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).

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.

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.

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.

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.

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.

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.

Diurnal Variation in Medical Emergency Team Calls at a Tertiary Care Children's Hospital.

Medical emergency teams (METs) bring critical care expertise to the bedsides of hospital ward patients who may be deteriorating. Diurnal variation in MET activation rates may identify inconsistencies in the detection of patients needing intervention. We aimed to determine whether such variation exists at our tertiary care children's hospital. METHODS: In this retrospective cohort study, we collected data including date and time of MET and disposition following MET for all inpatients at Cincinnati Children's Hospital Medical Center with a MET call between January 2008 and May 2014. The analysis compared the MET rate between days and nights, weekdays and weekends, and before and after nursing shift change. RESULTS: The number of METs per hour varied throughout the day. More METs were called during the day than at night (0.7 calls/shift ± 0.95 vs 0.6 ± 0.9, P < 0.001). There were also more METs per day on weekdays than weekends (1.4 ± 1 calls/d vs 1.2 ± 1, P < 0.001). Daytime METs were more likely to lead to transfer to the intensive care unit or operating room than those called at night (61.9% vs. 52.9%, P < 0.001). MET activation rates did not differ significantly in the 2 hours before nursing shift change compared to the 2 hours after. CONCLUSIONS: At our large tertiary care children's hospital, there are both diurnal variations and variations across weekdays versus weekends in the MET activation rate. This difference may indicate variations in our ability to detect deteriorating patients on the wards and be further studied.

Pregnancy rates from intrauterine insemination are equivalent following 1- versus 5-day letrozole administration for ovulation induction: a retrospective study.

OBJECTIVE: To compare the efficacy of single-dose letrozole (25 mg) with a 5-day course (5 mg/day) for ovulation induction (OI). DESIGN: Retrospective cohort study. SETTING: Hospital. PATIENTS: Patients undergoing first round of OI and intrauterine insemination with letrozole from January 2015 through December 2017. INTERVENTIONS: Patients received letrozole as either a single 25 mg dose for 1 day (1D) versus 5 mg daily for 5 days (5D). A secondary analysis was performed on patients also receiving gonadotropins (GND). MAIN OUTCOME MEASURES: Pregnancy rate (PR) determined by positive human chorionic GND. RESULTS: There were 847 patients included in the study, 302 in the 1D group and 284 in the 5D group; 261 patients had concurrent GND administration, 162 1D+GND and 99 5D+GND. There was no difference in smoking status, primary versus secondary infertility, or total motile sperm concentration. Comparing 1D with 5D, there was a statistically significant, although not clinically relevant, difference in both age and body mass index (31 vs. 31.8 years; 26.2 vs. 27.4, respectively). Similarly, comparing 1D+GND with 5D+GND, there was statistically significant difference in body mass index (27.19 vs. 29.1). Secondary outcomes included live birth rate (LBR), multiple gestation rate (MG), and miscarriage rate (SAB). There were no differences between 1D and 5D in the primary outcome of PR (14.2% vs. 11.6%), LBR (9.6% vs. 7%), MG (16.2% vs. 13.8%), or SAB (16.22% vs. 13.8%). In looking at the GND groups alone, there was no difference in PR (18.3% vs. 23.8%), LBR (11.72% vs. 17.86%), MG (8.7% vs. 5.56%), or SAB (13.64% vs. 5.56%). There was a significant difference in cycle cancellation rate in the 1D versus 5D groups (3.9% vs. 9.6%); however, this was not seen in the 1D+GND versus 5D+GND groups. CONCLUSIONS: A single-dose protocol with letrozole in an OI/intrauterine insemination cycle may be considered an alternative to standard 5D dosing protocols with the potential for improved compliance and similar reproductive outcomes.

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.

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.

Surface Expressions of Subsurface Sediment Mobilization Rooted into a Gas Hydrate-Rich Cryosphere on Mars.

We report on evidence for fluid circulation in the upper crust of Mars, which could create environments favorable for life and its development. We investigate the nature of the thumbprint terrains covering part of Arcadia Planitia in the Martian northern hemisphere. Our analytic procedure allowed us to (i) hypothesise a potential relationship between these thumbprint terrains and an inferred underground fracture network that extends to where the clathrate-rich cryosphere contacts with the underlying hydrosphere; (ii) support the hypothesis that these thumbprint terrains are made of fine grained loosely packed materials erupted from deep beneath the subsurface mobilized by water; and (iii) date the thumbprint terrains of Arcadia Planitia to ~370 Ma. We conclude that the study area is an area worthy of astrobiological investigation, bringing water and fine grained sediment from depth to the surface for investigation.

Apnea Threshold in Pediatric Brain Death: A Case with Variable Results Across Serial Examinations.

Consensus guidelines currently exist for the evaluation of pediatric patients with suspected brain death. The guidelines include the requirement for two consistent examinations separated by an observation period and a threshold of 60 mm Hg for PaCO 2 during apnea testing. We present a patient who met all prerequisites to perform brain death examination but had variability in examinations during apnea testing. We discuss our strategy in managing these unexpected findings, including the importance of open and ongoing communication with the family, and the implications for current guidelines for the determination of brain death in pediatric patients.

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.

The triggering factors of the Móafellshyrna debris slide in northern Iceland: Intense precipitation, earthquake activity and thawing of mountain permafrost.

On the 20th September 2012, a large debris slide occurred in the Móafellshyrna Mountain in the Tröllaskagi peninsula, central north Iceland. Our work describes and discusses the relative importance of the three factors that may have contributed to the failure of the slope: intense precipitation, earthquake activity and thawing of ground ice. We use data from weather stations, seismometers, witness reports and field observations to examine these factors. The slide initiated after an unusually warm and dry summer followed by a month of heavy precipitation. Furthermore, the slide occurred after three seismic episodes, whose epicentres were located ~60km NNE of Móafellshyrna Mountain. The main source of material for the slide was ice-rich colluvium perched on a topographic bench. Blocks of ice-cemented colluvium slid and then broke off the frontal part of the talus slope, and the landslide also involved a component of debris slide, which mobilized around 312,000-480,000m3 (as estimated from field data and aerial images of erosional morphologies). From our analysis we infer that intense precipitation and seismic activity prior to the slide are the main preparatory factors for the slide. The presence of ice-cemented blocks in the slide's deposits leads us to infer that deep thawing of ground ice was likely the final triggering factor. Ice-cemented blocks of debris have been observed in the deposits of two other recent landslides in northern Iceland, in the Torfufell Mountain and the Árnesfjall Mountain. This suggests that discontinuous mountain permafrost is degrading in Iceland, consistent with the decadal trend of increasing atmospheric temperature in Iceland. This study highlights a newly identified hazard in Iceland: landslides as a result of ground ice thaw. Knowledge of the detailed distribution of mountain permafrost in colluvium on the island is poorly constrained and should be a priority for future research in order to identify zones at risk from this hazard.

Water induced sediment levitation enhances downslope transport on Mars.

On Mars, locally warm surface temperatures (~293 K) occur, leading to the possibility of (transient) liquid water on the surface. However, water exposed to the martian atmosphere will boil, and the sediment transport capacity of such unstable water is not well understood. Here, we present laboratory studies of a newly recognized transport mechanism: "levitation" of saturated sediment bodies on a cushion of vapor released by boiling. Sediment transport where this mechanism is active is about nine times greater than without this effect, reducing the amount of water required to transport comparable sediment volumes by nearly an order of magnitude. Our calculations show that the effect of levitation could persist up to ~48 times longer under reduced martian gravity. Sediment levitation must therefore be considered when evaluating the formation of recent and present-day martian mass wasting features, as much less water may be required to form such features than previously thought.

Student and faculty perceptions about mandatory influenza vaccinations on a health sciences campus.

OBJECTIVE: To examine the perceptions among faculty and health professional students regarding mandatory vaccination policies on a health sciences campus. PARTICIPANTS: A total of 296 faculty and 244 students completed surveys during Fall 2015. METHODS: The online survey administered to individuals who received the influenza vaccine during the fall 2015 influenza vaccination clinic season included five items evaluating perceptions of employer mandatory vaccination requirements. RESULTS: Chi-square analysis indicated that although faculty and students agree mandatory vaccinations in a health care environment are appropriate, faculty are more likely than students to get vaccinated in the absence of a mandate. Additionally, a small fraction of faculty would consider employment elsewhere when facing this mandate. CONCLUSIONS: Overall, faculty and students had favorable perceptions about mandatory influenza vaccine policies. Since students were less likely to be vaccinated in the absence of a mandate, education of students should be improved to support the importance of vaccinations in a health care environment.

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.