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Abstract Background Hematopoietic stem cell transplantation (HSCT) is a curative treatment for many diverse blood and immune diseases. However, HSCT regimens currently commonly utilize genotoxic chemotherapy and/or total body irradiation (TBI) conditioning which causes significant morbidity and mortality through inducing broad tissue damage triggering infections, graft vs. host disease, infertility, and secondary cancers. We previously demonstrated that targeted monoclonal antibody (mAb)-based HSC depletion with anti(α)-CD117 mAbs could be an effective alternative conditioning approach for HSCT without toxicity in severe combined immunodeficiency (SCID) mouse models, which has prompted parallel clinical αCD117 mAbs to be developed and tested as conditioning agents in clinical trials starting with treatment of patients with SCID. Subsequent efforts have built upon this work to develop various combination approaches, though none are optimal and how any of these mAbs fully function is unknown. Methods To improve efficacy of mAb-based conditioning as a stand-alone conditioning approach for all HSCT settings, it is critical to understand the mechanistic action of αCD117 mAbs on HSCs. Here, we compare the antagonistic properties of αCD117 mAb clones including ACK2, 2B8, and 3C11 as well as ACK2 fragments in vitro and in vivo in both SCID and wildtype (WT) mouse models. Further, to augment efficacy, combination regimens were also explored. Results We confirm that only ACK2 inhibits SCF binding fully and prevents HSC proliferation in vitro. Further, we verify that this corresponds to HSC depletion in vivo and donor engraftment post HSCT in SCID mice. We also show that SCF-blocking αCD117 mAb fragment derivatives retain similar HSC depletion capacity with enhanced engraftment post HSCT in SCID settings, but only full αCD117 mAb ACK2 in combination with αCD47 mAb enables enhanced donor HSC engraftment in WT settings, highlighting that the Fc region is not required for single-agent efficacy in SCID settings but is required in immunocompetent settings. This combination was the only non-genotoxic conditioning approach that enabled robust donor engraftment post HSCT in WT mice. Conclusion These findings shed new insights into the mechanism of αCD117 mAb-mediated HSC depletion. Further, they highlight multiple approaches for efficacy in SCID settings and optimal combinations for WT settings. This work is likely to aid in the development of clinical non-genotoxic HSCT conditioning approaches that could benefit millions of people world-wide.

BackgroundUse of the proteasome inhibitor carfilzomib has become a standard of care in patients with relapsed/refractory multiple myeloma. An association between carfilzomib and cardiovascular adverse events has been well documented, but this had not been investigated in a racially diverse population. Black patients in particular are underrepresented in the reported outcomes of treatment with carfilzomib.ObjectiveThe purpose of this study was to identify risk factors for carfilzomib-associated cardiovascular events in a diverse, single-center population.MethodsWe conducted a retrospective review of 161 patients with multiple myeloma treated with carfilzomib between 2011 and 2020 at the University of Maryland Medical Center. Over half (86) were Black patients, with the remainder (75) being White patients. We did a multivariate analysis to determine risk factors for developing cardiovascular events during treatment with carfilzomib.ResultsThere was no statistically significant association with cardiotoxicity and race, gender, or age at first dose of carfilzomib. In multivariable analysis, patients with history of hypertension had a higher risk of cardiotoxicity [adjusted odds ratio (OR): 2.5; 95% CI: 1.1–5.9; P = 0.03] as did those with a history of smoking [OR: 2.8; 95% CI: 1.3–6.4; P = 0.01].ConclusionsHere we report the largest cohort of Black patients treated with carfilzomib as yet reported. The results of this single center retrospective study show history of hypertension and smoking are associated with carfilzomib associated cardiotoxicity in a diverse patient population. There is a need for well-designed prospective studies enrolling a diverse population to investigate potential interventions to prevent carfilzomib-associated cardiotoxicity.

Abstract Many migratory fish populations are declining, threatened by human‐induced pressures such as habitat loss and fragmentation caused by dams, roads, land use change, climate change and pollution. However, public awareness of fish migration and associated human pressures remains limited. It is important to communicate about hard‐to‐see and complex environmental topics and issues, such as fish migration, with young people, who stand to be the most affected by ongoing global changes. Young people are also at a critical stage in their attitude formation and may be particularly receptive to learning enrichment and engagement for behaviour change about environmental issues. Arts‐based methods can be particularly effective in fostering broad personal connections with nature, especially for complex topics like fish migration. The collaborative and creative processes involved in developing such media often lack critique, which limits learning from previous experiences. In this article, we reflect on the co‐creation of the Shout Trout Workout (STW), a lyric poem, comic and music video for 8‐ to 14‐year‐olds, designed to entertain, engage and enrich learning about migratory fishes and aquatic environments. We chart the process of creation, including conception of ideas, writing the poem, fact‐checking and developing the storyline with scientists and creating a comic and music video with visual artists and musicians. We explore some of the challenges and merits of collaborative working, consider the impacts of the COVID‐19 pandemic on the creative and initial engagement process and share what we learned about creative input, communication and respect. We also discuss how the experience shaped our thoughts about the nature of co‐creation itself, and how in creating STW, collaborators contributed to the process in multiple, nuanced and unanticipated ways (e.g. artistic input, ideas, science, dissemination), representing a spectrum of co‐creative practice. We hope that sharing our experiences and reflections is useful and inspiring for other cross‐disciplinary collaborations, and for those who aim to create learning enrichment and engagement material about ecological processes and environmental issues for young people. A free Plain Language Summary can be found within the Supporting Information of this article.

We report a case of coronary perforation during high-risk percutaneous coronary intervention with Impella (Abiomed, Danvers, Massachusetts) support that resulted in cessation of pulsatile arterial flow. Maintenance of systemic perfusion due to antecedent placement of Impella 2.5 allowed for successful treatment with pericardiocentesis and covered stent placement, early discharge, and complication-free follow-up. (Level of Difficulty: Intermediate.)

Objectives: Lead (Pb) exposure is associated with dental caries. Whether Pb affects tooth microhardness, is unclear. Our objective was to assess whether Pb concentration is associated with microhardness. Methods: Exfoliated primary teeth were collected from 46 volunteers. Teeth were sectioned, one half of each tooth was tested for enamel Knoop microhardness. The remaining half was digested and Pb measured using an inductively coupled plasma-mass spectrometer. Results: The correlations between Pb levels and microhardness were very low, and were not statistically significant at p < 0.05. Conclusions: Previous exposure to high levels of Pb was not associated with decreased tooth microhardness. Clinical significance: This study assessed whether Pb in deciduous teeth is associated with tooth microhardness. As this was not the case, further studies are needed to identify the mechanisms behind the association between lead exposure and tooth decay.

The amino acid L-arginine inhibits bacterial coaggregation, is involved in cell-cell signaling, and alters bacterial metabolism in a broad range of species present in the human oral cavity. Given the range of effects of L-arginine on bacteria, we hypothesized that L-arginine might alter multi-species oral biofilm development and cause developed multi-species biofilms to disassemble. Because of these potential biofilm-destabilizing effects, we also hypothesized that L-arginine might enhance the efficacy of antimicrobials that normally cannot rapidly penetrate biofilms. A static microplate biofilm system and a controlled-flow microfluidic system were used to develop multi-species oral biofilms derived from pooled unfiltered cell-containing saliva (CCS) in pooled filter-sterilized cell-free saliva (CFS) at 37° C. The addition of pH neutral L-arginine monohydrochloride (LAHCl) to CFS was found to exert negligible antimicrobial effects but significantly altered biofilm architecture in a concentration-dependent manner. Under controlled flow, the biovolume of biofilms (μm(3)/μm(2)) developed in saliva containing 100-500 mM LAHCl were up to two orders of magnitude less than when developed without LAHCI. Culture-independent community analysis demonstrated that 500 mM LAHCl substantially altered biofilm species composition: the proportion of Streptococcus and Veillonella species increased and the proportion of Gram-negative bacteria such as Neisseria and Aggregatibacter species was reduced. Adding LAHCl to pre-formed biofilms also reduced biovolume, presumably by altering cell-cell interactions and causing cell detachment. Furthermore, supplementing 0.01% cetylpyridinium chloride (CPC), an antimicrobial commonly used for the treatment of dental plaque, with 500 mM LAHCl resulted in greater penetration of CPC into the biofilms and significantly greater killing compared to a non-supplemented 0.01% CPC solution. Collectively, this work demonstrates that LAHCl moderates multi-species oral biofilm development and community composition and enhances the activity of CPC. The incorporation of LAHCl into oral healthcare products may be useful for enhanced biofilm control.

BACKGROUND: Pain is a subjective sensory and emotional experience that is influenced by variables such as stress, anxiety and sex.