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Background: Cytokine release syndrome, commonly associated with T-cell immunotherapies, was observed with talquetamab, a T-cell-redirecting bispecific antibody, in the phase I/II MonumenTAL-1 study, leading to elevated interleukin (IL)-6, which can suppress cytochrome P450 (CYP) enzyme activity., Objective: We aimed to evaluate the potential impact of elevated IL-6 on the exposure of co-administered CYP450 substrates for two scenarios: (1) the observed median IL-6 profile and (2) a profile with the highest IL-6 maximum concentration following talquetamab treatment., Methods: A physiologically based pharmacokinetic model was developed based on the literature and simulations performed using observed IL-6 profiles from patients in MonumenTAL-1 who received the subcutaneous recommended phase 2 doses (RP2Ds) of talquetamab: 0.4 mg/kg weekly (QW) and 0.8 mg/kg every other week (Q2W)., Results: Median IL-6 maximum concentration was 18.4 and 7.1 pg/mL, and maximum IL-6 maximum concentration was 213 and 3503 pg/mL for talquetamab QW and Q2W RP2Ds, respectively. For the median IL-6 profile, no interaction between IL-6 and studied CYP substrates was predicted at either RP2D. The maximum IL-6 profile predicted weak-to-moderate impact on exposure of CYP2C19, CYP3A4, and CYP3A5 substrates and minimal impact on exposure of CYP1A2 substrates at both RP2Ds. Impact on exposure of CYP2C9 substrates was predicted as minimal at QW and minimal-to-weak at Q2W RP2Ds. Time to return to 20% difference from baseline enzymatic activity was predicted as 7 and 9 days after start of cycle 1 for QW and Q2W RP2Ds, respectively., Conclusions: These modeling results suggest that IL-6 release due to talquetamab-induced cytokine release syndrome has limited impact on potential drug-drug interactions, with the highest likelihood of impact occurring from initiation of talquetamab step-up dosing up to 7 (QW) or 9 (Q2W) days after first treatment dose in cycle 1 and during and after cytokine release syndrome. Multiple myeloma can be treated with immunotherapies such as the bispecific antibody, talquetamab, which binds the novel antigen G protein-coupled receptor family C group 5 member D on multiple myeloma cells and CD3 on T cells and induces T-cell-mediated lysis of multiple myeloma cells. Following talquetamab treatment, many patients experience cytokine release syndrome, an inflammatory immune response where levels of proinflammatory cytokines, including interleukin (IL)-6, are increased. Interleukin-6 can suppress the activity of important enzymes in the body (cytochrome [CYP] P450s) that are involved in drug clearance. This study used a physiologically based pharmacokinetic computer model to investigate the potential impact of increased IL-6 levels on CYP450 enzymes to determine subsequent impact on drugs that are metabolized by CYP450 enzymes. The results showed no predicted interaction between median levels of IL-6 observed in patients and CYP substrates (such as caffeine and omeprazole) with talquetamab. In a simulation that assessed higher (maximum) IL-6 levels observed in patients, the predicted impact of IL-6 was minimal to weak for most of the CYP substrates assessed. The effect on CYP450 enzymatic activity was highest from initiation of talquetamab step-up dosing up to 7-9 days after the first treatment dose of talquetamab. These results suggest that, in this treatment time period, elevated IL-6 levels due to talquetamab-induced cytokine release syndrome have limited impact on drugs that are CYP substrates that may be used in conjunction with talquetamab, but that the concentration and toxicity of these drugs should be monitored and the dose of CYP substrate adjusted as required., Competing Interests: Declarations Funding The study was funded by Janssen Research & Development and medical writing support was funded by Janssen Global Services. Conflicts of Interest M-EW is employed by and has stock/other ownership interests in Janssen. JG is employed by Janssen at the time of the analysis and has stock/other ownership interests in Janssen. BWH is employed by Janssen Oncology and has stock/other ownership interests in Johnson & Johnson/Janssen. TM is employed by Janssen at the time of the analysis and has stock/other ownership interests in Janssen. JT is employed by Johnson & Johnson, has stock/other ownership interests in Johnson & Johnson, and has received research funding from Janssen Research & Development. TR is employed by Janssen Oncology and has stock/other ownership interests in Johnson & Johnson/Janssen. CH is employed by Janssen at the time of the analysis and has stock/other ownership interests in Janssen. CK is employed by Janssen at the time of the analysis and has stock/other ownership interests in Janssen. LDZ is employed by Janssen and has stock/other ownership interests in Janssen. SG is employed by Janssen at the time of the analysis, has stock/other ownership interests in Bristol Myers Squibb, Janssen, and Jazz Pharmaceuticals, and holds patents with Johnson & Johnson. XM is employed by Janssen at the time of the analysis and has stock/other ownership interests in Janssen. DO is employed by and has stock/other ownership interests in Janssen. Ethics Approval Not applicable. Consent to Participate Not applicable. Consent for Publication Not applicable. Availability of Data and Material The datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author upon reasonable request. Data Sharing The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinicaltrials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu. Code Availability Not applicable. Authors’ Contributions M-EW: wrote the manuscript, designed the research, performed the research, analyzed the data, and contributed significantly to the manuscript review and editing. JG: designed the research, performed the research, contributed to the data acquisition and interpretation, and writing (review and editing). BWH: contributed to conceptualization, data acquisition, investigation, methodology, validation, and writing (review and editing). TM: contributed to conceptualization, data acquisition, investigation, methodology, validation, and writing (review and editing). JT: contributed to conceptualization, data acquisition, investigation, methodology, validation, and writing (review and editing). TR: contributed to conceptualization, data acquisition, investigation, methodology, validation, and writing (review and editing). CH: contributed to conceptualization, data acquisition, investigation, methodology, validation, and writing (review and editing). CK: contributed to conceptualization, data acquisition, investigation, methodology, validation, and writing (review and editing). LDZ: designed the research, performed the research, analyzed the data, and contributed to writing (review and editing). SG: designed the research, contributed to the data analysis and interpretation, and writing (review and editing). XM: designed the research, analyzed the data, contributed to the data analysis and interpretation, and writing (review and editing). DO: designed the research, performed the research, analyzed the data, and contributed to writing (review and editing)., (© 2024. The Author(s).)

Objectives: Talquetamab is a newly approved bispecific antibody targeting the CD3 receptor on T cells and a receptor, G protein-coupled receptor family C group 5 member D (GPRC5D), highly expressed on multiple myeloma (MM) cells. In addition to immune therapy-related adverse events (AEs) associated with bispecific antibody therapies, talquetamab is associated with unique skin/nail and oral GPRC5D-related side effects that require additional supportive care. This review provides clinical management strategies for talquetamab based on oncology nurses' experience during the MonumenTAL-1 (NCT03399799/NCT04634552) clinical trial. The objective of this review is to raise awareness among nurses and patients to better understand and manage the side effects associated with talquetamab treatment in order to optimize patient outcomes., Data Sources: MonumenTAL-1 is a phase 1/2 clinical trial of talquetamab in patients with relapsed/refractory MM who are triple-class exposed. Details on overall response, safety, and AE incidence and occurrence were previously published. Management strategies for the T-cell-related and unique GPRC5D-related AEs were collected from oncology nurses from different study sites., Conclusion: Talquetamab has shown overall response rates of >71% in patients with relapsed/refractory MM in the MonumenTAL-1 study. AEs were low grade and predictable; few led to study discontinuation., Implications for Nursing Practice: Oncology nurses have specialized knowledge of treatment administration monitoring based on their participation in the MonumenTAL-1 trial. This review provides information for nurses in both the academic and community settings on how to monitor, counsel, and support patients, which will in turn improve patients' quality of life and overall survival., Competing Interests: Declaration of competing interest DC has received consulting fees from BMS; and has received payment for services on speakers’ bureaus and fees for participation on advisory boards from Janssen. CR, EE, SR, KH, SS have no conflicts to disclose. KP has received consulting fees from Janssen. SL has received fees for participation on advisory boards from BMS, Janssen, Legend, and Pfizer. LO, KG, JT, TR, SP, and LH are employed by Janssen., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Talquetamab is a bispecific antibody targeting the multiple myeloma-associated antigen G protein-coupled receptor family C group 5 member D (GPRC5D). In the phase 1/2 MonumenTAL-1 trial (NCT03399799/NCT04634552), overall responses rates were > 71% in patients with triple-class exposed relapsed/refractory multiple myeloma (RRMM). Due to the distribution of the target antigen, a unique pattern of GPRC5D-associated adverse events (AEs) was observed, together with T-cell redirection-associated AEs. Management strategies for talquetamab-associated AEs are described., Discussion: GPRC5D-associated AEs included dermatologic (rash, nonrash, and nail toxicities) and oral AEs (dysgeusia, dysphagia, and dry mouth). The incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were consistent with other T-cell redirection therapies. The incidence of high-grade infections was lower than observed with B-cell maturation antigen-targeting bispecific antibodies, with less frequent use of intravenous immunoglobulin required. GPRC5D-associated AEs were mostly low grade and led to few discontinuations. Skin toxicities were managed with emollients, topical corticosteroids, and oral corticosteroids (for high-grade, persistent, or AEs that progress). Nail toxicities were commonly managed with emollients. Based on investigator experience, dose modification may be effective for controlling oral events. Observation for potential weight changes is required. Infections were managed per standard of care. CRS and ICANS were effectively managed, consistent with other trials of T-cell redirection therapies., Conclusion: Although talquetamab had a distinct safety profile, AEs were considered clinically manageable and mostly low grade. With appropriate education and support, health care practitioners can ensure patients with RRMM maintain quality of life and treatment adherence. VIDEO ABSTRACT., (Copyright © 2024. Published by Elsevier Inc.)

Multiple myeloma is a genetically complex and heterogenous malignancy with a 5-year survival rate of approximately 60%. Despite advances in therapy, patients experience cycles of remission and relapse, with each successive line of therapy associated with poorer outcomes; therefore, therapies with different mechanisms of action against new myeloma antigens are needed. G protein-coupled receptor class C group 5 member D (GPRC5D) has emerged as a novel therapeutic target for the treatment of multiple myeloma. We review the biology and target validation of GPRC5D, and clinical data from early phase trials of GPRC5D-targeting bispecific antibodies, talquetamab and forimtamig, and chimeric antigen receptor T cell (CAR-T) therapies, MCARH109, OriCAR-017, and BMS-986393. In addition to adverse events (AEs) associated with T-cell-redirection therapies irrespective of target, a consistent pattern of dermatologic and oral AEs has been reported across several trials of GPRC5D-targeting bispecific antibodies, as well as rare cerebellar events with CAR-T therapy. Additional studies are needed to understand the underlying mechanisms involved in the development of skin- and oral-related toxicities. We review the strategies that have been used to manage these GPRC5D-related toxicities. Preliminary efficacy data showed overall response rates for GPRC5D-targeting T-cell-redirecting therapies were ≥64%; most responders achieved a very good partial response or better. Pharmacokinetics/pharmacodynamics showed that these therapies led to cytokine release and T-cell activation. In conclusion, results from early phase trials of GPRC5D-targeting T-cell-redirecting agents have shown promising efficacy and manageable safety profiles, including lower infection rates compared with B-cell maturation antigen- and Fc receptor-like protein 5-targeting bispecific antibodies. Further clinical trials, including those investigating GPRC5D-targeting T-cell-redirecting agents in combination with other anti-myeloma therapies and with different treatment modalities, may help to elucidate the future optimal treatment regimen and sequence for patients with multiple myeloma and improve survival outcomes. Video Summary., (© 2024. The Author(s).)

Importance: Bolstering the ranks of women and underrepresented groups in medicine (URM) among medical faculty can help address ongoing health care disparities and therefore constitutes a critical public health need. There are increasing proportions of URM faculty, but comparisons of these changes with shifts in regional populations are lacking., Objective: To quantify the representation of women and URM and assess changes and variability in representation by individual US medical schools., Design, Setting, and Participants: This retrospective cross-sectional study assessed US medical school faculty rosters for women and URM, including American Indian and Alaska Native, Black, Hispanic, and Native Hawaiian or other Pacific Islander faculty. US allopathic medical schools participating in the Association of American Medical Colleges (AAMC) Faculty Administrative Management Online User System from 1990 to 2019 (updated December 31 for each year), were included. Faculty data were analyzed from yearly cross-sections updated as of December 31 for each year from 1990 to 2019. For census data, decennial census data were used for years 1990, 2000, and 2010. Intercensal estimates were used for all other years from 1990 to 2019., Main Outcomes and Measures: Trends and variability in representation quotient (RQ), defined as representation of a group within an institution's faculty compared to its respective US county., Results: There were 121 AAMC member institutions (72 076 faculty) in 1990, which increased to 144 institutions (184 577 faculty) in 2019. The median RQ of women faculty increased from 0.42 (IQR, 0.37-0.46) to 0.80 (IQR, 0.74-0.89) (slope, +1.4% per year; P < .001). The median RQ of Black faculty increased from 0.10 (IQR, 0.06-0.22) to 0.22 (IQR, 0.14-0.41) (slope, +0.5% per year; P < .001), but remained low. In contrast, the median RQ of Hispanic faculty decreased from 0.44 (IQR, 0.19-1.22) to 0.34 (IQR, 0.23-0.62) (slope, -1.7% per year; P < .001) between 1990 and 2019. Absolute total change in RQ of URM showed an increase; however, the 30-year slope did not differ from zero (+0.1% per year; P = .052). Although RQ of women faculty increased for most institutions (127 [88.2%]), large variability in URM faculty trends were observed (57 institutions [39.6%] with increased RQ and 10 institutions [6.9%] with decreased RQ). Nearly one-quarter of institutions shifted from the top to bottom 50th percentile institutional ranking by URM RQ with county vs national comparisons., Conclusions and Relevance: The findings of this cross-sectional study suggest that representation of women in academic medicine improved with time, while URM overall experienced only modest increases with wide variability across institutions. Among URM, the Hispanic population has lost representational ground. County-based population comparisons provide new insights into institutional variation in representation among medical school faculty.

Since its 2015 update, MaizeGDB, the Maize Genetics and Genomics database, has expanded to support the sequenced genomes of many maize inbred lines in addition to the B73 reference genome assembly. Curation and development efforts have targeted high quality datasets and tools to support maize trait analysis, germplasm analysis, genetic studies, and breeding. MaizeGDB hosts a wide range of data including recent support of new data types including genome metadata, RNA-seq, proteomics, synteny, and large-scale diversity. To improve access and visualization of data types several new tools have been implemented to: access large-scale maize diversity data (SNPversity), download and compare gene expression data (qTeller), visualize pedigree data (Pedigree Viewer), link genes with phenotype images (MaizeDIG), and enable flexible user-specified queries to the MaizeGDB database (MaizeMine). MaizeGDB also continues to be the community hub for maize research, coordinating activities and providing technical support to the maize research community. Here we report the changes MaizeGDB has made within the last three years to keep pace with recent software and research advances, as well as the pan-genomic landscape that cheaper and better sequencing technologies have made possible. MaizeGDB is accessible online at https://www.maizegdb.org.

In the last two decades, tremendous advances have been made in the treatment of acute lymphocytic leukaemia (ALL) in children with 5 year 'cure' rates in excess of 90%. The maintenance of remission is due, in part, to individualisation of therapy which must consider age, body size, genetic constitution and the impact of disease on drug disposition and action. This review, focused on treatment of ALL and one of the therapeutic mainstays, 6-mercaptopurine, illustrates the importance of obesity as a modulating factor in dose individualisation., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Compared to adults, venous thromboembolism in the pediatric population is a rare event. Cancer, cardiac disease, antiphospholipid antibodies, and indwelling catheters are established risk factors for thromboembolism in children. We examined the literature related to thrombophilia in children, childhood cancer and thrombosis, cardiac disease and thrombosis, and antiphospholipid antibody syndrome in children. Citations in identified articles yielded additional articles for review. We found that studies of acquired thrombophilia in children are limited. Current treatment for thromboembolism in children is based on adult data therefore optimal treatment in this population remains unclear., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Safety-net hospitals will continue to play a critical role in the US health care system, as they will need to care for the more than twenty-three million people who are estimated to remain uninsured after the Affordable Care Act is implemented. Yet such hospitals will probably have less federal and state support for uncompensated care. At the same time, safety-net hospitals will need to reposition themselves in the marketplace to compete effectively for newly insured people who will have a choice of providers. We examine how five leading safety-net hospitals have begun preparing for reform. Building upon strong organizational attributes such as health information technology and system integration, the study hospitals' preparations include improving the efficiency and quality of care delivery, retaining current and attracting new patients, and expanding the medical home model.

International air medical transport requires reliable equipment, skilled personnel and precise planning. A report is presented of an experience with 31 international transports. Details concerning equipment, personnel and logistics are presented. Results and problem areas are discussed. This early experience demonstrates the capability for the repatriation of critically ill patients, and the evacuation of patients who require access to a level of care which may be unavailable outside the United States.

International air medical transport requires reliable equipment, skilled personnel and precise planning. A report is presented of an experience with 29 international transports. Details concerning equipment, personnel and logistics are presented. Results and problem areas are discussed. This early experience demonstrates the capability for the repatriation of critically ill patients, and the evacuation of patients who require access to a level of care which may be unavailable outside the United States.

Strain measurement within the cement surrounding stemmed total hip femoral components was accomplished using PMMA encapsulated and embedded strain gauges. Cement strain measurement associated with a well-bonded stem-cement interface and an unbonded stem-cement interface (i.e., loose prosthesis) was performed. The presence of a stem-cement bond was found to reduce proximal cement strain magnitudes while having little effect on distal cement strain magnitudes. The assurance of a stem-cement bond on only the proximal third of the interface was found to have an effect similar to that of a complete stem-cement bond. The results of this experimental investigation confirm the theoretical prediction that the stem-cement bond is important in maintaining the integrity of the cement mantle surrounding a stemmed femoral component.

The purposes of this study were (1) to describe normal wrist kinetics, and (2) to investigate the in-vitro kinetics of four currently available wrist prostheses (Swanson, Meuli, Volz, Hamas). The effective tendon moment arms of the six major wrist muscles were determined through the use of load cells and applied weights. Testing was conducted in a neutral wrist configuration with hand pronation-supination both constrained and unconstrained. The results indicate that each of the muscles studied has a unique set of effective tendon moment arms about the normal wrist as well as about wrists with the implanted prostheses, and that none of the prosthetic wrists studied duplicated normal wrist kinetics.

This article discusses preliminary results of a National Cancer Institute-sponsored pilot baseline survey in 1989 of smoking knowledge, attitude and habits among black smokers in four major U.S. cities: two in the North (Springfield, Massachusetts and Hartford, Connecticut) and two in the South (Durham, North Carolina and Columbia, South Carolina). It focuses on mass media readership, viewing and listening habits and a preliminary discussion of their application to practice.