Mitochondrial Pyruvate Import Promotes Long-Term Survival of Antibody-Secreting Plasma Cells.

Durable antibody production after vaccination or infection is mediated by long-lived plasma cells (LLPCs). Pathways that specifically allow LLPCs to persist remain unknown. Through bioenergetic profiling, we found that human and mouse LLPCs could robustly engage pyruvate-dependent respiration, whereas their short-lived counterparts could not. LLPCs took up more glucose than did short-lived plasma cells (SLPCs) in vivo, and this glucose was essential for the generation of pyruvate. Glucose was primarily used to glycosylate antibodies, but glycolysis could be promoted by stimuli such as low ATP levels and the resultant pyruvate used for respiration by LLPCs. Deletion of Mpc2, which encodes an essential component of the mitochondrial pyruvate carrier, led to a progressive loss of LLPCs and of vaccine-specific antibodies in vivo. Thus, glucose uptake and mitochondrial pyruvate import prevent bioenergetic crises and allow LLPCs to persist. Immunizations that maximize these plasma cell metabolic properties might thus provide enduring antibody-mediated immunity.

Ecodesign and Operational Strategies to Reduce the Carbon Footprint of MRI for Energy Cost Savings.

Background Radiology is a major contributor to health care's climate footprint due to energy-intensive devices, particularly MRI, which uses the most energy. Purpose To determine the energy, cost, and carbon savings that could be achieved through different scanner power management strategies. Materials and Methods In this retrospective evaluation, four outpatient MRI scanners from three vendors were individually equipped with power meters (1-Hz sampling rate). Power measurement logs were extracted for 39 days. Data were segmented into off, idle, prepared-to-scan, scan, or power-save modes for each scanner. Energy, cost (assuming a mean cost of $0.14 per kilowatt hour), and carbon savings were calculated for the lowest scanner activity modes. Data were summarized using descriptive statistics and 95% CIs. Results Projected annual energy consumption per scanner ranged from 82.7 to 171.1 MW-hours, with 72%-91% defined as nonproductive. Power draws for each mode were measured as 6.4 kW ± 0.1 (SD; power-save mode), 7.3 kW ± 0.6 to 9.7 kW ± 0.2 (off), 9.5 kW ± 0.9 to 14.5 kW ± 0.5 (idle), 17.3 kW ± 0.5 to 25.6 kW ± 0.6 (prepared-to-scan mode), and 28.6 kW ± 8.6 to 48.3 kW ± 11.8 (scan mode). Switching MRI units from idle to off mode for 12 hours overnight reduced power consumption by 25%-33%, translating to a potential annual savings of 12.3-21.0 MW-hours, $1717-$2943, and 8.7-14.9 metric tons of carbon dioxide (CO2) equivalent (MTCO2eq). The power-save mode further reduced consumption by 22%-28% compared with off mode, potentially saving an additional 8.8-11.4 MW-hours, $1226-$1594, and 6.2-8.1 MTCO2eq per year for 12 hours overnight. Implementation of a power-save mode for 12 hours overnight in all outpatient MRI units in the United States could save U.S. health care 58 863.2-76 288.2 MW-hours, $8.2-$10.7 million, and 41 606.4-54 088.3 MTCO2eq. Conclusion Powering down MRI units made radiology departments more energy efficient and showed substantial sustainability and cost benefits. © RSNA, 2023 Supplemental material is available for this article. See also the article by Vosshenrich and Heye in this issue.

Implementing an exclusive human milk diet for preterm infants: real-world experience in diverse NICUs.

BACKGROUND: Human milk-based human milk fortifier (HMB-HMF) makes it possible to provide an exclusive human milk diet (EHMD) to very low birth weight (VLBW) infants in neonatal intensive care units (NICUs). Before the introduction of HMB-HMF in 2006, NICUs relied on bovine milk-based human milk fortifiers (BMB-HMFs) when mother's own milk (MOM) or pasteurized donor human milk (PDHM) could not provide adequate nutrition. Despite evidence supporting the clinical benefits of an EHMD (such as reducing the frequency of morbidities), barriers prevent its widespread adoption, including limited health economics and outcomes data, cost concerns, and lack of standardized feeding guidelines. METHODS: Nine experts from seven institutions gathered for a virtual roundtable discussion in October 2020 to discuss the benefits and challenges to implementing an EHMD program in the NICU environment. Each center provided a review of the process of starting their program and also presented data on various neonatal and financial metrics associated with the program. Data gathered were either from their own Vermont Oxford Network outcomes or an institutional clinical database. As each center utilizes their EHMD program in slightly different populations and over different time periods, data presented was center-specific. After all presentations, the experts discussed issues within the field of neonatology that need to be addressed with regards to the utilization of an EHMD in the NICU population. RESULTS: Implementation of an EHMD program faces many barriers, no matter the NICU size, patient population or geographic location. Successful implementation requires a team approach (including finance and IT support) with a NICU champion. Having pre-specified target populations as well as data tracking is also helpful. Real-world experiences of NICUs with established EHMD programs show reductions in comorbidities, regardless of the institution's size or level of care. EHMD programs also proved to be cost effective. For the NICUs that had necrotizing enterocolitis (NEC) data available, EHMD programs resulted in either a decrease or change in total (medical + surgical) NEC rate and reductions in surgical NEC. Institutions that provided cost and complications data all reported a substantial cost avoidance after EHMD implementation, ranging between $515,113 and $3,369,515 annually per institution. CONCLUSIONS: The data provided support the initiation of EHMD programs in NICUs for very preterm infants, but there are still methodologic issues to be addressed so that guidelines can be created and all NICUs, regardless of size, can provide standardized care that benefits VLBW infants.

Esophageal atresia/tracheoesophageal fistula and proximal symphalangism in a patient with a NOG nonsense mutation.

Esophageal atresia and tracheoesophageal fistula (EA/TEF) are relatively common malformations of the human foregut. The etiology remains incompletely understood with genetic causes identified in a small minority of affected patients. We present the case of a newborn with type C EA/TEF along with proximal symphalangism found to have a de novo NOG nonsense mutation. Patients with chromosome 17q deletions including the NOG gene have previously been reported to have EA/TEF but mutations in the gene have not been identified in patients with this malformation. This case provides evidence that haploinsufficiency for NOG may be the cause for EA/TEF in the 17q deletion syndrome and suggests that the clinical spectrum of NOG-related symphalangism spectrum disorders may include EA/TEF.

Child Psychiatric Emergencies: Updates on Trends, Clinical Care, and Practice Challenges.

Over the past 15 years, the number of pediatric patients presenting to the emergency room in psychiatric crisis has nearly doubled. Suicidality and aggression are among the most common presenting problems, making it important for providers to have up-to-date knowledge about the assessment and management of these frequently encountered clinical issues. Psychometrically sound suicide risk assessment tools are available for use in the emergency room setting, which can be administered efficiently with minimal provider training. Rates of off-label medication use in the pediatric population continue to increase and are often used in the management of acute agitation in the pediatric population. The current literature will be reviewed and summarized for application in emergent treatment settings. Overall, evidence to inform best practice is limited, leading to opportunities for innovation in health care delivery, the development of new research aims, and discussion of challenging clinical dilemmas.

IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid mouse progenitors.

While most blood lineages are assumed to mature through a single cellular and developmental route downstream of HSCs, dendritic cells (DCs) can be derived from both myeloid and lymphoid progenitors in vivo. To determine how distinct progenitors can generate similar downstream lineages, we examined the transcriptional changes that accompany loss of in vivo myeloid potential as common myeloid progenitors differentiate into common DC progenitors (CDPs), and as lymphoid-primed multipotent progenitors (LMPPs) differentiate into all lymphoid progenitors (ALPs). Microarray studies revealed that IFN regulatory factor 8 (IRF-8) expression increased during each of these transitions. Competitive reconstitutions using Irf8(-/-) BM demonstrated cell-intrinsic defects in the formation of CDPs and all splenic DC subsets. Irf8(-/-) common myeloid progenitors and, unexpectedly, Irf8(-/-) ALPs produced more neutrophils in vivo than their wild-type counterparts at the expense of DCs. Retroviral expression of IRF-8 in multiple progenitors led to reduced neutrophil production and increased numbers of DCs, even in the granulocyte-macrophage progenitor (GMP), which does not normally possess conventional DC potential. These data suggest that IRF-8 represses a neutrophil module of development and promotes convergent DC development from multiple lymphoid and myeloid progenitors autonomously of cellular context.

Blood pressure abnormalities in children with sickle cell anemia.

BACKGROUND: Kidney disease is an important cause of morbidity and mortality in patients with sickle cell anemia (SCA). The factors that affect progression of renal disease are unknown, especially in children and adolescents. Alterations in blood pressure, including hypertension and lack of the normal nocturnal dip in blood pressure, are important determinants of diabetic nephropathy and other renal diseases and may play a role in sickle cell nephropathy. Our primary hypothesis was that children with SCA who have microalbuminuria will demonstrate less nocturnal dipping of blood pressure compared to patients without microalbuminuria. We also investigated other potential factors associated with microalbuminuria. PROCEDURE: This prospective study of 52 adolescents with SCA followed in the Children's Medical Center Dallas Comprehensive Sickle Cell Center characterized 24-hour ambulatory blood pressure profiles and presence of microalbuminuria. Stepwise logistic regression was performed to identify significant independent factors that are associated with microalbuminuria. RESULTS: Thirty-five percent of patients were identified as having previously unrecognized hypertension, and 17% had pre-hypertension (blood pressure greater than the 90th percentile but less than the 95th percentile). Fifty-six percent of patients lacked the normal nocturnal dip in blood pressure. In addition, 21% had microalbuminuria, and their percent nocturnal dip was significantly less than those without microalbuminuria (P = 0.01). CONCLUSIONS: Blood pressure abnormalities are common in adolescents with SCA and are a possible modifiable risk factor in the progression of sickle cell nephropathy.

Radiology Environmental Impact: What Is Known and How Can We Improve?

The healthcare sector generates approximately 10% of the total carbon emissions in the United States. Radiology is thought to be a top contributor to the healthcare carbon footprint due to high energy-consuming devices and waste from interventional procedures. In this article, we provide a background on Radiology's environmental impact, describe why hospitals should add sustainability as a quality measure, and give a framework for radiologists to reduce the carbon footprint through quality improvement and collaboration.

Invariant NKT cell development requires a full complement of functional CD3 zeta immunoreceptor tyrosine-based activation motifs.

Invariant NKT (iNKT) cells regulate early immune responses to infections, in part because of their rapid release of IFN-gamma and IL-4. iNKT cells are proposed to reduce the severity of Lyme disease following Borrelia burgdorferi infection. Unlike conventional T cells, iNKT cells express an invariant alphabeta TCR that recognizes lipids bound to the MHC class I-like molecule, CD1d. Furthermore, these cells are positively selected following TCR interactions with glycolipid/CD1d complexes expressed on CD4+CD8+ thymocytes. Whereas conventional T cell development can proceed with as few as 4/10 CD3 immunoreceptor tyrosine-based activation motifs (ITAMs), little is known about the ITAM requirements for iNKT cell selection and expansion. We analyzed iNKT cell development in CD3 zeta transgenic lines with various tyrosine-to-phenylalanine substitutions (YF) that eliminated the functions of the first (YF1,2), third (YF5,6), or all three (YF1-6) CD3 zeta ITAMs. iNKT cell numbers were significantly reduced in the thymus, spleen, and liver of all YF mice compared with wild type mice. The reduced numbers of iNKT cells resulted from significant reductions in the expression of the early growth response 2 and promyelocytic leukemia zinc finger transcription factors. In the mice with few to no iNKT cells, there was no difference in the severity of Lyme arthritis compared with wild type controls, following infections with the spirochete B. burgdorferi. These findings indicate that a full complement of functional CD3 zeta ITAMs is required for effective iNKT cell development.

The cytoplasmic tail of the T cell receptor CD3 epsilon subunit contains a phospholipid-binding motif that regulates T cell functions.

The CD3 epsilon subunit of the TCR complex contains two defined signaling domains, a proline-rich sequence and an ITAM. We identified a third signaling sequence in CD3 epsilon, termed the basic-rich stretch (BRS). Herein, we show that the positively charged residues of the BRS enable this region of CD3 epsilon to complex a subset of acidic phospholipids, including PI(3)P, PI(4)P, PI(5)P, PI(3,4,5)P(3), and PI(4,5)P(2). Transgenic mice containing mutations of the BRS exhibited varying developmental defects, ranging from reduced thymic cellularity to a complete block in T cell development. Peripheral T cells from BRS-modified mice also exhibited several defects, including decreased TCR surface expression, reduced TCR-mediated signaling responses to agonist peptide-loaded APCs, and delayed CD3 epsilon localization to the immunological synapse. Overall, these findings demonstrate a functional role for the CD3 epsilon lipid-binding domain in T cell biology.

Sickle cell nephropathy: challenging the conventional wisdom.

This review explores the current model of sickle cell nephropathy and the limitations of the model. Renal abnormalities are common complications of sickle cell disease (SCD). Beginning in childhood, patients with SCD develop a urinary concentrating defect resulting in polyuria and a predisposition to nocturnal enuresis and dehydration. The current model of sickle cell nephropathy suggests that destruction of the renal medulla induces production of renal vasodilating substances that feedback to the glomerulus causing hyperfiltration. Hyperfiltration leads to glomerulosclerosis and proteinuria, with eventual reduction in kidney function. The crucial steps of vasodilating substance production and hyperfiltration in children with SCD have not been proven. Treatment of sickle cell nephropathy is aimed at the reduction of proteinuria with angiotensin converting enzyme inhibitors or angiotensin receptor blockers. Hydroxyurea and chronic transfusion therapy may also alter the progression of sickle cell nephropathy in children. Further studies are needed to identify an accurate model and effective treatments for sickle cell nephropathy.

High-resolution µ CT imaging for characterizing microcalcification detection performance in breast CT.

Purpose: To demonstrate the utility of high-resolution micro-computed tomography ( µ CT ) for determining ground-truth size and shape properties of calcium grains for evaluation of detection performance in breast CT (bCT). Approach: Calcium carbonate grains ( ∼ 200 µ m ) were suspended in 1% agar solution to emulate microcalcifications ( µ Calcs ) within a fibroglandular tissue background. Ground-truth imaging was performed on a commercial µ CT scanner and was used for assessing calcium-grain size and shape, and for generating µ Calc signal profiles. Calcium grains were placed within a realistic breast-shaped phantom and imaged on a prototype bCT system at 3- and 6-mGy mean glandular dose (MGD) levels, and the non-prewhitening detectability was assessed. Additionally, the µ CT -derived signal profiles were used in conjunction with the bCT system characterization (MTF and NPS) to obtain predictions of bCT detectability. Results: Estimated detectability of the calcium grains on the bCT system ranged from 2.5 to 10.6 for 3 mGy and from 3.8 to 15.3 for 6 mGy with large fractions of the grains meeting the Rose criterion for visibility. Segmentation of µ CT images based on morphological operations produced accurate results in terms of segmentation boundaries and segmented region size. A regression model linking bCT detectability to µ Calc parameters indicated significant effects of µ Calc size and vertical position within the breast phantom. Detectability using µ CT -derived detection templates and bCT statistical properties (MTF and NPS) were in good correspondence with those measured directly from bCT ( R 2 > 0.88 ). Conclusions: Parameters derived from µ CT ground-truth data were shown to produce useful characterizations of detectability when compared to estimates derived directly from bCT. Signal profiles derived from µ CT imaging can be used in conjunction with measured or hypothesized statistical properties to evaluate the performance of a system, or system component, that may not currently be available.

Patient care, public health, and a pandemic: adapting educational experiences in the clinical years.

The University of Wisconsin Madison School of Medicine and Public Health rapidly adapted its four-year, three-phase medical doctorate clinical curriculum at the onset of the COVID-19 in Spring 2020. Medical students in clinical rotations, our Phase 2 and 3 of the ForWard curriculum, temporarily stopped face to face care of patients, transitioning instead to online learning. For Phase 2 students, this single 12- week interim course included didactic content from all required integrated blocks and the creation of a new content which taught public health principles in the context of historical pandemics. Phase 3 students were rescheduled into online electives, which course directors had offered in the past and agreed to offer again during this time. All Phase 3 students participated in a Public Health Preparedness course after its rapid redesign for online delivery and scaling for an entire class. Phase 2 students returned in July 2020 to abbreviated 8-week integrated blocks that retained approximately 83% of the clinical time students would have received in the intended 12-week integrated blocks. This was possible through the frontloading of teaching sessions to the interim course and creative scheduling of clinical experiences. The 2015 curricular redesign to the integrated curriculum facilitated effective coordination and teamwork that enabled these thoughtful, rapid adjustments to the curriculum.

Modular Synthesis of Peptide-Based Single- and Multimodal Targeted Molecular Imaging Agents.

A practical, modular synthesis of targeted molecular imaging agents (TMIAs) containing near-infrared dyes for optical molecular imaging (OMI) or chelated metals for magnetic resonance imaging (MRI) and single-photon emission correlation tomography (SPECT) or positron emission tomography (PET) has been developed. In the method, imaging modules are formed early in the synthesis by attaching imaging agents to the side chain of protected lysines. These modules may be assembled to provide a given set of single- or dual-modal imaging agents, which may be conjugated in the last steps of the synthesis under mild conditions to linkers and targeting groups. A key discovery was the ability of a metal such as gadolinium, useful in MRI, to serve as a protecting group for the chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). It was further discovered that two lanthanide metals, La and Ce, can double as protecting groups and placeholder metals, which may be transmetalated under mild conditions by metals used for PET in the final step. The modular method enabled the synthesis of discrete targeted probes with two of the same or different dyes, two same or different metals, or mixtures of dyes and metals. The approach was exemplified by the synthesis of single- or dual-modal imaging modules for MRI-OMI, PET-OMI, and PET-MRI, followed by conjugation to the integrin-seeking peptide, c(RGDyK). For Gd modules, their efficacy for MRI was verified by measuring the NMR spin-lattice relaxivity. To validate functional imaging of TMIAs, dual-modal agents containing Cy5.5 were shown to target A549 cancer cells by confocal fluorescence microscopy.

The Clumsy Horse: A Professional Development Tool for Facilitators of Self-Directed, Case-Based Learning.

Introduction: With the constant evolution of science and advancing technology, future physicians must learn to navigate an ever-changing health care environment by continuous learning throughout their professional careers. Lifelong, self-directed learning is a critical component of medical education to ensure future physicians are adept at identifying knowledge gaps and seeking, analyzing, and communicating new information. To train faculty who teach case-based, self-directed learning, we designed the Clumsy Horse Case. Methods: The Clumsy Horse Case was created as part of a faculty development program for facilitators of a new case-based, self-directed curriculum known as Patient-Centered Education (PaCE) Cases. An unfamiliar veterinary medicine case was designed to level the playing field for faculty from different specialty areas in order to provide an authentic self-directed learning experience. To determine effectiveness, faculty participants completed a standardized eight-question evaluation survey after the Clumsy Horse Case session, and facilitators received student feedback at the end of each semester via a standard faculty evaluation form. Results: Student ratings indicated that faculty were adequately prepared to be effective facilitators. The Clumsy Horse Case was an integral part of facilitator preparation and provided an engaging learning experience for over 60 faculty. Survey ratings and comments from faculty participants indicated a high level of engagement and satisfaction with the learning experience. Discussion: The Clumsy Horse Case is generalizable for developing faculty in any curriculum with a case-based, self-directed learning component. It can be modified to fit any school's curriculum and integrated into a professional development program.

Scientists as comedians: The effects of humor on perceptions of scientists and scientific messages.

Humor has been recommended for scientists looking to conduct communication activities despite relatively little empirical evidence demonstrating its effectiveness. Here, we examine the social environment of a joke through a two-condition experimental design that manipulates the presence or absence of audience laughter. Specifically, we examine how humor experienced from viewing a video clip of a science comedian embedded in an online survey can have downstream effects on whether people view comedy as a valid source of scientific information. We found that respondents who perceived more humor in the video clip (i.e. those in the condition with audience laughter) had more positive views about comedy as a valid source of scientific information. Interestingly, this relationship was mediated by perceived expertise, not likability, of the scientist engaging in comedy.

A prototype Multi-X-ray-source array (MXA) for digital breast tomosynthesis.

The design and testing of a prototype Multi-X-ray-source Array (MXA) for digital breast tomosynthesis is reported. The MXA is comprised of an array of tungsten filament cathodes with focus cup grid-controlled modulation and a common rotating anode housed in a single vacuum envelope. Prototypes consisting of arrays of three-source elements and eleven-source-elements were fabricated and evaluated. The prototype sources demonstrated focal spot sizes of 0.3 mm at 45 kV with 50 mA. Measured x-ray spectra were consistent with the molybdenum anode employed, and the tube output (air kerma) was between 0.6 mGy/100 mAs at 20 kV and 17 mGy/100 mAs at 45 kV with a distance of 100 cm. HVL measurements ranged from 0.5 mm Al at 30 kV to 0.8 mm Al at 45 kV, and x-ray pulse widths were varied from 20 ms to 110 ms at operating frequencies ultimately to be limited by source turn-on/off times of ∼1 ms. Initial results of reconstructed tomographic data are presented.

Cone beam CT multisource configurations: evaluating image quality, scatter, and dose using phantom imaging and Monte Carlo simulations.

The purpose of this study was to compare various multisource configurations applied to cone beam CT (CBCT) using phantom imaging and Monte Carlo simulations. Image quality, scatter, and dose were evaluated in both overlapping (large cone angle) and collimated (small cone angle) configurations for CBCT. Four x-ray tube configurations were considered: traditional one source, three source overlapping, six source overlapping, and six source collimated. Image quality was evaluated on a prototype breast CT system using the following five phantoms: a Defrise phantom, a previously reported CBCT QA phantom (Corgi), a polyethylene cylinder, and two anthropomorphic phantoms (hand and knee). Scatter contamination and radiation dose were evaluated using Monte Carlo simulations of a voxelized polyethylene cylinder. The modulation of the Defrise phantom disks on average was 2.7X greater for the six source collimated configuration than the six source overlapping configuration. The data lost from cone beam artifact (spatial domain) and the null cone (frequency domain) in the overlapping configuration were completely recovered using the collimated configuration. The maximum scatter-to-primary ratio (SPR) for the overlapping configuration was 0.81 and the maximum SPR for the collimated configuration was 0.26. The average dose and maximum dose was 4X less in the collimated six source configuration when compared with the overlapping configurations. The maximum dose for the overlapping configurations (one, three & six) remained constant, but the average dose for the multisource (three & six source) overlapping configurations increased 25% when compared to the one source configuration. Use of a collimated multisource x-ray tube configuration was shown to provide significant improvements in image quality throughout the cone-beam geometry field-of-view, reduction in scatter contamination, and more efficient use of dose in comparison to both the traditional CBCT geometry with a single source and the overlapping multisource configurations.