Negative regulation of Shh levels by Kras and Fgfr2 during hair follicle development.

Activating mutations in the KRAS oncogene are associated with three related human syndromes, which vary in hair and skin phenotypes depending on the involved allele. How variations in RAS signals are interpreted during hair and skin development is unknown. In this study, we investigated the developmental and transcriptional response of skin and hair to changes in RAS activity, using mouse genetic models and microarray analysis. While activation of Kras (Kras(G12D)) in the skin had strong effects on hair growth and hair shape, steady state changes in downstream RAS/MAPK effectors were subtle and detected only by transcriptional responses. To model the transcriptional response of multiple developmental pathways to active RAS, the effects of growth factor stimulation were studied in skin explants. Here FGF acutely suppressed Shh transcription within 90 min but had significantly less effect on Eda, WNT, Notch or BMP pathways. Furthermore, in vivo Fgfr2 loss-of-function in the ectoderm caused derepression of Shh, revealing a role for FGF in Shh regulation in the hair follicle. These studies define both dosage sensitive effects of RAS signaling on hair morphogenesis and reveal acute mechanisms for fine-tuning Shh levels in the hair follicle.

Reducing Erythrocyte Sedimentation Rate Ordering: De-implementation and Diagnostic Stewardship.

OBJECTIVES: The Choosing Wisely campaign recommends against the routine use of erythrocyte sedimentation rate (ESR) for the assessment of acute undiagnosed inflammation or infection. We examined ESR and C-reactive protein (CRP) ordering practices at a large, freestanding children's hospital. We found that 80% of ESR orders were placed concurrently with a CRP order. We aimed to reduce the ESR testing rate by 20% within 6 months in both inpatient and emergency department (ED) settings. METHODS: Applying Lean process improvement principles, we interviewed stakeholders from multiple subspecialties and engaged the institutional laboratory stewardship committee to identify the root causes of ESR ordering and design interventions. We conducted provider education (November 2020) and employed clinical decision support through an order panel in the electronic health record (April 2021). The outcome measures were monthly ESR testing rate per 1000 patient days (inpatient) and per 1000 ED visits, analyzed using statistical process control charts. CRP testing rate was a balancing measure. RESULTS: After intervention implementation, the ESR testing rate decreased from 11.4 to 8.9 tests per 1000 inpatient patient days (22% decrease) and from 49.4 to 29.5 tests per 1000 ED visits (40% decrease). This change has been sustained for >1 year postintervention. Interventions were effective even during the coronavirus disease 2019 pandemic when there was a rise in baseline ED ESR ordering rate. CRP testing rates did not increase after the interventions. CONCLUSIONS: Education and clinical decision support were effective in reducing the ESR ordering rate in both inpatient and ED settings.

Prescribing Patterns of Nonrecommended Medications for Children With Acute COVID-19.

OBJECTIVE: Repurposed medications for acute coronavirus disease 2019 (COVID-19) continued to be prescribed after results from rigorous studies and national guidelines discouraged use. We aimed to describe prescribing rates of nonrecommended medications for acute COVID-19 in children, associations with demographic factors, and provider type and specialty. METHODS: In this retrospective cohort of children <18 years in a large United States all-payer claims database, we identified prescriptions within 2 weeks of an acute COVID-19 diagnosis. We calculated prescription rate, performed multivariable logistic regression to identify risk factors, and described prescriber type and specialty during nonrecommended periods defined by national guidelines. RESULTS: We identified 3 082 626 COVID-19 diagnoses in 2 949 118 children between March 7, 2020 and December 31, 2022. Hydroxychloroquine (HCQ) and ivermectin were prescribed in 0.03% and 0.14% of COVID-19 cases, respectively, during nonrecommended periods (after September 12, 2020 for HCQ and February 5, 2021 for ivermectin) with considerable variation by state. Prescription rates were 4 times the national average in Arkansas (HCQ) and Oklahoma (ivermectin). Older age, nonpublic insurance, and emergency department or urgent care visit were associated with increased risk of either prescription. Additionally, residence in nonurban and low-income areas was associated with ivermectin prescription. General practitioners had the highest rates of prescribing. CONCLUSIONS: Although nonrecommended medication prescription rates were low, the overall COVID-19 burden translated into high numbers of ineffective and potentially harmful prescriptions. Understanding overuse patterns can help mitigate downstream consequences of misinformation. Reaching providers and parents with clear evidence-based recommendations is crucial to children's health.

Natural history of shedding and household transmission of severe acute respiratory syndrome coronavirus 2 using intensive high-resolution sampling.

IMPORTANCE: The COVID-19 pandemic has led to 775 million documented cases and over 7 million deaths worldwide as of March 2024 and is an ongoing health crisis. To limit viral spread within households and in the community, public health officials have recommended self-isolation, self-quarantine of exposed household contacts, and mask use. Yet, risk of household transmission (HHT) may be underestimated due to low frequency of sampling, and risk factors for HHT are not well understood. OBJECTIVES: To estimate the secondary attack rate of SARS-CoV-2 within households and to define the risk factors for new infections in household members who are in close contact with the index case. DESIGN, SETTING, AND PARTICIPANTS: In this prospective cohort study, from March 2020-December 2021 we enrolled 60 households with index cases who tested positive for SARS-CoV-2. All household contacts and index cases were tested daily for SARS-CoV-2 via reverse transcription polymerase chain reaction (RT-PCR) using self-collected anterior nares specimens. Households were followed until all study participants in the household tested negative for SARS-CoV-2 for seven consecutive days. We collected sex, age, race/ethnicity, comorbidities, and relationship to index case for secondary contacts, household level characteristics including primary income, household density, and square feet per person on property. We compared the sociodemographic variables between COVID-19 positive and negative household members and between households where secondary transmission did and did not occur. MAIN OUTCOMES AND MEASURES: Daily anterior nares swabs were tested for SARS-CoV-2 using RT-PCR, in order to assess duration of nasal shedding of SARS-CoV-2, as well as risk of transmission to secondary household contacts. RESULTS: Of the 163 participants in this study, 84 (51.5%) were women; median age (IQR) was 36.0 (17.0-54.0) years of age; 78 (47.8%) were white and 48 (29.5%) were Hispanic/LatinX. Of the fifty households with household contacts, at least one secondary case occurred in twenty-six households (52.0%) and forty-five household contacts (43.7%) were infected. Secondary attack rate was lowest among children of index cases (6/23, 26.1%). Modified Poisson regression identified that the risk of transmission to household contacts increases significantly with age (Risk ratio for each increase in years of age = 1.01, 95% CI = 1.00-1.02). Mixed effects regression models identified that participants with chronic diseases, such as asthma, diabetes, cancer, or cardiac disease, had higher Cts at baseline when compared to participants without chronic diseases (6.62, 95% CI: 1.46-11.77, p = 0.02) and show a slower rate of increase in Ct over time (-0.43, 95% CI: -0.77 to -0.09, p = 0.02). CONCLUSIONS AND RELEVANCE: This study suggests that HHT represents a key source of community-based infection of SARS-CoV-2. Allocation of resources for contact investigations and prevention interventions should focus on the individuals at highest risk of infection in households, especially those with higher density homes.

Medications and Adherence to Treatment Guidelines Among Children Hospitalized With Acute COVID-19.

OBJECTIVES: Coronavirus disease 2019 (COVID-19) treatment guidelines rapidly evolved during the pandemic. The December 2020 Infectious Diseases Society of America (IDSA) guideline, endorsed by the Pediatric Infectious Diseases Society, recommended steroids for critical disease, and suggested steroids and remdesivir for severe disease. We evaluated how medications for children hospitalized with COVID-19 changed after guideline publication. METHODS: We performed a multicenter, retrospective cohort study of children aged 30 days to <18 years hospitalized with acute COVID-19 at 42 tertiary care US children's hospitals April 2020 to December 2021. We compared medication use before and after the December 2020 IDSA guideline (pre- and postguideline) stratified by COVID-19 disease severity (mild-moderate, severe, critical) with interrupted time series. RESULTS: Among 18 364 patients who met selection criteria, 80.3% were discharged in the postguideline period. Remdesivir and steroid use increased postguideline relative to the preguideline period, although the trend slowed. Postguideline, among patients with severe disease, 75.4% received steroids and 55.2% remdesivir, and in those with critical disease, 82.4% received steroids and 41.4% remdesivir. Compared with preguideline, enoxaparin use increased overall but decreased among patients with critical disease. Postguideline, tocilizumab use increased and hydroxychloroquine, azithromycin, anakinra, and antibiotic use decreased. Antibiotic use remained high in severe (51.7%) and critical disease (81%). CONCLUSIONS: Although utilization of COVID-19 medications changed after December 2020 IDSA guidelines, there was a decline in uptake and incomplete adherence for children with severe and critical disease. Efforts should enhance reliable delivery of guideline-directed therapies to children hospitalized with COVID-19 and assess their effectiveness.

Reproducible breath metabolite changes in children with SARS-CoV-2 infection.

SARS-CoV-2 infection is diagnosed through detection of specific viral nucleic acid or antigens from respiratory samples. These techniques are relatively expensive, slow, and susceptible to false-negative results. A rapid non-invasive method to detect infection would be highly advantageous. Compelling evidence from canine biosensors and studies of adults with COVID-19 suggests that infection reproducibly alters human volatile organic compounds (VOCs) profiles. To determine whether pediatric infection is associated with VOC changes, we enrolled SARS-CoV-2-infected and -uninfected children admitted to a major pediatric academic medical center. Breath samples were collected from children and analyzed through state-of-the-art GCxGC-ToFMS. Isolated features included 84 targeted VOCs. Candidate biomarkers that were correlated with infection status were subsequently validated in a second, independent cohort of children. We thus find that six volatile organic compounds are significantly and reproducibly increased in the breath of SARS-CoV-2-infected children. Three aldehydes (octanal, nonanal, and heptanal) drew special attention, as aldehydes are also elevated in the breath of adults with COVID-19. Together, these biomarkers demonstrate high accuracy for distinguishing pediatric SARS-CoV-2 infection and support the ongoing development of novel breath-based diagnostics.

Reproducible Breath Metabolite Changes in Children with SARS-CoV-2 Infection.

SARS-CoV-2 infection is diagnosed through detection of specific viral nucleic acid or antigens from respiratory samples. These techniques are relatively expensive, slow, and susceptible to false-negative results. A rapid noninvasive method to detect infection would be highly advantageous. Compelling evidence from canine biosensors and studies of adults with COVID-19 suggests that infection reproducibly alters human volatile organic compound (VOC) profiles. To determine whether pediatric infection is associated with VOC changes, we enrolled SARS-CoV-2 infected and uninfected children admitted to a major pediatric academic medical center. Breath samples were collected from children and analyzed through state-of-the-art GCxGC-ToFMS. Isolated features included 84 targeted VOCs. Candidate biomarkers that were correlated with infection status were subsequently validated in a second, independent cohort of children. We thus find that six volatile organic compounds are significantly and reproducibly increased in the breath of SARS-CoV-2 infected children. Three aldehydes (octanal, nonanal, and heptanal) drew special attention, as aldehydes are also elevated in the breath of adults with COVID-19. Together, these biomarkers demonstrate high accuracy for distinguishing pediatric SARS-CoV-2 infection and support the ongoing development of novel breath-based diagnostics.

Factors Associated With COVID-19 Disease Severity in US Children and Adolescents.

BACKGROUND: Little is known about the clinical factors associated with COVID-19 disease severity in children and adolescents. METHODS: We conducted a retrospective cohort study across 45 US children's hospitals between April 2020 to September 2020 of pediatric patients discharged with a primary diagnosis of COVID-19. We assessed factors associated with hospitalization and factors associated with clinical severity (eg, admission to inpatient floor, admission to intensive care unit [ICU], admission to ICU with mechanical ventilation, shock, death) among those hospitalized. RESULTS: Among 19,976 COVID-19 encounters, 15,913 (79.7%) patients were discharged from the emergency department (ED) and 4063 (20.3%) were hospitalized. The clinical severity distribution among those hospitalized was moderate (3222, 79.3%), severe (431, 11.3%), and very severe (380, 9.4%). Factors associated with hospitalization vs discharge from the ED included private payor insurance (adjusted odds ratio [aOR],1.16; 95% CI, 1.1-1.3), obesity/type 2 diabetes mellitus (type 2 DM) (aOR, 10.4; 95% CI, 8.9-13.3), asthma (aOR, 1.4; 95% CI, 1.3-1.6), cardiovascular disease, (aOR, 5.0; 95% CI, 4.3- 5.8), immunocompromised condition (aOR, 5.9; 95% CI, 5.0-6.7), pulmonary disease (aOR, 5.3; 95% CI, 3.4-8.2), and neurologic disease (aOR, 3.2; 95% CI, 2.7-5.8). Among children and adolescents hospitalized with COVID-19, greater disease severity was associated with Black or other non-White race; age greater than 4 years; and obesity/type 2 DM, cardiovascular, neuromuscular, and pulmonary conditions. CONCLUSIONS: Among children and adolescents presenting to US children's hospital EDs with COVID-19, 20% were hospitalized; of these, 21% received care in the ICU. Older children and adolescents had a lower risk for hospitalization but more severe illness when hospitalized. There were differences in disease severity by race and ethnicity and the presence of selected comorbidities. These factors should be taken into consideration when prioritizing mitigation and vaccination strategies.

Assessment of the impact of inpatient infectious events in pediatric patients with newly diagnosed acute leukemia at Dr. Robert Reid Cabral Children's Hospital, Dominican Republic.

Survival rates for pediatric acute leukemia vary dramatically worldwide. Infections are a leading cause of morbidity and mortality, and the impact is amplified in low and middle-income countries. Defining the epidemiology of infection in a specific health care setting is paramount to developing effective interventions. This study aimed to define the epidemiology of and outcomes from infection in children with acute leukemia treated in a large public pediatric hospital in the Dominican Republic. A retrospective cohort was assembled of children newly diagnosed with acute leukemia between July 1, 2015 to June 30, 2017 at Hospital Infantil Dr. Robert Reid Cabral in Santo Domingo. Patients were identified from the Pediatric Oncology Network Database (PONDTM) and hospital admissions from the Oncology admissions logbook. Medical records and microbiology results were reviewed to identify all inpatient invasive infections. Distance from a child's home to the hospital was determined using ArcGIS by Esri. Infection rates were described in discrete time periods after diagnosis and risk factors for invasive infection were explored using negative binomial regression. Overall, invasive infections were common and a prominent source of death in this cohort. Rates were highest in the first 60 days after diagnosis. Gastroenteritis/colitis, cellulitis, and pneumonia were most frequent, with bacteremia common early on. Multidrug resistant bacteria were prevalent among a small number of positive cultures. In a multivariate negative binomial regression model, age ≥ 10 years and distance from the hospital > 100 km were each protective against invasive infection in the first 180 days after diagnosis, findings that were unexpected and warrant further investigation. Over one-third of patient deaths were related to infection. Interventions aimed at reducing infection should target the first 60 days after diagnosis, improved supportive care inside and outside the hospital, and increased antimicrobial stewardship and infection prevention and control measures.

A Pediatric Infectious Diseases Perspective of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Novel Coronavirus Disease 2019 (COVID-19) in Children.

Understanding the role that children play in the clinical burden and propagation of severe acute respiratory syndrome coronavirus 2, responsible for coronavirus disease 2019 (COVID-19) infections, is emerging. While the severe manifestations and acute clinical burden of COVID-19 have largely spared children compared with adults, understanding the epidemiology, clinical presentation, diagnostics, management, and prevention opportunities and the social and behavioral impacts on child health is vital. Foremost is clarifying the contribution of asymptomatic and mild infections to transmission within the household and community and the clinical and epidemiologic significance of uncommon severe post-infectious complications. Here, we summarize the current knowledge, identify resources, and outline research opportunities. Pediatric infectious diseases clinicians have a unique opportunity to advocate for the inclusion of children in epidemiological, clinical, treatment, and prevention studies to optimize their care as well as to represent children in the development of guidance and policy during pandemic response.

The complexity of diagnosing latent tuberculosis infection in older adults in long-term care facilities.

OBJECTIVES: In the USA, tuberculosis disease rates are highest in older adults. Diagnostic testing for latent tuberculosis infection (LTBI) has not been evaluated carefully in this group. The aim of this study was to define the relationship between tuberculin skin test (TST) results, T-SPOT.TB results, and T-cell responses to Mycobacterium tuberculosis antigens. METHODS: Long-term care facility residents with known prior TST results (positive or negative) were retested with TSTs and T-SPOT.TB. Prior exposure to M. tuberculosis was assessed by quantifying T-cell activation to mycobacterial antigens in vitro. RESULTS: The median age of the 37 participants was 77 years (range 57-98 years). Among 18 participants with a prior positive TST, three (16.7%) had a negative TST when retested (TST reversion); two had a negative T-SPOT.TB. Of the 15 who were historically and currently TST-positive, four (26.7%) had a negative T-SPOT.TB and one (6.7%) had a borderline result. Percentages of CD4+ T-cells responding to mycobacterial antigens were higher in participants with positive TST and T-SPOT.TB (18.2%) compared to those with a positive TST but negative T-SPOT.TB (6.4%, p=0.16) and negative TST and T-SPOT.TB (5.9%, p<0.001). CONCLUSIONS: LTBI testing in older adults is complicated by TST reversion and TST-positive/T-SPOT.TB-negative discordance, which may reflect clearance of infection or waning immunity.

Descriptive analysis of immunization policy decision making in the Americas.

OBJECTIVES: Reducing and eliminating vaccine-preventable diseases requires evidence-based and informed policy decision making. Critical to determining the functionality of the decision-making process for introduction of a new vaccine is understanding the role of the national immunization technical advisory group (ITAG) in each country. The aim of this study is to document the current situation of national level immunization policy decision making for use in the Pan American Health Organization (PAHO) ProVac Initiative. METHODS: A structured 66-variable questionnaire developed by the World Health Organization (WHO) in collaboration with the University of Ottawa was distributed to all WHO regions; it was composed of dichotomous, multiple-choice, and open-ended questions. Questionnaires were e-mailed or faxed to the six WHO regional offices and the offices distributed them to all member states. This paper analyzes surveys from the Americas as part of PAHO's ProVac Initiative. RESULTS: Twenty-nine countries of the Americas answered the survey. They conveyed that immunization policy making needed to be improved and further supported by organizations such as PAHO. Areas of improvement ranged from organization and technical support to strengthening capacity and infrastructure to improved coordination among stakeholders. This survey also highlighted a variety of ITAG processes that need further investigation. CONCLUSION: This survey supports the efforts of PAHO's ProVac Initiative to disseminate knowledge and best practices for an immunization policy decision-making framework through the development of clear definitions and guidelines. By highlighting each problem noted in this study, ProVac will assist countries in Latin America and the Caribbean to build national capacity for making evidence-based decisions about introduction of new vaccines.

Descriptive analysis of immunization policy decision making in the Americas / Análisis descriptivo de la toma de decisión sobre políticas de vacunación en las Américas

OBJECTIVES: Reducing and eliminating vaccine-preventable diseases requires evidence-based and informed policy decision making. Critical to determining the functionality of the decision-making process for introduction of a new vaccine is understanding the role of the national immunization technical advisory group (ITAG) in each country. The aim of this study is to document the current situation of national level immunization policy decision making for use in the Pan American Health Organization (PAHO) ProVac Initiative. METHODS: A structured 66-variable questionnaire developed by the World Health Organization (WHO) in collaboration with the University of Ottawa was distributed to all WHO regions; it was composed of dichotomous, multiple-choice, and open-ended questions. Questionnaires were e-mailed or faxed to the six WHO regional offices and the offices distributed them to all member states. This paper analyzes surveys from the Americas as part of PAHO's ProVac Initiative. RESULTS: Twenty-nine countries of the Americas answered the survey. They conveyed that immunization policy making needed to be improved and further supported by organizations such as PAHO. Areas of improvement ranged from organization and technical support to strengthening capacity and infrastructure to improved coordination among stakeholders. This survey also highlighted a variety of ITAG processes that need further investigation. CONCLUSION: This survey supports the efforts of PAHO's ProVac Initiative to disseminate knowledge and best practices for an immunization policy decision-making framework through the development of clear definitions and guidelines. By highlighting each problem noted in this study, ProVac will assist countries in Latin America and the Caribbean to build national capacity for making evidence-based decisions about introduction of new vaccines.

OBJETIVOS: Para reducir y eliminar las enfermedades prevenibles por vacunación se requiere tomar decisiones basadas en datos científicos y una política informada. Con el fin de determinar la funcionalidad del proceso de toma de decisiones para introducir una nueva vacuna es vital comprender el papel de los grupos técnicos asesores nacionales sobre vacunación (GTAN) de cada país. En este trabajo se documenta la situación actual de la toma de decisión sobre políticas de vacunación a nivel nacional como insumo de la Iniciativa ProVac de la Organización Panamericana de la Salud (OPS). MÉTODOS: Se distribuyó a todas las regiones de la Organización Mundial de la Salud (OMS) un cuestionario estructurado con 66 variables, desarrollado por la OMS en colaboración con la Universidad de Ottawa, Canadá. El cuestionario contenía preguntas abiertas, dicotómicas y de selección múltiple y se envió por correo electrónico o fax a las seis oficinas regionales de la OMS y estas lo distribuyeron a todos los estados miembros. En este manuscrito se analizan las respuestas procedentes de las Américas, como parte de la Iniciativa ProVac de la OPS. RESULTADOS: Respondieron la encuesta 29 países de las Américas. Todos coincidieron en que la formulación de políticas de vacunación debe mejorar y se necesita más apoyo de organizaciones como la OPS. Las áreas que requieren mejoras van desde la organización y el apoyo técnico hasta el fortalecimiento de la capacidad y la infraestructura, y el perfeccionamiento de la coordinación entre los diferentes actores. También se destacan algunos procesos de los GTAN que requieren mayor investigación. CONCLUSIÓN: Esta encuesta apoya los esfuerzos de la iniciativa ProVac de la OPS para diseminar el conocimiento y las mejores prácticas para elaborar un marco de trabajo para la toma de decisiones sobre políticas de vacunación mediante el desarrollo de definiciones y directivas claras. Al poner de manifiesto cada problema observado ...