Single-cell landscape analysis unravels molecular programming of the human B cell compartment in chronic GVHD.

Alloreactivity can drive autoimmune syndromes. After allogeneic hematopoietic stem cell transplantation (allo-HCT), chronic graft-versus-host disease (cGVHD), a B cell-associated autoimmune-like syndrome, commonly occurs. Because donor-derived B cells continually develop under selective pressure from host alloantigens, aberrant B cell receptor (BCR) activation and IgG production can emerge and contribute to cGVHD pathobiology. To better understand molecular programing of B cells in allo-HCT, we performed scRNA-Seq analysis on high numbers of purified B cells from patients. An unsupervised analysis revealed 10 clusters, distinguishable by signature genes for maturation, activation, and memory. Within the memory B cell compartment, we found striking transcriptional differences in allo-HCT patients compared with healthy or infected individuals, including potentially pathogenic atypical B cells (ABCs) that were expanded in active cGVHD. To identify intrinsic alterations in potentially pathological B cells, we interrogated all clusters for differentially expressed genes (DEGs) in active cGVHD versus patients who never had signs of immune tolerance loss (no cGVHD). Active cGVHD DEGs occurred in both naive and BCR-activated B cell clusters. Remarkably, some DEGs occurred across most clusters, suggesting common molecular programs that may promote B cell plasticity. Our study of human allo-HCT and cGVHD provides understanding of altered B cell memory during chronic alloantigen stimulation.

Lethal Pediatric Cerebral Vasculitis Triggered by Severe Acute Respiratory Syndrome Coronavirus 2.

BACKGROUND: We report the clinical, radiological, laboratory, and neuropathological findings in support of the first diagnosis of lethal, small-vessel cerebral vasculitis triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a pediatric patient. PATIENT DESCRIPTION: A previously healthy, eight-year-old Hispanic girl presented with subacute left-sided weakness two weeks after a mild febrile illness. SARS-CoV-2 nasopharyngeal swab was positive. Magnetic resonance imaging revealed an enhancing right frontal lobe lesion with significant vasogenic edema. Two brain biopsies of the lesion showed perivascular and intraluminal lymphohistiocytic inflammatory infiltrate consistent with vasculitis. Despite extensive treatment with immunomodulatory therapies targeting primary angiitis of the central nervous system, she experienced neurological decline and died 93 days after presentation. SARS-CoV-2 testing revealed positive serum IgG and positive cerebrospinal fluid IgM. Comprehensive infectious, rheumatologic, hematologic/oncologic, and genetic evaluation did not identify an alternative etiology. Postmortem brain autopsy remained consistent with vasculitis. CONCLUSION: This is the first pediatric presentation to suggest that SARS-CoV-2 can lead to a fatal, postinfectious, inflammatory small-vessel cerebral vasculitis. Our patient uniquely included supportive cerebrospinal fluid and postmortem tissue analysis. While most children recover from the neurological complications of SARS-CoV-2, we emphasize the potential mortality in a child with no risk factors for severe disease.

Percutaneous Coronary Intervention Outcomes in Patients With Prior Thoracic Radiation Therapy: A Systematic Review and Meta-Analysis.

Background: Thoracic radiation predisposes patients to accelerated coronary artery disease. There is a paucity of data in both short-term and long-term outcomes following revascularization in patients who have undergone thoracic radiation. Methods: We performed a search of the Medline, Cochrane, and Scopus databases for studies that compared outcomes in cancer patients who have undergone thoracic radiation and percutaneous coronary intervention (PCI). The primary outcome of our meta-analysis was all-cause mortality. Secondary outcomes included cardiac mortality, myocardial infarction (MI), and restenosis. Results: The analysis included four observational studies with a total of 13,941 patients for the primary outcome of all-cause mortality. There were a total of 1,322 patients analyzed for cardiac mortality, 13,103 for MI, and 10,530 for restenosis. The longest follow-up for the primary outcome was 16 years. There was statistically significant higher risk of all-cause mortality in patients who underwent thoracic radiation (risk ratio (RR): 1.29, 95% confidence interval (CI): 1.08 - 1.54, P = 0.004). There was no statistically significant difference in cardiac mortality (RR: 1.15, 95% CI: 0.83 - 1.61, P = 0.40), MI (RR: 1.01, 95% CI: 0.20 - 5.08, P = 0.99), and restenosis (RR: 1.92, 95% CI: 0.24 - 15.35, P = 0.54). Conclusion: In this meta-analysis, we found a higher risk of all-cause mortality in patients with a history of thoracic radiation undergoing PCI, likely from underlying malignancy itself.

Clinical Characteristics and Outcomes in Immune Checkpoint Inhibitor Therapy-Associated Myocarditis.

Immune checkpoint inhibitor (ICI) therapy has played an important role in the treatment of several groups of cancers. Although a life prolonging treatment, many side effects have been shown with ICI therapy. This study looked at individual level clinical characteristics and outcomes with ICI therapy in patients who developed ICI-related myocarditis. A comprehensive review of the National Library of Medicine PubMed database was performed. Inclusion criteria were all studies that were composed of case reports and case series of individual patients undergoing ICI therapy that developed myocarditis. To appreciate individual patient level data, observational studies, clinical trials, systematic reviews, and meta-analyses were excluded. Our search yielded 333 results with 71 cases reviewed of ICI therapy-related myocarditis. The findings included an average age of 68 years, higher incidence in men, and pretreatment cardiac history of hypertension. Melanoma was the most prevalent malignancy with nivolumab being the most used ICI therapy. Heart failure was the most prevalent adverse event that was co-prevalent with myocarditis. Corticosteroid therapy alone was the most utilized therapy to treat ICI-related myocarditis. Mortality was seen in nearly half of the patient population. Our study reviewed the preexisting literature of prior reported myocarditis secondary to ICI therapy. Periodic surveillance should be performed by the cardio-oncologist and internist. Due to the expanding role of ICI therapy in treating a variety of cancer patients, appreciation of its impact on the development of myocarditis is needed.

Influence of landscape management practices on urban greenhouse gas budgets.

BACKGROUND: With a lack of United States federal policy to address climate change, cities, the private sector, and universities have shouldered much of the work to reduce carbon dioxide (CO2) and other greenhouse gas emissions. This study aims to determine how landcover characteristics influence the amount of carbon (C) sequestered and respired via biological processes, evaluating the role of land management on the overall C budget of an urban university. Boston University published a comprehensive Climate Action Plan in 2017 with the goal of achieving C neutrality by 2040. In this study, we digitized and discretized each of Boston University's three urban campuses into landcover types, with C sequestration and respiration rates measured and scaled to provide a University-wide estimate of biogenic C fluxes within the broader context of total University emissions. RESULTS: Each of Boston University's three highly urban campuses were net sources of biogenic C to the atmosphere. While trees were estimated to sequester 0.6 ± 0.2 kg C m-2 canopy cover year-1, mulch and lawn areas in 2018 emitted C at rates of 1.7 ± 0.4 kg C m-2 year-1 and 1.4 ± 0.4 kg C m-2 year-1, respectively. C uptake by tree canopy cover, which can spatially overlap lawn and mulched landcovers, was not large enough to offset biogenic emissions. The proportion of biogenic emissions to Scope 1 anthropogenic emissions on each campus varied from 0.5% to 2%, and depended primarily on the total anthropogenic emissions on each campus. CONCLUSIONS: Our study quantifies the role of urban landcover in local C budgets, offering insights on how landscaping management strategies-such as decreasing mulch application rates and expanding tree canopy extent-can assist universities in minimizing biogenic C emissions and even potentially creating a small biogenic C sink. Although biogenic C fluxes represent a small fraction of overall anthropogenic emissions on urban university campuses, these biogenic fluxes are under active management by the university and should be included in climate action plans.

The pink elephant in the room: Declining public interest in breast cancer and the impact of marketing efforts.

BACKGROUND: Public interest in breast cancer is associated with breast cancer awareness month. However, no study has analyzed the temporal trends in breast cancer interest or assessed how funding for breast cancer research is influenced by public interest. METHODS: We performed a cross-sectional analysis of Google Trends using the search query "Breast Cancer" between January 2004 - July 2020. We then computed bivariate correlations to assess the association between relative search interest (RSI) and the financial records of the Susan G. Komen Foundation. RESULTS: Average search interest has declined since 2004. We identified increasing breast cancer RSI beginning in October 2009, corresponding with breast cancer awareness month, with an overall peak in 2012 followed by a downtrend through 2017. These fluctuations in peak RSI corresponded with the U.S. National Football League's initiation of "Pink October" during which the players wore pink jerseys which started in 2009 and ceased in 2017. We also found a strong correlation between peak RSI and Susan G. Komen Foundation net assets as well as funding of public health screening services and public health education. CONCLUSIONS: Average interest in breast cancer has been declining since 2004 and peak interest, as well as breast cancer funding, has been declining since 2012. This suggests new marketing efforts are needed to improve breast cancer awareness and to increase fundraising. POLICY SUMMARY: Considering the decline in breast cancer interest and funding, we recommend implementing local, regional, and national policies that improve marketing campaigns and improve breast cancer awareness.

Factors influencing clinical trial participation for adult and pediatric patients with cystic fibrosis.

There remains a limited understanding of the factors influencing clinical trial participation for individuals with Cystic Fibrosis (CF). A comprehensive survey was developed to examine the interests, preferences, and barriers/facilitators to research and clinical trial participation for CF patients. A consecutive sample of 198 CF adults attending the St. Paul's Hospital CF Clinic and parents of children with CF attending the BC Children's Hospital CF Clinic from Vancouver, Canada were surveyed. Parents of pediatric patients were less comfortable with blood collection, required more safety data prior to participating, and were more concerned about potential side effects. Very few respondents (<10%) appeared able/willing to fulfill the typical requirements to participate in a phase 1 clinical trial. Overall, there were more similarities than differences between the responses of adult and parents of pediatric CF patients. The patient-centered information can be used to inform the design of future clinical trials to enhance feasibility.

Prenatal diagnosis of Proteus syndrome: Diagnosis of an AKT1 mutation from amniocytes.

Proteus syndrome is a mosaic genetic overgrowth disorder caused by a postzygotic, mosaic activating mutation in AKT1. Rare prenatal presentations include segmental tissue overgrowth, and skeletal and CNS anomalies. We present the first report of prenatally diagnosed and molecularly confirmed Proteus syndrome. Prenatal imaging identified megalencephaly, brain and eye malformations, focal soft tissue enlargement, and ambiguous genitalia. Exome sequencing performed on cultured amniocytes demonstrated an AKT1 pathogenic variant consistent with Proteus syndrome, and postnatal examination confirmed the diagnosis. Postnatal Sanger sequencing could not identify the AKT1 pathogenic variant. This case underscores the importance of prenatal exome sequencing on cultured amniocytes for mosaic overgrowth disorders, as well as provides additional information on the prenatal phenotype of Proteus syndrome, and highlights the impact of prenatal diagnosis on postnatal management.

Outcome of Isolated Absent Septum Pellucidum Diagnosed by Fetal Magnetic Resonance Imaging (MRI) Scan.

Improved fetal imaging has resulted in increased diagnosis of isolated absent septum pellucidum without other intracranial abnormalities. There is little literature regarding outcomes for these fetuses. This study hypothesized the majority of infants diagnosed by fetal magnetic resonance imaging (MRI) with isolated absent septum pellucidum would retain this diagnosis postnatally. Specifically, in the absence of postnatal endocrine or ophthalmologic abnormalities, postnatal imaging would find no additional related findings, and fetuses would be at low risk for developmental delay. Two of 8 subjects met postnatal criteria for septo-optic dysplasia; remaining subjects had normal postnatal endocrine and ophthalmologic evaluations and no significant related findings on postnatal MRI. One subject without septo-optic dysplasia had delays on developmental screening; all others had normal screening (range of follow-up 8-72 months). Our study questions the necessity of postnatal imaging for prenatally diagnosed isolated absent septum pellucidum. Majority of fetuses with isolated absent septum pellucidum retained this diagnosis postnatally.

Consequences of Inadequate Intakes of Vitamin A, Vitamin B12, Vitamin D, Calcium, Iron, and Folate in Older Persons.

PURPOSE OF REVIEW: This review broadly discusses the consequences of inadequate consumption, by deficit or excess, of selected micronutrients on the quality of life and morbidity during aging, specifically considering increases in life expectancy and the costs of care in the older persons. RECENT FINDINGS: A literature review of the periods 2012 to 2018, focusing on vitamins A, B12, and D, calcium, iron and folate, was completed as these micronutrients are found to significantly affect the aging process. Causation and application of these micronutrients to disorders related to aging are controversial and mixed. This review highlights research needs and controversial points on the role of these micronutrients. SUMMARY: Micronutrient deficiencies are a common and avoidable contributor to decreased quality of life and healthcare costs in the older persons. Further research is needed to determine adequate intakes and innovative uses, including appropriate thresholds for improved health outcomes for this population.