Showing papers by "Boston Children's Hospital published in 2022"

Tracking the 2022 monkeypox outbreak with epidemiological data in real-time

Abstract: Monkeypox virus was first documented in humans in the 1970s and outbreaks have been reported in many countries, with most cases restricted to endemic areas.1Rimoin AW Mulembakani PM Johnston SC et al.Major increase in human monkeypox incidence 30 years after smallpox vaccination campaigns cease in the Democratic Republic of Congo.Proc Natl Acad Sci USA. 2010; 107: 16 262-16 267Crossref Scopus (246) Google Scholar In early May, 2022, monkeypox cases were reported in the UK, Spain, and elsewhere in Europe (figure, appendix).2UK Health Security AgencyMonkeypox cases confirmed in England—latest updates.https://www.gov.uk/government/news/monkeypox-cases-confirmed-in-england-latest-updatesDate: May 14, 2022Date accessed: May 25, 2022Google Scholar The pattern of geographical dispersal was much larger compared with past outbreaks that were more localised and occurred often in under-resourced communities.3Nakoune E Olliaro P Waking up to monkeypox.BMJ. 2022; 377o1321PubMed Google Scholar The size of the outbreak clusters is growing each day, as is the geographical spread across Europe and North America. Within the first week of the initial report, 24 countries reported suspected and confirmed cases of monkeypox virus, some of which had known travel links to the UK, Spain, Canada, and western Europe. As of June 5, 2022, there have been 920 confirmed and 70 suspected cases. Of 64 confirmed cases with known travel history, 32 were associated with travel from Europe, three from west Africa, two from Canada, and one from Australia. For 26 cases, travel history locations remain unknown. WHO convened a meeting of experts and technical advisory groups on May 20, 2022,4WHOWHO working closely with countries responding to monkeypox.https://www.who.int/news/item/20-05-2022-who-working-closely-with-countries-responding-to-monkeypoxDate: May 20, 2022Date accessed: May 25, 2022Google Scholar to investigate the causes of the outbreak and have released updated guidance on surveillance, case investigation, and contact tracing.5WHOSurveillance, case investigation and contact tracing for monkeypox.https://www.who.int/publications/i/item/WHO-MPX-surveillance-2022.1Date: May 22, 2022Date accessed: May 25, 2022Google Scholar The reason for the outbreak having a broader geographical reach is being investigated by the international and national public health community and the research community, contributing to a finer scale understanding of the outbreak dynamics. However, cessation of smallpox vaccination programmes, encroachment of humans into forested areas, and growing international mobility seem to be playing important roles in the epidemiology of monkeypox virus outbreaks.6Bunge EM Hoet B Chen L et al.The changing epidemiology of human monkeypox—a potential threat? A systematic review.PLoS Negl Trop Dis. 2022; 16e0010141Crossref PubMed Scopus (75) Google Scholar To support global response efforts, our team created an open-access database and visualisation to track the occurrence of cases in different countries. In addition, where available, we added information on age (aggregated into age ranges, with a minimum range of 5 years), gender, dates of symptom onset and laboratory confirmation, symptoms, locations (aggregated to the state level), travel history, and additional metadata defined by WHO.5WHOSurveillance, case investigation and contact tracing for monkeypox.https://www.who.int/publications/i/item/WHO-MPX-surveillance-2022.1Date: May 22, 2022Date accessed: May 25, 2022Google Scholar Data are compiled from verified sources, including reports from governments and public health organisations and news media reporting of health official statements. As verified information and official statements are published, we document secondary sources and update the metadata in the dataset. An on-call schedule for curators that runs 24 h a day, 7 days a week was established to ensure data are updated in near real-time. Each case is seen and discussed by at least two curators before being made available via our Global.health GitHub repository, and pushed to the map visualisation at least four times per day. During the early stages of outbreaks, obtaining reliable, synthesised data on the characteristics of cases is a challenge, especially at a global scale. Our work attempts to harmonise information across countries and provide additional data to support the epidemiological understanding of the origins and transmission dynamics of this outbreak. Ideally, these data are paired with virus genomic data and integrated directly with countries' epidemiological line-list data. In our repository, we are also working with colleagues and the WHO Hub for Pandemic and Epidemic Intelligence to define a contact data schema allowing countries and researchers to estimate and re-estimate key epidemiological parameters, such as the incubation period and serial interval, across different settings. Real-time data are necessary to plan effective control measures should this outbreak grow further. The work builds on infrastructure developed for epidemic control and pandemic preparedness and was used for the COVID-19 pandemic.7Kraemer MUG Scarpino SV Marivate V et al.Data curation during a pandemic and lessons learned from COVID-19.Nat Comput Sci. 2021; 1: 9-10Crossref Scopus (10) Google Scholar Global efforts are needed to ensure similar efforts to rapidly harmonise and publish detailed epidemiological data are supported during future outbreaks of emerging and re-emerging pathogens. This example will be a learning pathway to build better surveillance systems globally. MUGK and JSB report funding from The Rockefeller Foundation and Google.org. TdO received fees from Illumina as a member of the Infectious Disease Testing Advisory Board and received partial travel support to attend the Nobel Symposium of Medicine in May, 2022. IIB received consulting fees from BlueDot and NHL Players' Association. All other authors declare no competing interests. Download .pdf (2.09 MB) Help with pdf files Supplementary appendix

An aluminum hydroxide:CpG adjuvant enhances protection elicited by a SARS-CoV-2 receptor binding domain vaccine in aged mice

Abstract: Global deployment of vaccines that can provide protection across several age groups is still urgently needed to end the COVID-19 pandemic, especially in low- and middle-income countries. Although vaccines against SARS-CoV-2 based on mRNA and adenoviral vector technologies have been rapidly developed, additional practical and scalable SARS-CoV-2 vaccines are required to meet global demand. Protein subunit vaccines formulated with appropriate adjuvants represent an approach to address this urgent need. The receptor binding domain (RBD) is a key target of SARS-CoV-2 neutralizing antibodies but is poorly immunogenic. We therefore compared pattern recognition receptor (PRR) agonists alone or formulated with aluminum hydroxide (AH) and benchmarked them against AS01B and AS03-like emulsion-based adjuvants for their potential to enhance RBD immunogenicity in young and aged mice. We found that an AH and CpG adjuvant formulation (AH:CpG) produced an 80-fold increase in anti-RBD neutralizing antibody titers in both age groups relative to AH alone and protected aged mice from the SARS-CoV-2 challenge. The AH:CpG-adjuvanted RBD vaccine elicited neutralizing antibodies against both wild-type SARS-CoV-2 and the B.1.351 (beta) variant at serum concentrations comparable to those induced by the licensed Pfizer-BioNTech BNT162b2 mRNA vaccine. AH:CpG induced similar cytokine and chemokine gene enrichment patterns in the draining lymph nodes of both young adult and aged mice and enhanced cytokine and chemokine production in human mononuclear cells of younger and older adults. These data support further development of AH:CpG-adjuvanted RBD as an affordable vaccine that may be effective across multiple age groups.

Dual-responsive fluorescent probe for imaging NAD(P)H and mitochondrial viscosity and its application in cancer cell ferroptosis

Abstract: Herein, we design and synthesize a dual-responsive fluorescent probe 3Q-2 and use it to reveal the dynamic changes of NAD(P)H and mitochondrial viscosity during ferroptosis, a newly discovered form of cell death. 3Q-2 displays two separate spectra when responding to NAD(P)H and mitochondrial viscosity, respectively, with high sensitivity, selectivity, and no cross-interference. We find that cancer cells possess distinct levels of NAD(P)H and mitochondrial viscosity during ferroptosis induced by cystine transporter SLC7A11 inhibitor erastin and glutathione peroxidase 4 (GPX4) inhibitor RSL4, respectively. As a robust method simultaneously detecting NAD(P)H and mitochondrial viscosity, 3Q-2 may be expected to find more applications in other physiological and pathological scenarios.

Evaluation of Daily Low-Dose Prednisolone During Upper Respiratory Tract Infection to Prevent Relapse in Children With Relapsing Steroid-Sensitive Nephrotic Syndrome

Abstract: In children with corticosteroid-sensitive nephrotic syndrome, many relapses are triggered by upper respiratory tract infections. Four small studies found that administration of daily low-dose prednisolone for 5 to 7 days at the time of an upper respiratory tract infection reduced the risk of relapse, but the generalizability of their findings is limited by location of the studies and selection of study population.To investigate the use of daily low-dose prednisolone for the treatment of upper respiratory tract infection-related relapses.This double-blind, placebo-controlled randomized clinical trial (Prednisolone in Nephrotic Syndrome [PREDNOS] 2) evaluated 365 children with relapsing steroid-sensitive nephrotic syndrome with and without background immunosuppressive treatment at 122 pediatric departments in the UK from February 1, 2013, to January 31, 2020. Data from the modified intention-to-treat population were analyzed from July 1, 2020, to December 31, 2020.At the start of an upper respiratory tract infection, children received 6 days of prednisolone, 15 mg/m2 daily, or matching placebo preparation. Those already taking alternate-day prednisolone rounded their daily dose using trial medication to the equivalent of 15 mg/m2 daily or their alternate-day dose, whichever was greater.The primary outcome was the incidence of first upper respiratory tract infection-related relapse. Secondary outcomes included overall rate of relapse, changes in background immunosuppressive treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, and quality of life.The modified intention-to-treat analysis population comprised 271 children (mean [SD] age, 7.6 [3.5] years; 174 [64.2%] male), with 134 in the prednisolone arm and 137 in the placebo arm. The number of patients experiencing an upper respiratory tract infection-related relapse was 56 of 131 (42.7%) in the prednisolone arm and 58 of 131 (44.3%) in the placebo arm (adjusted risk difference, -0.02; 95% CI, -0.14 to 0.10; P = .70). No evidence was found that the treatment effect differed according to background immunosuppressive treatment. No significant differences were found in secondary outcomes between the treatment arms. A post hoc subgroup analysis assessing the primary outcome in 54 children of South Asian ethnicity (risk ratio, 0.66; 95% CI, 0.40-1.10) vs 208 children of other ethnicity (risk ratio, 1.11; 95% CI, 0.81-1.54) found no difference in efficacy of intervention in those of South Asian ethnicity (test for interaction P = .09).The results of PREDNOS 2 suggest that administering 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of nephrotic syndrome in children in the UK. Further work is needed to investigate interethnic differences in treatment response.isrctn.org Identifier: ISRCTN10900733; EudraCT 2012-003476-39.

Immunogenicity and Safety of SARS-CoV-2 mRNA Vaccines in a Cohort of Patients With Type 1 Diabetes

Abstract: Patients with type 1 diabetes (T1D) may develop severe outcomes during coronavirus disease 2019 (COVID-19), but their ability to generate an immune response against the SARS-CoV-2 mRNA vaccines remains to be established. We evaluated the safety, immunogenicity, and glycometabolic effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines in patients with T1D. A total of 375 patients (326 with T1D and 49 subjects without diabetes) who received two doses of the SARS-CoV-2 mRNA vaccines (mRNA-1273, BNT162b2) between March and April 2021 at ASST Fatebenefratelli Sacco were included in this monocentric observational study. Local and systemic adverse events were reported in both groups after SARS-CoV-2 mRNA vaccination, without statistical differences between them. While both patients with T1D and subjects without diabetes exhibited a parallel increase in anti-SARS-CoV-2 spike titers after vaccination, the majority of patients with T1D (70% and 78%, respectively) did not show any increase in the SARS-CoV-2–specific cytotoxic response compared with the robust increase observed in all subjects without diabetes. A reduced secretion of the T-cell–related cytokines interleukin-2 and tumor necrosis factor-α in vaccinated patients with T1D was also observed. No glycometabolic alterations were evident in patients with T1D using continuous glucose monitoring during follow-up. Administration of the SARS-CoV-2 mRNA vaccine is associated with an impaired cellular SARS-CoV-2–specific cytotoxic immune response in patients with T1D.

WEE1 inhibition induces anti-tumor immunity by activating ERV and the dsRNA pathway.

Abstract: Targeted therapies represent attractive combination partners with immune checkpoint blockade (ICB) to increase the population of patients who benefit or to interdict the emergence of resistance. We demonstrate that targeting WEE1 up-regulates immune signaling through the double-stranded RNA (dsRNA) viral defense pathway with subsequent responsiveness to immune checkpoint blockade even in cGAS/STING-deficient tumors, which is a typical phenotype across multiple cancer types. WEE1 inhibition increases endogenous retroviral elements (ERVs) expression by relieving SETDB1/H3K9me3 repression through down-regulating FOXM1. ERVs trigger dsRNA stress and interferon response, increasing recruitment of anti-tumor T cells with concurrent PD-L1 elevation in multiple tumor models. Furthermore, combining WEE1 inhibition and PD-L1 blockade induced striking tumor regression in a CD8+ T cell-dependent manner. A WEE1 inhibition-induced viral defense signature provides a potentially informative biomarker for patient selection for combination therapy with WEE1 and ICB. WEE1 inhibition stimulates anti-tumor immunity and enhances sensitivity to ICB, providing a rationale for the combination of WEE1 inhibitors and ICB in clinical trials.

Transcription factor network analysis identifies REST/NRSF as an intrinsic regulator of CNS regeneration in mice

Abstract: Abstract The inability of neurons to regenerate long axons within the CNS is a major impediment to improving outcome after spinal cord injury, stroke, and other CNS insults. Recent advances have uncovered an intrinsic program that involves coordinate regulation by multiple transcription factors that can be manipulated to enhance growth in the peripheral nervous system. Here, we use a systems genomics approach to characterize regulatory relationships of regeneration-associated transcription factors, identifying RE1-Silencing Transcription Factor (REST; Neuron-Restrictive Silencer Factor, NRSF) as a predicted upstream suppressor of a pro-regenerative gene program associated with axon regeneration in the CNS. We validate our predictions using multiple paradigms, showing that mature mice bearing cell type-specific deletions of REST or expressing dominant-negative mutant REST show improved regeneration of the corticospinal tract and optic nerve after spinal cord injury and optic nerve crush, which is accompanied by upregulation of regeneration-associated genes in cortical motor neurons and retinal ganglion cells, respectively. These analyses identify a role for REST as an upstream suppressor of the intrinsic regenerative program in the CNS and demonstrate the utility of a systems biology approach involving integrative genomics and bio-informatics to prioritize hypotheses relevant to CNS repair.

A community-based trial of a psychosocial eHealth intervention for parents of children with cancer

Abstract: Background The Electronic Surviving Cancer Competently Intervention Program (eSCCIP), a psychosocial eHealth intervention for parents and caregivers of children with cancer (parents), was delivered in a community-based psychosocial oncology center. Primary endpoints were intervention acceptability, feasibility, and accessibility, with a secondary exploratory focus on psychosocial outcomes. Procedure Oncology therapists in a psychosocial oncology center were trained in eSCCIP delivery. Participants were eligible for participation if they were the primary caregiver of a child with cancer between the ages 0 and 17, could read and write in English, and had reliable internet access to complete eSCCIP. Surveys were administered electronically at baseline and post intervention to evaluate study endpoints. Effect sizes (Cohen's d) were computed for exploratory psychosocial outcomes. Nineteen parents completed the intervention. Results Parents rated eSCCIP as highly acceptable, feasible, and accessible. A large clinical effect was detected for acute distress (d = 0.79). Moderate clinical effects were reported for overall posttraumatic stress disorder (PTSD) symptoms (d = 0.37), negative mood/cognitions (d = 0.59), and symptoms of anxiety (d = 0.48). Conclusions Results indicate that eSCCIP is an acceptable, feasible, and accessible psychosocial intervention for parents. Exploratory analyses suggest that participation in eSCCIP may contribute to decreases in acute distress, symptoms of anxiety, and symptoms of PTSD.

Self-supervised IVIM DWI parameter estimation with a physics based forward model.

Abstract: PURPOSE To assess the robustness and repeatability of intravoxel incoherent motion model (IVIM) parameter estimation for the diffusion-weighted MRI in the abdominal organs under the constraints of noisy diffusion signal using a novel neural network method. METHODS Clinically acquired abdominal scans of Crohn's disease patients were retrospectively analyzed with regions segmented in the kidney cortex, spleen, liver, and bowel. A novel IVIM parameter fitting method based on the principle of a physics guided self-supervised convolutional neural network that does not require reference parameter estimates for training was compared to a conventional non-linear least squares (NNLS) algorithm, and a voxelwise trained artificial neural network (ANN). RESULTS Results showed substantial increase in parameter robustness to the noise corrupted signal. In an intra-session repeatability experiment, the proposed method showed reduced coefficient of variation (CoV) over multiple acquisitions in comparison to conventional NLLS method and comparable performance to ANN. The use of D and f estimates from the proposed method led to the smallest misclassification error in linear discriminant analysis for characterization between normal and abnormal Crohn's disease bowel tissue. The fitting of D∗ parameter remains to be challenging. CONCLUSION The proposed method yields robust estimates of D and f IVIM parameters under the constraints of noisy diffusion signal. This indicates a potential for the use of the proposed method in conjunction with accelerated DW-MRI acquisition strategies, which would typically result in lower signal to noise ratio.

Exploring the Effect of COVID-19 on Graduate Nursing Education

Abstract: Graduate nursing students are both nurses and adult learners. During the COVID-19 pandemic, many found themselves working on the frontlines while maintaining their studies and confronting challenges in their professional, educational, and personal lives. Changes in work environments, including redeployments, increased hours, and furloughs, challenged their work-study balance. The rapid pivot to virtual instruction allowed graduate nursing students to continue their coursework, but asynchronous delivery of course content increased their isolation and stress. Academic institutions supported graduate nursing students through innovations such as regular town hall meetings and flexible attendance policies, while the widespread closure of clinical learning sites became one of their biggest challenges. A minimum of 500 hours of supervised direct patient care is required to prepare a student to practice as a nurse practitioner, but there is no formal, financed clinical placement system for nurse practitioner students-leaving this clinical learning requirement particularly vulnerable to disruption during the pandemic. Some of the clinical learning alternatives employed included occupational health work, tele-precepting, and simulation. Since telehealth will be a part of the future of health care delivery, tele-precepting practices should be further developed, but simulation was underused and not an acceptable replacement for supervised direct patient care. A postpandemic future needs to limit gaps in the development of safe, competent health care providers by viewing graduate nursing students as essential workers and ensuring their access to the robust didactic and clinical learning opportunities that will best position them as leaders in health care.