Adopting electric school buses in the United States: Health and climate benefits.

Electric school buses have been proposed as an alternative to reduce the health and climate impacts of the current U.S. school bus fleet, of which a substantial share are highly polluting old diesel vehicles. However, the climate and health benefits of electric school buses are not well known. As they are substantially more costly than diesel buses, assessing their benefits is needed to inform policy decisions. We assess the health benefits of electric school buses in the United States from reduced adult mortality and childhood asthma onset risks due to exposure to ambient fine particulate matter (PM2.5). We also evaluate climate benefits from reduced greenhouse-gas emissions. We find that replacing the average diesel bus in the U.S. fleet in 2017 with an electric bus yields $84,200 in total benefits. Climate benefits amount to $40,400/bus, whereas health benefits amount to $43,800/bus due to 4.42*10-3 fewer PM2.5-attributable deaths ($40,000 of total) and 7.42*10-3 fewer PM2.5-attributable new childhood asthma cases ($3,700 of total). However, health benefits of electric buses vary substantially by driving location and model year (MY) of the diesel buses they replace. Replacing old, MY 2005 diesel buses in large cities yields $207,200/bus in health benefits and is likely cost-beneficial, although other policies that accelerate fleet turnover in these areas deserve consideration. Electric school buses driven in rural areas achieve small health benefits from reduced exposure to ambient PM2.5. Further research assessing benefits of reduced exposure to in-cabin air pollution among children riding buses would be valuable to inform policy decisions.

Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis.

Normothermic ex-vivo kidney perfusion (NEVKP) results in significantly improved graft function in porcine auto-transplant models of donation after circulatory death injury compared with static cold storage (SCS); however, the molecular mechanisms underlying these beneficial effects remain unclear. We performed an unbiased proteomics analysis of 28 kidney biopsies obtained at three time points from pig kidneys subjected to 30 min of warm ischemia, followed by 8 h of NEVKP or SCS, and auto-transplantation. 70/6593 proteins quantified were differentially expressed between NEVKP and SCS groups (false discovery rate < 0.05). Proteins increased in NEVKP mediated key metabolic processes including fatty acid ß-oxidation, the tricarboxylic acid cycle, and oxidative phosphorylation. Comparison of our findings with external datasets of ischemia-reperfusion and other models of kidney injury confirmed that 47 of our proteins represent a common signature of kidney injury reversed or attenuated by NEVKP. We validated key metabolic proteins (electron transfer flavoprotein subunit beta and carnitine O-palmitoyltransferase 2, mitochondrial) by immunoblotting. Transcription factor databases identified members of the peroxisome proliferator-activated receptors (PPAR) family of transcription factors as the upstream regulators of our dataset, and we confirmed increased expression of PPARA, PPARD, and RXRA in NEVKP with reverse transcription polymerase chain reaction. The proteome-level changes observed in NEVKP mediate critical metabolic pathways. These effects may be coordinated by PPAR-family transcription factors and may represent novel therapeutic targets in ischemia-reperfusion injury.

The benefits and costs of U.S. employer COVID-19 vaccine mandates.

In 2021, the Biden Administration issued mandates requiring COVID-19 vaccinations for U.S. federal employees and contractors and for some healthcare and private sector workers. These mandates have been challenged in court; some have been halted or delayed. However, their costs and benefits have not been rigorously appraised. This study helps fill that gap. We estimate the direct costs and health-related benefits that would have accrued if these vaccination requirements had been implemented as intended. Compared with the January 2022 vaccination rates, we find that the mandates could have led to 15 million additional vaccinated individuals, increasing the overall proportion of the fully vaccinated U.S. population from 64% to 68%. The associated net benefits depend on the subsequent evolution of the pandemic-information unavailable ex ante to analysts or policymakers. In scenarios involving the emergence of a novel, more transmissible variant, against which vaccination and previous infection offer moderate protection, the estimated net benefits are potentially large. They reach almost $20,000 per additional vaccinated individual, with more than 20,000 total deaths averted over the 6-month period assessed. In scenarios involving a fading pandemic, existing vaccination-acquired or infection-acquired immunity provides sufficient protection, and the mandates' benefits are unlikely to exceed their costs. Thus, mandates may be most useful when the consequences of inaction are catastrophic. However, we do not compare the effects of mandates with alternative policies for increasing vaccination rates or for promoting other protective measures, which may receive stronger public support and be less likely to be overturned by litigation.

Role of the CX3CL1-CX3CR1 axis in renal disease.

Excessive infiltration of immune cells into the kidney is a key feature of acute and chronic kidney diseases. The family of chemokines comprises key drivers of this process. Fractalkine [chemokine (C-X3-C motif) ligand 1 (CX3CL1)] is one of two unique chemokines synthesized as a transmembrane protein that undergoes proteolytic cleavage to generate a soluble species. Through interacting with its cognate receptor, chemokine (C-X3-C motif) receptor 1 (CX3CR1), CX3CL1 was originally shown to act as a conventional chemoattractant in the soluble form and as an adhesion molecule in the transmembrane form. Since then, other functions of CX3CL1 beyond leukocyte recruitment have been described, including cell survival, immunosurveillance, and cell-mediated cytotoxicity. This review summarizes diverse roles of CX3CL1 in kidney disease and potential uses as a therapeutic target and novel biomarker. As the CX3CL1-CX3CR1 axis has been shown to contribute to both detrimental and protective effects in various kidney diseases, a thorough understanding of how the expression and function of CX3CL1 are regulated is needed to unlock its therapeutic potential.

Introduction to Special Issue on Risk Assessment, Economic Evaluation, and Decisions.

Integrating risk assessment, economic evaluation, and uncertainty to inform policy decisions is a core challenge to risk analysis. In September 2019, the Harvard Center for Risk Analysis, with support from the Society for Risk Analysis Economics and Benefits Analysis Specialty Group and others, convened a workshop to address this issue. The workshop built in part on the recommendations of the 2009 National Research Council report, Science and Decisions: Advancing Risk Assessment. It honored John S. Evans, whose thoughtful and innovative teaching and scholarship have significantly advanced thinking on these issues. This special issue features a profile of Dr. Evans and nine articles that build on work presented at the workshop.

Do the Benefits of COVID-19 Policies Exceed the Costs? Exploring Uncertainties in the Age-VSL Relationship.

Numerous analyses of the benefits and costs of COVID-19 policies have been completed quickly as the crisis has unfolded. The results often largely depend on the approach used to value mortality risk reductions, typically expressed as the value per statistical life (VSL). Many analyses rely on a population-average VSL estimate; some adjust VSL for life expectancy at the age of death. We explore the implications of theory and empirical studies, which suggest that the relationship between age and VSL is uncertain. We compare the effects of three approaches: (1) an invariant population-average VSL; (2) a constant value per statistical life-year (VSLY); and (3) a VSL that follows an inverse-U pattern, peaking in middle age. We find that when applied to the U.S. age distribution of COVID-19 deaths, these approaches result in average VSL estimates of $10.63 million, $4.47 million, and $8.31 million. We explore the extent to which applying these estimates alters the conclusions of frequently cited analyses of social distancing, finding that they significantly affect the findings. However, these analyses do not address other characteristics of COVID-19 deaths that may increase or decrease the VSL estimates. Examples include the health status and income level of those affected, the size of the risk change, and the extent to which the risk is dreaded, uncertain, involuntarily incurred, and outside of one's control. The effects of these characteristics and their correlation with age are uncertain; it is unclear whether they amplify or diminish the effects of age on VSL.

Estimating the Potential Health Benefits of Air Quality Warnings.

National, state, and local air quality authorities issue warnings urging residents to stay indoors or to take other precautions when pollutant levels are expected to exceed defined thresholds. Previous work explores the impact of warnings on specific activities but not the health improvements that might result if individuals fully responded to the recommendations. We estimate these potential health impacts using recent pollution data in three U.S. locations: Denver, Colorado; Los Angeles, California; and Pittsburgh, Pennsylvania. We focus on mortality risks among the elderly, who are particularly vulnerable. Under the strong assumptions of no infiltration and no offsetting indoor sources, we estimate that the benefits associated with avoiding ambient ozone and fine particle exposure are generally less than $14 per person for one additional hour spent indoors on days when air quality thresholds are exceeded. These estimates are sensitive to assumptions regarding the relationship between decreased exposure and mortality risks. Individuals' decisions to stay indoors likely depend on the value of the health benefits compared with the value of forgone work and leisure activities. While the national warning system provides flexibility and allows individuals to tailor their responses to personal circumstances, our analysis suggests that its benefits under typical conditions are small. The benefits of warnings under wildfire or other extreme conditions may be much greater.

Inhibition of BRD4 Reduces Neutrophil Activation and Adhesion to the Vascular Endothelium Following Ischemia Reperfusion Injury.

Renal ischemia reperfusion injury (IRI) is associated with inflammation, including neutrophil infiltration that exacerbates the initial ischemic insult. The molecular pathways involved are poorly characterized and there is currently no treatment. We performed an in silico analysis demonstrating changes in NFκB-mediated gene expression in early renal IRI. We then evaluated NFκB-blockade with a BRD4 inhibitor on neutrophil adhesion to endothelial cells in vitro, and tested BRD4 inhibition in an in vivo IRI model. BRD4 inhibition attenuated neutrophil adhesion to activated endothelial cells. In vivo, IRI led to increased expression of cytokines and adhesion molecules at 6 h post-IRI with sustained up-regulated expression to 48 h post-IRI. These effects were attenuated, in part, with BRD4 inhibition. Absolute neutrophil counts increased significantly in the bone marrow, blood, and kidney 24 h post-IRI. Activated neutrophils increased in the blood and kidney at 6 h post-IRI and remained elevated in the kidney until 48 h post-IRI. BRD4 inhibition reduced both total and activated neutrophil counts in the kidney. IRI-induced tubular injury correlated with neutrophil accumulation and was reduced by BRD4 inhibition. In summary, BRD4 inhibition has important systemic and renal effects on neutrophils, and these effects are associated with reduced renal injury.

Normothermic ex vivo kidney perfusion for graft quality assessment prior to transplantation.

Normothermic ex vivo kidney perfusion (NEVKP) represents a novel approach for graft preservation and functional improvement in kidney transplantation. We investigated whether NEVKP also allows graft quality assessment before transplantation. Kidneys from 30-kg pigs were recovered in a model of heart-beating donation (group A) after 30 minutes (group B) or 60 minutes (group C) (n = 5/group) of warm ischemia. After 8 hours of NEVKP, contralateral kidneys were resected, grafts were autotransplanted, and the pigs were followed for 3 days. After transplantation, renal function measured based on peak serum creatinine differed significantly among groups (P < .05). Throughout NEVKP, intrarenal resistance was lowest in group A and highest in group C (P < .05). intrarenal resistance at the initiation of NEVKP correlated with postoperative renal function (P < .001 at NEVKP hour 1). Markers of acid-base homeostasis (pH, HCO3- , base excess) differed among groups (P < .05) and correlated with posttransplantation renal function (P < .001 for pH at NEVKP hour 1). Similarly, lactate and aspartate aminotransferase were lowest in noninjured grafts versus donation after circulatory death kidneys (P < .05) and correlated with posttransplantation kidney function (P < .001 for lactate at NEVKP hour 1). In conclusion, assessment of perfusion characteristics and clinically available perfusate biomarkers during NEVKP allows the prediction of posttransplantation graft function. Thus, NEVKP might allow decision-making regarding whether grafts are suitable for transplantation.

Isolated cutaneous mucormycosis in a pediatric renal transplant recipient.

Mucormycosis is a rare and potentially life-threatening infection, typically affecting immunocompromised hosts. We report a case of an adolescent boy who developed primary isolated cutaneous mucormycosis in the early period following kidney transplantation. Surgical excision was performed using intraoperative fungal staining to obtain clear margins, followed by topical and systemic antifungal therapy. A skin graft was then applied to the excised area with good healing, and the patient made a full recovery.

Validation of serum creatinine-based formulae in pediatric renal transplant recipients.

BackgroundAccurate monitoring of kidney function is important post-renal transplant; however, the routine use of measured glomerular filtration rate (GFR) or addition of newer serum markers is prohibitively expensive for routine clinical use, especially in children. We validated the modified Schwartz formula in pediatric renal transplant recipients across a range of demographic and clinical characteristics.MethodsIn a retrospective cohort study with nested cross-sectional analysis, we compared 505 measurements of estimated GFR using serum creatinine to simultaneous diethylenetriaminepentaacetic acid (DTPA) nuclear GFR (nGFR) measurements from 173 pediatric kidney transplant recipients who were < 18 years of age from 1 January 2001 to 31 December 2012 accounting for repeated measures.ResultsAmong 173 children, 62% were males, 85% with nGFR of ≥60 ml/min/1.73 m2, and the median age at transplant was 13.6 years (interquartile range 8.3-16 years). Overall, the modified Schwartz and Pottel formulae had better bias (0.07 and -0.03 ml/min/1.73 m2, respectively) and accuracy within 30% (both 84.4%) in comparison to Lyon and Zappitelli formulae. The 30% accuracy varied for girls and children <5 and >15 years.ConclusionModified Schwartz is a practical, non-invasive, and a valid bedside tool that provides a valid measurement of GFR in pediatric kidney transplant recipients.

The Neurorepellent Slit2 Inhibits Postadhesion Stabilization of Monocytes Tethered to Vascular Endothelial Cells.

The secreted neurorepellent Slit2, acting through its transmembrane receptor, Roundabout (Robo)-1, inhibits chemotaxis of varied cell types, including leukocytes, endothelial cells, and vascular smooth muscle cells, toward diverse attractants. The role of Slit2 in regulating the steps involved in recruitment of monocytes in vascular inflammation is not well understood. In this study, we showed that Slit2 inhibited adhesion of monocytic cells to activated human endothelial cells, as well as to immobilized ICAM-1 and VCAM-1. Microfluidic live cell imaging showed that Slit2 inhibited the ability of monocytes tethered to endothelial cells to stabilize their actin-associated anchors and to resist detachment in response to increasing shear forces. Transfection of constitutively active plasmids revealed that Slit2 inhibited postadhesion stabilization of monocytes on endothelial cells by preventing activation of Rac1. We further found that Slit2 inhibited chemotaxis of monocytes toward CXCL12 and CCL2. To determine whether Slit2 and Robo-1 modulate pathologic monocyte recruitment associated with vascular inflammation and cardiovascular disease, we tested PBMC from patients with coronary artery disease. PBMC from these patients had reduced surface levels of Robo-1 compared with healthy age- and sex-matched subjects, and Slit2 failed to inhibit chemotaxis of PBMC of affected patients, but not healthy control subjects, toward CCL2. Furthermore, administration of Slit2 to atherosclerosis-prone LDL receptor-deficient mice inhibited monocyte recruitment to nascent atherosclerotic lesions. These results demonstrate that Slit2 inhibits chemotaxis of monocytes, as well as their ability to stabilize adhesions and resist detachment forces. Slit2 may represent a powerful new tool to inhibit pathologic monocyte recruitment in vascular inflammation and atherosclerosis.

Recombinant N-Terminal Slit2 Inhibits TGF-ß-Induced Fibroblast Activation and Renal Fibrosis.

Fibrosis and inflammation are closely intertwined injury pathways present in nearly all forms of CKD for which few safe and effective therapies exist. Slit glycoproteins signaling through Roundabout (Robo) receptors have been described to have anti-inflammatory effects through regulation of leukocyte cytoskeletal organization. Notably, cytoskeletal reorganization is also required for fibroblast responses to TGF-ß Here, we examined whether Slit2 also controls TGF-ß-induced renal fibrosis. In cultured renal fibroblasts, which we found to express Slit2 and Robo-1, the bioactive N-terminal fragment of Slit2 inhibited TGF-ß-induced collagen synthesis, actin cytoskeletal reorganization, and Smad2/3 transcriptional activity, but the inactive C-terminal fragment of Slit2 did not. In mouse models of postischemic renal fibrosis and obstructive uropathy, treatment with N-terminal Slit2 before or after injury inhibited the development of renal fibrosis and preserved renal function, whereas the C-terminal Slit2 had no effect. Our data suggest that administration of recombinant Slit2 may be a new treatment strategy to arrest chronic injury progression after ischemic and obstructive renal insults by not only attenuating inflammation but also, directly inhibiting renal fibrosis.

Valuing Reductions in Fatal Illness Risks: Implications of Recent Research.

The value of mortality risk reductions, conventionally expressed as the value per statistical life, is an important determinant of the net benefits of many government policies. US regulators currently rely primarily on studies of fatal injuries, raising questions about whether different values might be appropriate for risks associated with fatal illnesses. Our review suggests that, despite the substantial expansion of the research base in recent years, few US studies of illness-related risks meet criteria for quality, and those that do yield similar values to studies of injury-related risks. Given this result, combining the findings of these few studies with the findings of the more robust literature on injury-related risks appears to provide a reasonable range of estimates for application in regulatory analysis. Our review yields estimates ranging from about $4.2 million to $13.7 million with a mid-point of $9.0 million (2013 dollars). Although the studies we identify differ from those that underlie the values currently used by Federal agencies, the resulting estimates are remarkably similar, suggesting that there is substantial consensus emerging on the values applicable to the general US population. Copyright © 2015 John Wiley & Sons, Ltd.

Should we stop dosing steroids per body surface area for nephrotics?

In this edition of Pediatric Nephrology, Vaishnavi Raman et al. have published an open-labeled randomized clinical trial of 100 children with idiopathic nephrotic syndrome who were allocated either a body weight- or body surface area-based prednisolone dosing for a duration of 12 weeks. The authors used Kaplan-Meier analysis for comparison of the time to remission. They also compared the relapse rate and found no difference. This editorial discusses the strengths of the current study as well some limitations. The inclusion of relapsing patients in the study protocol is problematic. The follow-up period of only 6 months forms another limitation. No subgroup analysis by age was performed. This editorial also highlights the lack of correlation between steroid dose and steroid exposure and the need for considering the age dependency (ontogeny) of drug disposition. Finally, the need for adherence to CONSORT criteria for reporting randomized controlled clinical trials is emphasized.

Perspectives on edema in childhood nephrotic syndrome.

There have been two major theories surrounding the development of edema in nephrotic syndrome (NS), namely, the under- and overfill hypotheses. Edema is one of the cardinal features of NS and remains one of the principal reasons for admission of children to the hospital. Recently, the discovery that proteases in the glomerular filtrate of patients with NS are activating the epithelial sodium channel (ENaC), resulting in intrarenal salt retention and thereby contributing to edema, might suggest that targeting ENaC with amiloride might be a suitable strategy to manage the edema of NS. Other potential agents, particularly urearetics and aquaretics, might also prove useful in NS. Recent evidence also suggests that there may be other areas involved in salt storage, especially the skin, and it will be intriguing to study the implications of this in NS.

Slit2-Robo signaling in inflammation and kidney injury.

Acute kidney injury is an increasingly common global health problem and is associated with severe morbidity and mortality. In addition to facing high mortality rates, the survivors of acute kidney injury are at increased risk of developing chronic kidney disease and end-stage renal disease. Renal ischemia-reperfusion injury (IRI) is the most common cause of acute kidney injury, and results from impaired delivery of oxygen and nutrients to the kidney. Massive leukocyte influx into the post-ischemic kidney is one of the hallmarks of IRI. The recruited leukocytes exacerbate tissue damage and, if uncontrolled, initiate the progressive changes that lead to renal fibrosis and chronic kidney disease. Early on, recruitment and activation of platelets promotes microthrombosis in the injured kidney, further exacerbating kidney damage. The diversity, complexity, and multiplicity of pathways involved in leukocyte recruitment and platelet activation make it extremely challenging to control these processes, and past efforts have met with limited success in human trials. A generalized strategy to inhibit infiltration of inflammatory leukocytes and platelets, thereby reducing inflammation and injury, may prove to be more beneficial. In this review, we summarize recent findings demonstrating that the neuronal guidance cues, Slit and Roundabout (Robo), prevent the migration of multiple leukocyte subsets towards diverse inflammatory chemoattractants, and have potent anti-platelet functions in vitro and in vivo. These properties uniquely position Slit2 as a novel therapeutic that could be used to prevent acute kidney injury associated with IRI.

Introduction to the Special Series on Research Synthesis: A Cross-Disciplinary Approach.

To estimate the effects of a policy change, analysts must often rely on available data as time and resource constraints limit their ability to commission new primary research. Research synthesis methods-including systematic review, meta-analysis, and expert elicitation-play an important role in ensuring that this evidence is appropriately weighed and considered. We present the conclusions of a multidisciplinary Harvard Center for Risk Analysis project that evaluated and applied these methods, and introduce the resulting series of articles. The first step in any analysis is to clearly define the problem to be addressed; the second is a systematic review of the literature. Whether additional analysis is needed depends on the quality and relevance of the available data to the policy question, and the likely effect of uncertainty on the policy decision. Meta-analysis promotes understanding the variation between studies and may be used to combine the estimates to develop values for application in policy analysis. Formal, structured expert elicitation promotes careful consideration of the evidence when data are limited or inconsistent, and aids in extrapolating to the policy context. Regardless of the methods used, clear communication of the approach, assumptions, and uncertainty is essential.