR and MRD negativity (10-5) were higher with daratumumab vs control, regardless of progression/relapse timing. Although daratumumab is unable to fully overcome the adverse prognosis of early relapse, our results support the use of daratumumab for patients with 1 prior line of therapy, including for those who progress/relapse early after initial therapy and are considered to have functional high-risk MM. These trials were registered at www.clinicaltrials.gov as #NCT02136134 (CASTOR) and #NCT02076009 (POLLUX)., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

BAZ1B is one of 25-27 coding genes deleted in canonical Williams syndrome, a multi-system disorder causing slow growth, vascular stenosis, and gastrointestinal complaints, including constipation. BAZ1B is involved in (among other processes) chromatin organization, DNA damage repair, and mitosis, suggesting reduced BAZ1B may contribute to Williams syndrome symptoms. In mice, loss of Baz1b causes early neonatal death. 89.6% of Baz1b -/- mice die within 24 h of birth without vascular anomalies or congenital heart disease (except for patent ductus arteriosus). Some (<50%) Baz1b -/- were noted to have prolonged neonatal cyanosis, patent ductus arteriosus, or reduced lung aeration, and none developed a milk spot. Meanwhile, 35.5% of Baz1b +/- mice die over the first three weeks after birth. Surviving Baz1b heterozygotes grow slowly (with variable severity). 66.7% of Baz1b +/- mice develop bowel dilation, compared to 37.8% of wild-type mice, but small bowel and colon transit studies were normal. Additionally, enteric neuron density appeared normal in Baz1b -/- mice except in distal colon myenteric plexus, where neuron density was modestly elevated. Combined with several rare phenotypes (agnathia, microphthalmia, bowel dilation) recovered, our work confirms the importance of BAZ1B in survival and growth and suggests that reduced copy number of BAZ1B may contribute to the variability in Williams syndrome phenotypes., Competing Interests: Declaration of competing interest ROH was a consultant for BlueRock Therapeutics and for Takeda., (Copyright © 2023 Elsevier Inc. All rights reserved.)