Cellular therapies for the treatment and prevention of SARS-CoV-2 infection.

Patients with blood disorders who are immune suppressed are at increased risk for infection with severe acute respiratory syndrome coronavirus 2. Sequelae of infection can include severe respiratory disease and/or prolonged duration of viral shedding. Cellular therapies may protect these vulnerable patients by providing antiviral cellular immunity and/or immune modulation. In this recent review of the field, phase 1/2 trials evaluating adoptive cellular therapies with virus-specific T cells or natural killer cells are described along with trials evaluating the safety, feasibility, and preliminary efficacy of immune modulating cellular therapies including regulatory T cells and mesenchymal stromal cells. In addition, the immunologic basis for these therapies is discussed.

The sequential action of miR156 and miR172 regulates developmental timing in Arabidopsis.

The transition from the juvenile to the adult phase of shoot development in plants is accompanied by changes in vegetative morphology and an increase in reproductive potential. Here, we describe the regulatory mechanism of this transition. We show that miR156 is necessary and sufficient for the expression of the juvenile phase, and regulates the timing of the juvenile-to-adult transition by coordinating the expression of several pathways that control different aspects of this process. miR156 acts by repressing the expression of functionally distinct SPL transcription factors. miR172 acts downstream of miR156 to promote adult epidermal identity. miR156 regulates the expression of miR172 via SPL9 which, redundantly with SPL10, directly promotes the transcription of miR172b. Thus, like the larval-to-adult transition in Caenorhabditis elegans, the juvenile-to-adult transition in Arabidopsis is mediated by sequentially operating miRNAs. miR156 and miR172 are positively regulated by the transcription factors they target, suggesting that negative feedback loops contribute to the stability of the juvenile and adult phases.

Improving infectious adverse event reporting for children and adolescents enrolled in clinical trials for acute lymphoblastic leukemia: A report from the Children's Oncology Group.

Infections cause substantial morbidity for children with acute lymphoblastic leukemia (ALL). Therefore, accurate characterization of infectious adverse events (AEs) reported on clinical trials is imperative to defining, comparing, and managing safety and toxicity. Here, we describe key processes implemented to improve reporting of infectious AEs on two active phase III Children's Oncology Group (COG) ALL trials. Processes include: (a) identifying infections as a targeted toxicity, (b) incorporation of infection-specific case report form questions, and (c) physician review of AEs with real-time data cleaning. Preliminary assessment of these processes suggests improved reporting, as well as opportunities for further improvement.

Multisystem Inflammatory Syndrome of Children: Subphenotypes, Risk Factors, Biomarkers, Cytokine Profiles, and Viral Sequencing.

OBJECTIVE: To assess demographic, clinical, and biomarker features distinguishing patients with multisystem inflammatory syndrome in children (MIS-C); compare MIS-C sub-phenotypes; identify cytokine biosignatures; and characterize viral genome sequences. STUDY DESIGN: We performed a prospective observational cohort study of 124 children hospitalized and treated under the institutional MIS-C Task Force protocol from March to September 2020 at Children's National, a quaternary freestanding children's hospital in Washington, DC. Of this cohort, 63 of the patients had the diagnosis of MIS-C (39 confirmed, 24 probable) and 61 were from the same cohort of admitted patients who subsequently had an alternative diagnosis (controls). RESULTS: Median age and sex were similar between MIS-C and controls. Black (46%) and Latino (35%) children were over-represented in the MIS-C cohort, with Black children at greatest risk (OR 4.62, 95% CI 1.151-14.10; P = .007). Cardiac complications were more frequent in critically ill patients with MIS-C (55% vs 28%; P = .04) including systolic myocardial dysfunction (39% vs 3%; P = .001) and valvular regurgitation (33% vs 7%; P = .01). Median cycle threshold was 31.8 (27.95-35.1 IQR) in MIS-C cases, significantly greater (indicating lower viral load) than in primary severe acute respiratory syndrome coronavirus 2 infection. Cytokines soluble interleukin 2 receptor, interleukin [IL]-10, and IL-6 were greater in patients with MIS-C compared with controls. Cytokine analysis revealed subphenotype differences between critically ill vs noncritically ill (IL-2, soluble interleukin 2 receptor, IL-10, IL-6); polymerase chain reaction positive vs negative (tumor necrosis factor-α, IL-10, IL-6); and presence vs absence of cardiac abnormalities (IL-17). Phylogenetic analysis of viral genome sequences revealed predominance of GH clade originating in Europe, with no differences comparing patients with MIS-C with patients with primary coronavirus disease 19. Treatment was well tolerated, and no children died. CONCLUSIONS: This study establishes a well-characterized large cohort of MIS-C evaluated and treated following a standardized protocol and identifies key clinical, biomarker, cytokine, viral load, and sequencing features. Long-term follow-up will provide opportunity for future insights into MIS-C and its sequelae.

Active Boulder Movement at High Martian Latitudes.

Lobate stony landforms occur on steep slopes at high latitudes on Mars. We demonstrate active boulder movement at seven such sites. Submeter-scale boulders frequently move distances of a few meters. The movement is concentrated in the vicinity of the lobate landforms but also occurs on other slopes. This provides evidence for a newly discovered, common style of activity on Mars, which may play an important role in slope degradation. It also opens the possibility that the lobate features are currently forming in the absence of significant volumes of liquid water.

Proton Pump Inhibitor Use in Older Adults: Long-Term Risks and Steps for Deprescribing.

Proton pump inhibitors (PPIs) are commonly prescribed for treatment of acid-related gastrointestinal disorders. PPI use is approved for a duration of 2 to 12 weeks, depending on complication and severity. Many users lack an appropriate indication for continued therapy past the recommended duration. Long-term PPI use is associated with several adverse drug events, including acute interstitial nephritis, fractures, and Clostridium difficile-associated diarrhea (CDAD). Cautious prescribing and regular monitoring is essential, especially for older adults, as they may be at higher risk for these adverse effects. Deprescribing, defined as lowering dosage, switching to as-needed use, or complete discontinuation, should be considered for many PPI users. Patient education is critical. Alternative therapy considerations include histamine-2-receptor antagonists, as they are found to be associated with reduced CDAD and fracture events. Additional strategies include tapering off PPIs and modifying lifestyle to reduce the potential rebound hypersecretion that may occur as a result of discontinuation. The most significant lifestyle modification is weight loss. Additional lifestyle interventions include upright head of bed elevation, avoiding meals close to bedtime, and avoiding high-fat meals within two to three hours of reclining.

Review of the Next Generation of Long-Acting Basal Insulins: Insulin Degludec and Insulin Glargine.

Older adults are at an increased risk of developing type 2 diabetes mellitus (T2DM). Although oral agents (i.e., metformin) are the preferred first-line therapy, older adults often eventually require the addition of insulin to control their blood glucose. Long-acting insulin analogues are the preferred insulin products for older adults with T2DM. Insulin degludec and insulin glargine U-300 are both new generation long-acting insulins. When compared with the standard of care, long-acting insulin product insulin glargine U-100, insulin degludec, and insulin glargine U-300 had similar glucose-lowering effects, longer half-lives and durations of action, and a more even distribution over a 24-hour period. Additionally, the new generation insulins were superior with regard to rates and severity of nocturnal hypoglycemia. The long-term cardiovascular safety of these products has not been established yet. Although the new generation long-acting insulins will not revolutionize diabetes management, they appear to be an improvement over previous long-acting insulins.

Analysis of a Genetic Polymorphism in the Costimulatory Molecule TNFSF4 with Hematopoietic Stem Cell Transplant Outcomes.

Despite stringent procedures to secure the best HLA matching between donors and recipients, life-threatening complications continue to occur after hematopoietic stem cell transplantation (HSCT). Studying single nucleotide polymorphism (SNP) in genes encoding costimulatory molecules could help identify patients at risk for post-HSCT complications. In a stepwise approach we selected SNPs in key costimulatory molecules including CD274, CD40, CD154, CD28, and TNFSF4 and systematically analyzed their association with post-HSCT outcomes. Our discovery cohort analysis of 1157 HLA-A, -B, -C, -DRB1, and -DQB1 matched cases found that patients with donors homozygous for the C variant of rs10912564 in TNFSF4 (48%) had better disease-free survival (P = .029) and overall survival (P = .009) with less treatment-related mortality (P = .006). Our data demonstrate the TNFSF4C variant had a higher affinity for the nuclear transcription factor Myb and increased percentage of TNFSF4-positive B cells after stimulation compared with CT or TT genotypes. However, these associations were not validated in a more recent cohort, potentially because of changes in standard of practice or absence of a true association. Given the discovery cohort, functional data, and importance of TNFSF4 in infection clearance, TNFSF4C may associate with outcomes and warrants future studies.

Vegetative phase change is mediated by a leaf-derived signal that represses the transcription of miR156.

Vegetative phase change in Arabidopsis is regulated by miR156, a microRNA that promotes the expression of the juvenile phase and represses the expression of the adult phase. miR156 is expressed at a very high level early in shoot development and then decreases, leading to the onset of the adult phase. To determine the source of the factors that regulate vegetative phase change, we examined the effect of root and leaf ablation on the timing of this transition. Ablation of the root system or cotyledons had no effect on the timing of vegetative phase change, but ablation of leaf primordia delayed this transition in a miR156-dependent fashion. This treatment produced an increase in the overall abundance of miR156, which was attributable to an increase in the transcription of some, but not all, of the miR156 genes in Arabidopsis, and decreased the expression of SPL genes regulated by miR156. miR156 levels were also elevated by leaf ablation in Nicotiana benthamiana and in rejuvenating shoot apices of maize cultured in vitro. We conclude that vegetative phase change is initiated by a signal(s) produced by leaf primordia, which acts by repressing the transcription of specific members of the miR156 gene family.

Evaluation of dabigatran exposures reported to poison control centers.

BACKGROUND: Dabigatran is a novel oral anticoagulant for which a well-defined range of toxicity and proven antidote has not been established. OBJECTIVE: The primary objective of this study was to characterize dabigatran exposures reported to poison centers by dose ingested, clinical effects, treatments used, and managment sites to gain a better understanding of patient outcomes. METHODS: A retrospective database review was conducted for dabigatran exposures reported to the National Poison Data System for the American Association of Poison Control Centers (AAPCC) over the period October 2010 to December 2012. RESULTS: There were 802 human dabigatran exposures involving adults predominantly (91% of cases). Exposure chronicity was acute in 43%, acute-on-chronic in 46%, and chronic in 11%, with the most common reason for an exposure call being an unintentional therapeutic error (70.6%). The most common management sites were on-site in 72% of cases and within a health care facility for 26%. Bleeding events and coagulopathies were the most commonly observed clinical effects. Treatments administered included activated charcoal, blood and coagulation products, hemodialysis, and supportive measures. Confirmed outcomes included death in 13 patients (1.6%), major effects in 23 (2.9%), and moderate effects in 50 (6.2%). More severe outcomes were significantly associated with adverse drug reactions, patients ≥65 years of age, those treated with blood and coagulation products and/or dialysis, and renal dysfunction (P < .05). Children experienced few moderate effects and no major effects or deaths. CONCLUSIONS: Severe outcomes from dabigatran exposures were not common, occurring in approximately 5% of cases.

Influenza vaccination by pharmacists in a health sciences center: A 3-year experience.

OBJECTIVE: To assess the design and implementation of influenza vaccination clinics across campus, assess participant satisfaction with the pharmacist-led clinics, and educate and increase visibility of the role of pharmacists as vaccinators. SETTING: University of Oklahoma Health Sciences Center (OUHSC), a comprehensive health sciences center. PRACTICE INNOVATION: The College of Pharmacy on the OUHSC campus developed and implemented a vaccination program to increase influenza vaccination of OUHSC employees. MAIN OUTCOME MEASURES: Number of employees receiving influenza vaccination, employee satisfaction with the pharmacist-led clinics, and employee awareness of the pharmacist's role in vaccination. RESULTS: Reported OUHSC employee influenza vaccination rates increased from approximately 35% before implementation of the pharmacy-based program to 54% in 2012 after implementation. The increase was attributed to maintaining no out-of-pocket costs for employees, offering various clinic locations, and using media resources to educate employees about influenza infection and vaccination. Employees reported high satisfaction with the influenza vaccination clinics and with receiving vaccinations from pharmacists and student pharmacists. In the first 2 years of the program, the percentage of surveyed employees "very familiar" with the pharmacist's role in vaccinations increased from 23% to 66%. CONCLUSION: A college of pharmacy on a large health sciences center developed and successfully implemented an influenza vaccination program, providing an accessible and convenient route for influenza prevention to employees, as well as enhanced the visibility of pharmacists as vaccination providers.

Use of bisphosphonates in older adults: how long is long enough?

OBJECTIVE: To assess the benefits and risks of long-term bisphosphonates for treatment of osteoporosis in older adults. DATA SOURCES: A MEDLINE search was performed using PubMed from 1966 through 2011 to identify relevant publications. Key words searched included: adverse effects (AEs), aged, alendronate, atrial fibrillation, atypical fractures, bisphosphonate-associated osteonecrosis of the jaw, bisphosphonates, diaphyseal fractures, gastrointestinal cancer, ibandronate, musculoskeletal pain, osteoporosis, risedronate, subtrochanteric fractures, and zoledronic acid. Additional sources were obtained through bibliographic review of selected articles. STUDY SELECTION: Relevant studies that examined efficacy and safety of bisphosphonates in the treatment of osteoporosis were included. Focus was given to data involving older adults. Stronger levels of evidence (prospective trials) were given preference as the predominant body of literature, when available. DATA SYNTHESIS: Osteoporosis affects millions of elderly patients. Bisphosphonates represent first-line therapy. Recent literature has heightened concerns regarding AEs associated with long-term use, leading to the proposition of a "drug holiday." Additionally, there is a lack of literature concerning management of bisphosphonates in older adults. CONCLUSION: Evidence indicates that bisphosphonates maintain their efficacy and safety in older adults. Consideration must be given on a case-by-case basis to potential AEs associated with long-term use, as well as the derived benefit. Drug holidays may be appropriate given consideration of certain patient characteristics. Well-designed, prospective studies are needed to evaluate long-term use and AEs in older adults; therefore, clinical judgment combined with available evidence will have to suffice as the current practice.

20-Valent Pneumococcal Conjugate Vaccine in Older People.

Objective To review the current literature available regarding the efficacy and safety of the 20-valent pneumococcal vaccine in older people and summarize the current recommendation for use in this patient population. Data Sources PubMed was searched using the following terms: (PCV20 [Title] or 20-valent [Title] or 20-valent Pneumococcal conjugate vaccine [Title]) and English (Language). The current recommendations from the Advisory Committee on Immunization Practices and manufacturer package inserts were also reviewed. Study Selection/Data Extraction Nine articles on 20-valent Pneumococcal vaccine were identified based on the above search terms. Those selected for inclusion were randomized control trials including primary or subgroup analysis of PCV20 in older people. Data Synthesis Two randomized controlled trials have assessed the immunogenicity and safety of PCV20 in adults 65 years of age and older, one in a population previously vaccinated with PPSV23 and one in a vaccine-naive population. Both trials demonstrated PCV20 elicited a robust immune response one month after vaccination. PCV20 was well-tolerated with adverse events similar to earlier Pneumococcal vaccine formulations. Conclusion The simplified Pneumococcal vaccine regimen of a singular PCV20 vaccination offers a compelling advancement. Longer-term studies are needed to show if PCV20 will improve vaccination rates and reduce Pneumococcal morbidity and mortality.

A holistic approach to integrating patient, family, and lived experience voices in the development of the BrainHealth Databank: a digital learning health system to enable artificial intelligence in the clinic.

Artificial intelligence, machine learning, and digital health innovations have tremendous potential to advance patient-centred, data-driven mental healthcare. To enable the clinical application of such innovations, the Krembil Centre for Neuroinformatics at the Centre for Addiction and Mental Health, Canada's largest mental health hospital, embarked on a journey to co-create a digital learning health system called the BrainHealth Databank (BHDB). Working with clinicians, scientists, and administrators alongside patients, families, and persons with lived experience (PFLE), this hospital-wide team has adopted a systems approach that integrates clinical and research data and practices to improve care and accelerate research. PFLE engagement was intentional and initiated at the conception stage of the BHDB to help ensure the initiative would achieve its goal of understanding the community's needs while improving patient care and experience. The BHDB team implemented an evolving, dynamic strategy to support continuous and active PFLE engagement in all aspects of the BHDB that has and will continue to impact patients and families directly. We describe PFLE consultation, co-design, and partnership in various BHDB activities and projects. In all three examples, we discuss the factors contributing to successful PFLE engagement, share lessons learned, and highlight areas for growth and improvement. By sharing how the BHDB navigated and fostered PFLE engagement, we hope to motivate and inspire the health informatics community to collectively chart their paths in PFLE engagement to support advancements in digital health and artificial intelligence.

SARS-CoV-2 infections in patients enrolled on the Children's Oncology Group standard-risk B-cell acute lymphoblastic leukemia trial, AALL1731.

Hematologic malignancy is a risk factor for severe coronavirus disease 2019 (COVID-19) in adults; however, data specific to children with leukemia are limited. High-quality infectious adverse event data from the ongoing Children's Oncology Group (COG) standard-risk B acute lymphoblastic leukemia/lymphoma (ALL/LLy) trial, AALL1731, were analyzed to provide a disease-specific estimate of SARS-CoV-2 infection outcomes in pediatric ALL. Of 253 patients with reported infections, the majority (77.1%) were asymptomatic or mildly symptomatic (CTCAE grade 1/2) and there was a single COVID-19-related death. These data suggest SARS-CoV-2 infection does not confer substantial morbidity among young patients with B-lymphoblastic leukemia/lymphoma (B-ALL/LLy).

Donor and recipient chemokine receptor CCR5 genotype is associated with survival after bone marrow transplantation.

Despite continual improvement, morbidity and mortality after hematopoietic stem cell transplantation (HSCT) remain high. The importance of chemokines in HSCT lies in their regulation of immune responses that determine transplantation outcomes. We investigated the role of recipient and donor chemokine system gene polymorphisms by using a candidate gene approach on the incidence of graft-versus-host disease and posttransplantation outcomes in 1370 extensively human leukocyte antigen-matched, unrelated donor-recipient pairs by using multivariate Cox regression models. Our analysis identified that recipients homozygous for a common CCR5 haplotype (H1/H1) had better disease-free survival (DFS; P = .005) and overall survival (P = .021). When the same genotype of both the donor and recipient were considered in the models, a highly significant association with DFS and overall survival was noted (P < .001 and P = .007, respectively) with absolute differences in survival of up to 20% seen between the groups at 3 years after transplantation (50% DFS for pairs with recipient CCR5 H1/H1 vs 30% for pairs with donor CCR5 H1/H1). This finding suggests that donor and/or recipient CCR5 genotypes may be associated with HSCT outcome and suggests new diagnostic and therapeutic strategies for optimizing therapy.

Transcriptomic analysis reveals optimal cytokine combinations for SARS-CoV-2-specific T cell therapy products.

Adoptive T cell immunotherapy has been used to restore immunity against multiple viral targets in immunocompromised patients after bone-marrow transplantation and has been proposed as a strategy for preventing coronavirus 2019 (COVID-19) in this population. Ideally, expanded severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-virus-specific T cells (CSTs) should demonstrate marked cell expansion, T cell specificity, and CD8+ T cell skewing prior to adoptive transfer. However, current methodologies using IL-4 + IL-7 result in suboptimal specificity, especially in CD8+ cells. Using a microexpansion platform, we screened various cytokine cocktails (IL-4 + IL-7, IL-15, IL-15 + IL-4, IL-15 + IL-6, and IL-15 + IL-7) for the most favorable culture conditions. IL-15 + IL-7 optimally balanced T cell expansion, polyfunctionality, and CD8+ T cell skewing of a final therapeutic T cell product. Additionally, the transcriptomes of CD4+ and CD8+ T cells cultured with IL-15 + IL-7 displayed the strongest induction of antiviral type I interferon (IFN) response genes. Subsequently, microexpansion results were successfully translated to a Good Manufacturing Practice (GMP)-applicable format where IL-15 + IL-7 outperformed IL-4 + IL-7 in specificity and expansion, especially in the desirable CD8+ T cell compartment. These results demonstrate the functional implications of IL-15-, IL-4-, and IL-7-containing cocktails for therapeutic T cell expansion, which could have broad implication for cellular therapy, and pioneer the use of RNA sequencing (RNA-seq) to guide viral-specific T cell (VST) product manufacturing.

SARS-CoV-2-Specific T Cell Responses Are Stronger in Children With Multisystem Inflammatory Syndrome Compared to Children With Uncomplicated SARS-CoV-2 Infection.

Background: Despite similar rates of infection, adults and children have markedly different morbidity and mortality related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Compared to adults, children have infrequent severe manifestations of acute infection but are uniquely at risk for the rare and often severe Multisystem Inflammatory Syndrome in Children (MIS-C) following infection. We hypothesized that these differences in presentation are related to differences in the magnitude and/or antigen specificity of SARS-CoV-2-specific T cell (CST) responses between adults and children. We therefore set out to measure the CST response in convalescent adults versus children with and without MIS-C following SARS-CoV-2 infection. Methods: CSTs were expanded from blood collected from convalescent children and adults post SARS-CoV-2 infection and evaluated by intracellular flow cytometry, surface markers, and cytokine production following stimulation with SARS-CoV-2-specific peptides. Presence of serum/plasma antibody to spike and nucleocapsid was measured using the luciferase immunoprecipitation systems (LIPS) assay. Findings: Twenty-six of 27 MIS-C patients, 7 of 8 non-MIS-C convalescent children, and 13 of 14 adults were seropositive for spike and nucleocapsid antibody. CST responses in MIS-C patients were significantly higher than children with uncomplicated SARS-CoV-2 infection, but weaker than CST responses in convalescent adults. Interpretation: Age-related differences in the magnitude of CST responses suggest differing post-infectious immunity to SARS-CoV-2 in children compared to adults post uncomplicated infection. Children with MIS-C have CST responses that are stronger than children with uncomplicated SARS-CoV-2 infection and weaker than convalescent adults, despite near uniform seropositivity.

Biomarker Panels in Critical Care.

Biomarker panels have the potential to advance the field of critical care medicine by stratifying patients according to prognosis and/or underlying pathophysiology. This article discusses the discovery and validation of biomarker panels, along with their translation to the clinical setting. The current literature on the use of biomarker panels in sepsis, acute respiratory distress syndrome, and acute kidney injury is reviewed.