Background: Identifying the cause of infection is important for clinical management and public health decisions, including vaccination strategies. In low-resource settings, causes of fever are often not identified. In this study, molecular testing panels were used to identify the causes of pediatric fever in the Kathmandu Valley, Nepal. A dengue fever outbreak facilitated the investigation of dengue diagnostics. Methods: Children under 14 years of age were recruited to this prospective cohort study at Patan Hospital, Nepal. Clinical data and routine diagnostics were used to classify cases, including nonstructural protein 1 (NS1) antigen testing for dengue. Additional molecular diagnostics were performed on blood (12 viral, 26 bacterial and 6 fungal targets) and respiratory samples (17 viral and 3 bacterial targets). Results: From September 1, 2021, to April 19, 2023, 565 children were enrolled, median age 3 (interquartile-range 1-7) years. Pathogens identified included dengue virus (n = 101), respiratory syncytial virus (n = 30), influenza (n = 25), typhoidal Salmonella spp. (n = 7) and Neisseria meningitidis (n = 2). During the dengue outbreak, dengue polymerase chain reaction (PCR) and NS1 positivity rates were both high early in dengue disease, but if >3 days of symptoms, PCR positivity rates declined (10.3%) while NS1 positivity remained high into the second week of illness (80%). Conclusions: This prospective cohort study is the most comprehensive effort to date to describe the causes of pediatric fever in the Kathmandu Valley, Nepal. The United States Centers for Disease Control and Prevention recommends dengue PCR or NS1 antigen testing during the first 7 days of dengue fever. Our data indicate that PCR positivity declines after 3 days of symptoms, resulting in missed cases when relying solely on PCR.

Background Respiratory viruses commonly cause pneumonia in children. We aimed to identify respiratory viral nucleic acids in the nasopharynx of children admitted with pneumonia from 2014 to 2018, a period including a major earthquake (April 2015), pneumococcal conjugate vaccine (PCV10) introduction (August 2015), and a fuel shortage (October 2015 to March 2016). Methods Children 2 months to 14 years admitted to Patan Hospital between March 2014 and February 2018 with a clinical diagnosis of pneumonia had nasopharyngeal swabs collected and tested with a multiplex panel for the presence of genetic material from 23 respiratory pathogens. Results Of 1343 children with pneumonia, 974 (72.5%) had the nucleic acids of at least one respiratory virus in the nasopharynx. The median age of children with any viral genetic material detected was lower than those without (1.18, IQR: 0.59-2.39 years; vs 2.01 years, IQR: 0.81-4.34 years; P < .001). Commonly detected viral nucleic acids included those of respiratory syncytial virus (RSV) (21.0%), rhino/enterovirus (30.8%), and parainfluenza (7.4%). The odds of detecting any respiratory viral genetic material in children with pneumonia increased by 1.88 (95% confidence interval: 1.15, 3.06) in the year after the earthquake, when there were several aftershocks and a fuel crisis, relative to other periods and accounting for other potential confounding factors. Conclusions These findings highlight the importance of viral diagnostics in pediatric pneumonia and suggest that public health measures addressing environmental conditions during disasters might help reduce respiratory infections.

Importance:The upsurge in invasive disease caused by Streptococcus pyogenes among children reported in several European countries during 2022 to 2023 has not been fully explained. Objective:To evaluate whether changes in the circulation of common respiratory pathogens associated with the introduction of nonpharmaceutical interventions (NPIs) during the COVID-19 pandemic were associated with acquisition of immunity to S pyogenes and common respiratory viruses. Design, Setting, and Participants:This cross-sectional study recruited children with suspected infection and afebrile control participants at hospitals in 10 European countries. Data were collected before (September 2016 to March 2020) and after (April 2020 to July 2023) the introduction of NPIs. Main Outcomes and Measures:Molecular detection of bacterial and viral pathogens on throat swabs and age-stratified total serum immunoglobin G (IgG) reactivity to S pyogenes cell wall extract from 2 strains, respiratory syncytial virus (RSV), 5 influenza viruses, 4 common cold coronaviruses, and SARS-CoV-2, measured by immunoassay. Results:Throat swabs from 1942 children aged 0 to 4 years were tested for respiratory pathogens (1449 recruited before introduction of NPIs [median (IQR) age, 19.7 (8.2-38.1) months; 798 (55.1%) male]; 493 recruited after [median (IQR) age, 20.7 (9.7-38.1) months; 269 (54.7%) male]). A decrease in detection of S pyogenes, RSV, common cold coronaviruses, and influenza viruses was observed between March 2020 to July 2021, corresponding to the maximal period of NPIs. Antibodies to S pyogenes were measured in 252 children recruited before NPIs and 200 thereafter. Antibodies to viral antigens were measured in 230 children before NPIs and 92 thereafter. Total IgG to S pyogenes and RSV was significantly lower in children aged 3 to 4 years recruited after NPI introduction compared with those recruited before (S pyogenes emm1 strain: after, 67 participants; median [IQR] 0.13 [0.44-0.44] relative units [RU]; before, 87 participants; median [IQR] 0.35 [0.10-0.65] RU; P = .007. RSV: after, 30 participants; median [IQR] 49.6 [31.1-120.7] mesoscale units [MU]/1000; before, 76 participants; median [IQR] 141.8 [78.1-423.1] MU/1000; P < .001). No such differences were observed for children aged 0 to 2 years or for individual influenza viruses or SARS-CoV-2. Conclusions and Relevance:In this cross-sectional study, there was a significant reduction in serum antibodies to S pyogenes and RSV in children aged 3 to 4 years after introduction of NPIs. Equivalent to approximately a 1-year delay in acquisition of immunity, these data suggest a putative biological basis for the 2022 to 2023 upsurge in severe S pyogenes infections in this age group.

OBJECTIVES:To assess characteristics and outcomes of children with suspected or confirmed infection requiring emergency transport and PICU admission and to explore the association between the 2024 Phoenix Sepsis Score (PSS) criteria and mortality. DESIGN:Retrospective analysis of curated data from a 2014-2016 multicenter cohort study. SETTING:PICU admission following emergency transport in South East England, United Kingdom, from April 2014 to December 2016. PATIENTS:Children 0-16 years old ( n = 663) of whom 444 (67%) had suspected or confirmed infection. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:The PSS was calculated as a sum of four individual organ subscores (respiratory, cardiovascular, neurological, and coagulation) using the worst values during transport (i.e., from referral until the time of PICU admission). A score cutoff of greater than or equal to 2 points was used to define sepsis; and septic shock was defined as sepsis plus 1 or more cardiovascular subscore points. Sepsis occurred in 260 of 444 children (58.6%) with suspected or confirmed infection, with septic shock occurring in 177 of 260 (68.1%) of those with sepsis. A PSS score greater than or equal to 2 points occurred in 37 of 67 bronchiolitis cases, 19 of 35 meningoencephalitis cases, 30 of 47 pneumonia/empyema cases, 38 of 46 septic/toxic shock cases, nine of 15 severe sepsis cases, and 58 of 118 definite viral infections. Overall, 14 of 444 children died (3.2%). There were 12 deaths in the 260 children with PSS greater than or equal to 2, and two deaths in the 184 children with PSS less than 2 (4.6% vs. 1.1%; absolute difference, 3.5%; 95% CI, 0.1-6.9%; p = 0.04). CONCLUSIONS:In 2014-2016, over half of the critically ill children undergoing emergency transport to PICU with presumed or confirmed infection, and meeting retrospectively applied PSS criteria for sepsis, had a range of clinical diagnoses including bronchiolitis, meningoencephalitis, and pneumonia/empyema. Furthermore, the PSS criteria for categorization of sepsis and septic shock were associated with outcome and may be of value in future risk-stratification in clinical trials.

Importance:Important advances have been made in extracorporeal blood purification therapies (EBPTs) due to new technologies and biomaterials; however, the lack of established guidelines is a factor in great variability in clinical practice. This aspect is accentuated in pediatric intensive care given the small number of patients with diverse diagnoses treated with EBPT and the technical challenges in treating small children, potentiating the risk of adverse events. Objective:To understand what experienced users of EBPT think about its relevant issues, insight that may have implications for the design of future studies, and the application of EBPTs in patient care. Evidence Review:Literature search was conducted using the PubMed and Embase databases between January 1, 2020, and July 15, 2024, and a combination of key medical terms. A panel of experts was formed (composed of 15 authors and pediatric intensivists) to develop a consensus statement using a modified Delphi-based model between 2022 and 2024. The panel's core team drafted the initial questionnaire, which explored EBPT use in pediatric intensive care units (PICUs), including clinical indications for initiating and discontinuing use and outcomes for assessing effectiveness and safety. SurveyMonkey was used in the distribution, completion, and revision of the questionnaire, and findings were analyzed. Panelists were asked to rank answer choices. Numerical value for each ranking was translated to a percentage defining the strength of consensus (>90% agreement from panelists signifying strong consensus; <49% signifying no consensus). Findings:A total of 116 survey responses were received from panelists from 8 European countries. Strong consensus was achieved on 6 of 24 questions and consensus (75%-90% agreement) was reached on 18 of 24 questions. According to the panelists, the continuous renal replacement therapy standard or enhanced adsorption hemofilter and plasma exchange were of interest, representing the most applied EBPTs across various applications. While evidence on hemoadsorption is growing, it remains limited. Conclusions and Relevance:This consensus statement on EBPTs in critically ill pediatric patients was developed by an international panel of experts in areas where clinical evidence is still limited. This consensus statement could support pediatric intensivists in bedside decision-making and guide future research on EBPTs in PICUs.

In recent years, the stratification of adult critical illness into phenotypes with shared clinical features, and endotypes with shared biological mechanisms of disease, has gained traction (1). These developments fore-shadowed and followed an emphasis on sepsis in adults as a dysregulated host response to infection (2) in the Sepsis-3 definition (2), increased recognition of inflammation in noninfectious diseases (3), and co-opted "big" gene expression and clinical datasets (1). The COVID-19 pandemic further accelerated these efforts. With exceptions, childhood critical illness remains more amorphous: sepsis is still defined by measurement of the systemic inflammatory response syndrome (SIRS) that has little prognostic accuracy for predicting severe disease (4,5). The etiology of childhood pneumonia is stubbornly opaque to even the most thorough research (6). Trauma, malignancies, and postoperative critical illness are less numerous (7) and have until recently been considered as separate from critical illness caused by infection. In addition, less proximate causes of childhood mortality, including malnutrition and complications of prematurity have been placed within the rubric of public health. Despite these challenges, severity scoring for childhood illness has progressed with the development of age-adjusted sequential (sepsis) organ failure assessment (SOFA) scoring, pediatric logistic organ dysfunction score-2 (PELOD-2), pediatric early warning system (PEWS), and iterations of the pediatric index of mortality (currently PIM3, used to bench-mark pediatric ICU performance) among others (5). A new definition of sepsis in children is planned for early 2024 (8), and the updated pediatric Surviving Sepsis Campaign International Guidelines remain a robust source of recommendations for management (9), including specific guidance to limit fluid bolus administration in settings without critical care capacity following the fluid expansion as supportive therapy (FEAST) trial in east African children (10). For adults with sepsis, a dysregulated host response to infection has been operationalized by a two-point increase in the full SOFA score. This is an ordinal score from 0 to 24 encompassing Pao2/Fio2 ratio, platelet count, serum bilirubin concentration, mean arterial pressure/vasoactive infusion rate, Glasgow coma score, and either serum creatinine concentration or urine output (2). Typically the area under the receiver-operating characteristic (AUROC) curve—a measure of sensitivity and specificity that varies from 0.5 (no discrimination) to 1.0 (perfect discrimination)—is used to summarize the accuracy of a linear continuous or ordinal score for a binary outcome (such as mortality) (5). In large (> 1 million cases) mainly North American adult intensive care cohorts, SOFA had an AUROC curve of 0.74 and SIRS an AUROC of 0.64 for intensive care mortality (2). In small (< 500 cases) southeast Asian adult cohorts SOFA had an AUROC of 0.68 (mixed ICU and non-ICU) (11). The reduced prognostic accuracy in the southeast Asian cohorts may be secondary to a different etiological mix of critical illness, or a marker of host susceptibility, or a marker of differing therapeutic interventions in these units. In this issue of Pediatric Critical Care Medicine, Chandna et al (12) set out to evaluate nine existing pediatric severity scores on prospectively collected routine data from over 1,500 child admissions, 97 of whom died, to a pediatric critical care unit in semi-rural Cambodia. The unit is capable of mechanical ventilation, vasoactive therapy, peritoneal dialysis, and specialist nursing care. The majority had presumed infection, nearly two-thirds had respiratory distress, and more than one in five had reduced alertness. The most common diagnoses in the cohort were pneumonia, bronchiolitis, and dengue shock syndrome/hemorrhagic fever—reflective of the high infectious disease burden in rural Cambodia (13). Pneumonia, bronchiolitis, undifferentiated sepsis, and melioidosis (infection with the Gram-negative bacterium Burkholderia pseudomallei) were the most common causes of death. In the primary analysis, eight of the published severity scores including quick (q)SOFA, qPELOD-2, and PEWS had AUROC curve values of 0.71–0.76, as did scores derived from resource-limited settings, including the FEAST-pediatric emergency triage (FEAST-PET) score (10) and PEWS-RL (resource-limited). In contrast, SIRS performed less well with an AUROC curve of 0.59. Crucially, these scores used clinical markers of disease such as heart rate, systolic blood pressure and mental status (qSOFA), or presence of lung crepitations (included in FEAST-PET). As in many pediatric settings, accurate measurement of blood pressure in young infants was difficult (14). None of the scores included weight-for-age, despite malnutrition being both prevalent and associated with acute mortality in children in this setting (13). Nor, except for white cell count in SIRS, were laboratory markers included despite their inclusion in nonabbreviated severity scores, such as SOFA and PELOD-2. The authors subsequently derived their own new prognostic model for in-PICU mortality in Cambodia using routine respiratory, cardiovascular, and neurologic data, weight-for-age, and travel time to hospital. As with the Livepool (L)qSOFA score (heart rate, respiratory rate, capillary refill time, and mental status), problematic measurement of blood pressure was replaced with capillary refill time (14). The relationship of each candidate predictor to the outcome was examined individually before derivation of the model using penalized (ridge) logistic regression. Ridge penalization counters over-optimism in a model by using cross-validation to estimate a penalty parameter that is then used to shrink model coefficients and therefore reduce over-fitting. This new model had an AUROC of 0.84, significantly better than other assessed models. Validation of this model based on larger internal and external cohorts is planned. The lack of validation on a separate cohort of patients was an acknowledged limitation of this study. By extension, a further limitation is the heterogeneity of critical illness etiology across locations with emerging critical care capacity: any model of disease severity will need considerable external validation to be widely implemented. A further limitation of the work was the use of abbreviated severity scoring systems, such as qSOFA in contrast to full scoring systems, such as the six variables of a 30-point SOFA score. However, the use of simple abbreviated scores was both pragmatic (the SOFA score requires Pao2/Fio2 ratio which is often not available to critical care pediatricians, in any setting), and justified by prior data that suggest negligible difference in prognostic accuracy between qSOFA and SOFA (5,15). So why is this article important? At an institutional level, application of the score to critical care admissions could be used to triage the approximate 13% of children with a predicted mortality of greater than or equal to 10% to a high acuity clinical area with increased resource allocation. More broadly, these high-quality data from rural southeast Asia will contribute to regionally and globally applicable markers of severity in childhood critical illness. Regional sentinel sites for the surveillance of invasive bacterial disease already exist and several of these could provide high-quality, case-level clinical data for the development of severity scores from regions with a high childhood mortality burden. The varied prevalence of specific critical illnesses by region, such as dengue shock syndrome/hemorrhagic fever in southeast Asia, or falciparum malaria in sub-Saharan Africa, may mean that different severity scores are needed by disease-prevalence region. Alternatively, abbreviated severity scores may be appropriate across settings, which would have the advantage of enabling inter-regional and global comparisons. A compromise may be to have an abbreviated core data set standardized across settings, with additional variables by disease-prevalence region. There is no doubt that further high-quality data from the majority world, across a diverse range of settings, are needed. In contrast to other severity scores, the new model presented by Chandna and colleagues contains two under-appreciated but easily measured variables: weight-for-age z score and estimated travel time to hospital. Both reflect socioeconomic status (undernutrition is highly prevalent in rural Cambodia, and poorer families tend to live away from the hospital) (13). A longer travel time may also reflect a delay in instituting therapy for critical illness that may be associated with mortality (9). More fundamentally, these two variables account for the question, "what sort of child is this?"; or in Bayesian parlance, "what is the prior probability of mortality in this child?" The incorporation of socioeconomic variables into critical illness severity scores may be contentious, in part because it refocuses the attention of the critical care physician on the more profound, and political, speciality of public health. However, if the incorporation of these variables as prognostic markers improves model performance then there is no clear reason why they should not be used. Perhaps the final transformative effect of COVID-19 will be an appreciation that we critical care practitioners must also account for less proximate socioeconomic risk factors for mortality in our patients, and become more knowledgeable public health physicians at the same time?

Sepsis disproportionally affects children across all health-care settings and is one of the leading causes of morbidity and mortality in neonatal and paediatric age groups. As shown in the first paper in this Series, the age-specific incidence of sepsis is highest during the first years of life, before approaching adult incidence rates during adolescence. In the second paper in this Series, we focus on the unique susceptibility of paediatric patients to sepsis and how the underlying dysregulated host response relates to developmental aspects of children's immune system, genetic, perinatal, and environmental factors, and comorbidities and socioeconomic determinants of health, which often differ between children and adults. State-of-the-art clinical management of paediatric sepsis is organised around three treatment pillars—diagnosis, early resuscitation, and titration of advanced care—and we examine available treatment guidelines and the limitations of their supporting evidence. Serious evidence gaps remain in key areas of paediatric sepsis care, especially surrounding recognition, common interventions, and survivor support, and to this end we offer a research roadmap for the next decade that could accelerate targeted diagnostics and personalised use of immunomodulation. However, improving outcomes for children with sepsis relies fundamentally on systematic quality improvement in both recognition and treatment, which is the theme of the third paper in this Series. Digital health, as shown in the fourth and final paper of this Series, holds promising potential in breaking down the barriers that hinder progress in paediatric sepsis care and, ultimately, global child health.

Multisystem inflammatory syndrome in children (MIS-C) is a rare condition following SARS-CoV-2 infection associated with intestinal manifestations. Genetic predisposition, including inborn errors of the OAS-RNAseL pathway, has been reported. We sequenced 154 MIS-C patients and utilized a novel statistical framework of gene burden analysis, "burdenMC," which identified an enrichment for rare predicted-deleterious variants in BTNL8 (OR = 4.2, 95% CI: 3.5-5.3, P < 10-6). BTNL8 encodes an intestinal epithelial regulator of Vγ4+γδ T cells implicated in regulating gut homeostasis. Enrichment was exclusive to MIS-C, being absent in patients with COVID-19 or bacterial disease. Using an available functional test for BTNL8, rare variants from a larger cohort of MIS-C patients (n = 835) were tested which identified eight variants in 18 patients (2.2%) with impaired engagement of Vγ4+γδ T cells. Most of these variants were in the B30.2 domain of BTNL8 implicated in sensing epithelial cell status. These findings were associated with altered intestinal permeability, suggesting a possible link between disrupted gut homeostasis and MIS-C-associated enteropathy triggered by SARS-CoV-2.

Sepsis is a dysregulated host response to infection that leads to life-threatening organ dysfunction. Half of the 50 million people affected by sepsis globally every year are neonates and children younger than 19 years. This burden on the paediatric population translates into a disproportionate impact on global child health in terms of years of life lost, morbidity, and lost opportunities for children to reach their developmental potential. This Series on paediatric sepsis presents the current state of diagnosis and treatment of sepsis in children, and maps the challenges in alleviating the burden on children, their families, and society. Drawing on diverse experience and multidisciplinary expertise, we offer a roadmap to improving outcomes for children with sepsis. This first paper of the Series is a narrative review of the burden of paediatric sepsis from low-income to high-income settings. Advances towards improved operationalisation of paediatric sepsis across all age groups have facilitated more standardised assessment of the Global Burden of Disease estimates of the impact of sepsis on child health, and these estimates are expected to gain further precision with the roll out of the new Phoenix criteria for sepsis. Sepsis remains one of the leading causes of childhood morbidity and mortality, with immense direct and indirect societal costs. Although substantial regional differences persist in relation to incidence, microbiological epidemiology, and outcomes, these cannot be explained by differences in income level alone. Recent insights into post-discharge sequelae after paediatric sepsis, ranging from late mortality and persistent neurodevelopmental impairment to reduced health-related quality of life, show how common post-sepsis syndrome is in children. Targeting sepsis as a key contributor to poor health outcomes in children is therefore an essential component of efforts to meet the Sustainable Development Goals.

We evaluated whether the quantification of IgG to pneumococcal capsular polysaccharides is an accurate diagnostic test for pneumococcal infection in children with pneumonia in Nepal. Children with pneumococcal pneumonia did not have higher convalescent, or higher fold change, IgG to pneumococcal polysaccharides than children with other causes of pneumonia. Caution is needed in interpreting antibody responses in pneumococcal infections.

Ramnarayan, Padmanabhan1; Hageman, Joshua1; Carter, Michael1; Feinstein, Yael2 Author Information

This protocol is for extraction of genomic DNA from Sporosarcina pasteurii. It is based on a standard phenol-chloroform DNA extraction method.

Carter, Michael1; Hageman, Joshua1; Feinstein, Yael2; Ramnarayan, Padmanabhan1 Author Information

Severe febrile illnesses in children encompass life-threatening organ dysfunction caused by diverse pathogens and other severe inflammatory syndromes. A comparative approach to these illnesses may identify shared and distinct features of host immune dysfunction amenable to immunomodulation. Here, using immunophenotyping with mass cytometry and cell stimulation experiments, we illustrate trajectories of immune dysfunction in 74 children with multi-system inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, 30 with bacterial infection, 16 with viral infection, 8 with Kawasaki disease, and 42 controls. We explore these findings in a secondary cohort of 500 children with these illnesses and 134 controls. We show that neutrophil activation and apoptosis are prominent in multi-system inflammatory syndrome, and that this is partially shared with bacterial infection. We show that memory T cells from patients with multi-system inflammatory syndrome and bacterial infection are exhausted. In contrast, we show viral infection to be characterized by a distinct signature of decreased interferon signaling and lower interferon receptor gene expression. Improved understanding of immune dysfunction may improve approaches to immunomodulator therapy in severe febrile illnesses in children. Severe febrile illnesses in children may be various in presentation and aetiology but involve immune dysfunction amenable to immunomodulation. Here, the authors identify shared neutrophil and T cell dysfunction and a distinct interferon signature in critically ill children with severe febrile illness.

Severe febrile illnesses in children, such as multi-system inflammatory syndrome in children (MIS-C), severe bacterial infection (SBI), severe viral infection (SVI), and Kawasaki disease (KD), have shared clinical features. We used immunophenotyping with mass cytometry and cell stimulation experiments to illustrate shared and distinct mechanisms of immune dysfunction in 74 children with MIS-C, 30 with SBI, 16 with SVI, 8 with KD, and 42 controls. We then used targeted gene expression analysis to explore these findings in a secondary cohort of 500 children with these illnesses and 134 controls. Immunophenotyping and clustering analysis revealed neutrophil activation and apoptosis and T cell activation to be prominent in MIS-C and SBI. Cell stimulation experiments showed T cells from patients with acute MIS-C were exhausted. SVI was characterized by phosphorylated STAT signaling but lower gene expression for interferon receptors. Improved understanding of immune dysfunction may improve immunomodulator therapy in severe childhood febrile illnesses.

Abstract Background To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. Methods Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). Results In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%–98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%–97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. Conclusions MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.

Background Percutaneous tracheostomy is rarely used in children due to limited experience and safety concerns, in contrast to adult patients where the overwhelming majority of tracheostomies are placed via the percutaneous route. To assess the feasibility of percutaneous dilatational tracheostomy (PDT) using the modified fibroscopic-guided Ciaglia technique, we prospectively recorded and analyzed all PDT procedures performed for persistent failure to wean from mechanical ventilation and inability to protect the airway in our pediatric intensive care unit. Results From January 2003 to March 2022, 27 children (median age 12, range 5–17, years; median weight 38, range 19.5–80 kg; median PRISM II 10, range 6–11) underwent a PDT for acute encephalitis (10 children), neurovascular disease (5 children), and other indications, using a Shiley cannula ranging from 5.5 to 7 mm internal diameter (ID) after a median length of mechanical ventilation of 13 (range 10–22) days. Early complications included a few minor events, and we did not observe significant peristomal granulation nor infection. Three patients required transient tracheal stenting for suprastomal collapse, and four others developed severe subglottis (1) or substromal tracheal stenosis (3). The overall in-hospital mortality was 27%. Among the long-term survivors, cannulas were removed in 85% of cases after a median length of tracheostomy of 47 (range 31–77) days. Conclusions PDT is feasible and could be an alternative option to traditional surgical tracheostomy in adolescents and children over the age of 5.

Carbon metabolism provides organisms with energy and building blocks for cellular functions and growth. The tight regulation between degradation and assimilation of carbon substrates is central for optimal growth.

Little is known about the risk of multisystem inflammatory syndrome in children (MIS-C) with different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. In southeast England, MIS-C rates per confirmed SARS-CoV-2 infections in children aged 0-16 years were 56% lower (rate ratio [RR], 0.34 [95% confidence interval {CI}, .23-.50]) during prevaccine Delta, 66% lower (RR, 0.44 [95% CI, .28-.69]) during postvaccine Delta, and 95% lower (RR, 0.05 [95% CI, .02-.10]) during the Omicron period.

Current production of traditional concrete requires enormous energy investment that accounts for approximately 5 to 8% of the world's annual CO2 production. Biocement is a building material that is already in industrial use and has the potential to rival traditional concrete as a more convenient and more environmentally friendly alternative. Biocement relies on biological structures (enzymes, cells, and/or cellular superstructures) to mineralize and bind particles in aggregate materials (e.g., sand and soil particles). Sporosarcina pasteurii is a workhorse organism for biocementation, but most research to date has focused on S. pasteurii as a building material rather than a biological system. In this review, we synthesize available materials science, microbiology, biochemistry, and cell biology evidence regarding biological CaCO3 precipitation and the role of microbes in microbially induced calcium carbonate precipitation (MICP) with a focus on S. pasteurii. Based on the available information, we provide a model that describes the molecular and cellular processes involved in converting feedstock material (urea and Ca2+) into cement. The model provides a foundational framework that we use to highlight particular targets for researchers as they proceed into optimizing the biology of MICP for biocement production.