Pre-existing Immunocompromising Conditions and Outcomes of Acute COVID-19 Patients Admitted for Pediatric Intensive Care.

BACKGROUND: We aimed to determine if pre-existing immunocompromising conditions (ICCs) were associated with the presentation or outcome of patients with acute coronavirus disease 2019 (COVID-19) admitted for pediatric intensive care. METHODS: 55 hospitals in 30 U.S. states reported cases through the Overcoming COVID-19 public health surveillance registry. Patients <21 years admitted March 12, 2020-December 30, 2021 to the pediatric intensive care unit (PICU) or high acuity unit for acute COVID-19 were included. RESULTS: Of 1,274 patients, 105 (8.2%) had an ICC including 33 (31.4%) hematologic malignancies, 24 (22.9%) primary immunodeficiencies and disorders of hematopoietic cells, 19 (18.1%) nonmalignant organ failure with solid organ transplantation, 16 (15.2%) solid tumors and 13 (12.4%) autoimmune disorders. Patients with ICCs were older, had more underlying renal conditions, and had lower white blood cell and platelet counts than those without ICCs, but had similar clinical disease severity upon admission. In-hospital mortality from COVID-19 was higher (11.4% vs. 4.6%, p = 0.005) and hospitalization was longer (p = 0.01) in patients with ICCs. New major morbidities upon discharge were not different between those with and without ICC (10.5% vs 13.9%, p = 0.40). In patients with ICC, bacterial co-infection was more common in those with life-threatening COVID-19. CONCLUSIONS: In this national case series of patients <21 years of age with acute COVID-19 admitted for intensive care, existence of a prior ICCs were associated with worse clinical outcomes. Reassuringly, most patients with ICCs hospitalized in the PICU for severe acute COVID-19 survived and were discharged home without new severe morbidities.

Multisystem Inflammatory Syndrome in Children - Initial Therapy and Outcomes.

BACKGROUND: The assessment of real-world effectiveness of immunomodulatory medications for multisystem inflammatory syndrome in children (MIS-C) may guide therapy. METHODS: We analyzed surveillance data on inpatients younger than 21 years of age who had MIS-C and were admitted to 1 of 58 U.S. hospitals between March 15 and October 31, 2020. The effectiveness of initial immunomodulatory therapy (day 0, indicating the first day any such therapy for MIS-C was given) with intravenous immune globulin (IVIG) plus glucocorticoids, as compared with IVIG alone, was evaluated with propensity-score matching and inverse probability weighting, with adjustment for baseline MIS-C severity and demographic characteristics. The primary outcome was cardiovascular dysfunction (a composite of left ventricular dysfunction or shock resulting in the use of vasopressors) on or after day 2. Secondary outcomes included the components of the primary outcome, the receipt of adjunctive treatment (glucocorticoids in patients not already receiving glucocorticoids on day 0, a biologic, or a second dose of IVIG) on or after day 1, and persistent or recurrent fever on or after day 2. RESULTS: A total of 518 patients with MIS-C (median age, 8.7 years) received at least one immunomodulatory therapy; 75% had been previously healthy, and 9 died. In the propensity-score-matched analysis, initial treatment with IVIG plus glucocorticoids (103 patients) was associated with a lower risk of cardiovascular dysfunction on or after day 2 than IVIG alone (103 patients) (17% vs. 31%; risk ratio, 0.56; 95% confidence interval [CI], 0.34 to 0.94). The risks of the components of the composite outcome were also lower among those who received IVIG plus glucocorticoids: left ventricular dysfunction occurred in 8% and 17% of the patients, respectively (risk ratio, 0.46; 95% CI, 0.19 to 1.15), and shock resulting in vasopressor use in 13% and 24% (risk ratio, 0.54; 95% CI, 0.29 to 1.00). The use of adjunctive therapy was lower among patients who received IVIG plus glucocorticoids than among those who received IVIG alone (34% vs. 70%; risk ratio, 0.49; 95% CI, 0.36 to 0.65), but the risk of fever was unaffected (31% and 40%, respectively; risk ratio, 0.78; 95% CI, 0.53 to 1.13). The inverse-probability-weighted analysis confirmed the results of the propensity-score-matched analysis. CONCLUSIONS: Among children and adolescents with MIS-C, initial treatment with IVIG plus glucocorticoids was associated with a lower risk of new or persistent cardiovascular dysfunction than IVIG alone. (Funded by the Centers for Disease Control and Prevention.).

Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene.

Only five children with pathogenic PMPCB gene variants have been described and all carried missense variants. Clinical features included a Leigh-like syndrome of developmental regression, basal ganglia lesions and ataxia with or without dystonia and epilepsy. Three of the five died in childhood and none was older than age six when described. We report the first splice site variant in the PMPCB gene in a 39-year old individual who experienced developmental regression and ataxia following otitis media in childhood. A minigene assay confirms this variant results in aberrant splicing and skipping of exon 12.

Protein architecture of the human kinetochore microtubule attachment site.

Chromosome segregation requires assembly of kinetochores on centromeric chromatin to mediate interactions with spindle microtubules and control cell-cycle progression. To elucidate the protein architecture of human kinetochores, we developed a two-color fluorescence light microscopy method that measures average label separation, Delta, at <5 nm accuracy. Delta analysis of 16 proteins representing core structural complexes spanning the centromeric chromatin-microtubule interface, when correlated with mechanical states of spindle-attached kinetochores, provided a nanometer-scale map of protein position and mechanical properties of protein linkages. Treatment with taxol, which suppresses microtubule dynamics and activates the spindle checkpoint, revealed a specific switch in kinetochore architecture. Cumulatively, Delta analysis revealed that compliant linkages are restricted to the proximity of chromatin, suggested a model for how the KMN (KNL1/Mis12 complex/Ndc80 complex) network provides microtubule attachment and generates pulling forces from depolymerization, and identified an intrakinetochore molecular switch that may function in controlling checkpoint activity.

Author Correction: Environment and host as large-scale controls of ectomycorrhizal fungi.

Change history: In the HTML version of this Article, author 'Filipa Cox' had no affiliation in the author list, although she was correctly associated with affiliation 3 in the PDF. In addition, the blue circles for 'oak' were missing from Extended Data Fig. 1. These errors have been corrected online.

Environment and host as large-scale controls of ectomycorrhizal fungi.

Explaining the large-scale diversity of soil organisms that drive biogeochemical processes-and their responses to environmental change-is critical. However, identifying consistent drivers of belowground diversity and abundance for some soil organisms at large spatial scales remains problematic. Here we investigate a major guild, the ectomycorrhizal fungi, across European forests at a spatial scale and resolution that is-to our knowledge-unprecedented, to explore key biotic and abiotic predictors of ectomycorrhizal diversity and to identify dominant responses and thresholds for change across complex environmental gradients. We show the effect of 38 host, environment, climate and geographical variables on ectomycorrhizal diversity, and define thresholds of community change for key variables. We quantify host specificity and reveal plasticity in functional traits involved in soil foraging across gradients. We conclude that environmental and host factors explain most of the variation in ectomycorrhizal diversity, that the environmental thresholds used as major ecosystem assessment tools need adjustment and that the importance of belowground specificity and plasticity has previously been underappreciated.

Wide Institutional Variability in the Treatment of Pediatric Critical Asthma: A Multicenter Retrospective Study.

OBJECTIVES: Children with status asthmaticus refractory to first-line therapies of systemic corticosteroids and inhaled beta-agonists often receive additional treatments. Because there are no national guidelines on the use of asthma therapies in the PICU, we sought to evaluate institutional variability in the use of adjunctive asthma treatments and associations with length of stay (LOS) and PICU use. DESIGN: Multicenter retrospective cohort study. SETTING: Administrative data from the Pediatric Health Information Systems (PHIS) database. PATIENTS: All inpatients 2-18 years old were admitted to a PHIS hospital between 2013 and 2021 with a diagnostic code for asthma. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: This study included 213,506 inpatient encounters for asthma, of which 29,026 patient encounters included care in a PICU from 39 institutions. Among these PICU encounters, large variability was seen across institutions in both the number of adjunctive asthma therapies used per encounter (min: 0.6, median: 1.7, max: 2.5, p < 0.01) and types of adjunctive asthma therapies (aminophylline, ipratropium, magnesium, epinephrine, and terbutaline) used. The center-level median hospital LOS ranged from 1 (interquartile range [IQR]: 1, 3) to 4 (3, 6) days. Among all the 213,506 inpatient encounters for asthma, the range of asthma admissions that resulted in PICU admission varied between centers from 5.2% to 47.3%. The average number of adjunctive therapies used per institution was not significantly associated with hospital LOS ( p = 0.81) nor the percentage of encounters with PICU admission ( p = 0.47). CONCLUSIONS: Use of adjunctive therapies for status asthmaticus varies widely among large children's hospitals and was not associated with hospital LOS or the percentage of encounters with PICU admission. Wide variance presents an opportunity for standardizing care with evidence-based guidelines to optimize outcomes and decrease adverse treatment effects and hospital costs.

Suicide and Self-Harm in Adolescents During the COVID-19 Pandemic: A U.S. Virtual Pediatric Systems, LLC, Database Study of PICU Admissions, 2016-2021.

OBJECTIVES: To characterize the epidemiology of suicide and self-harm among adolescents admitted to PICUs during the first 2 years of the COVID-19 pandemic in the United States. DESIGN: Descriptive analysis of a large, multicenter, quality-controlled database (Virtual Pediatric Systems [VPS]), and of a national public health dataset (U.S. Centers for Disease Control and Prevention web-based Wide-ranging ONline Data for Epidemiology Research [CDC WONDER]). SETTING: The 69 PICUs participating in the VPS database that contributed data for the entire the study period, January 1, 2016, to December 31, 2021. PATIENTS: Adolescents older than 12 years to younger than 18 years old admitted to a participating PICU during the study period with a diagnosis involving self-harm or a suicide attempt (VPS sample), or adolescent suicide deaths over the same period (CDC WONDER sample). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 10,239 suicide deaths and 7,692 PICU admissions for self-harm, including 5,414 admissions in the pre-pandemic period (Q1-2016 to Q1-2020) and 2,278 in the pandemic period (Q2-2020 to Q4-2021). Compared with the pre-pandemic period, there was no increase in the median (interquartile range) number of suicide deaths per quarter (429 [399-453] vs. 416 [390-482]) or PICU admissions for self-harm per quarter (315 [289-353] vs. 310 [286-387]) during the pandemic period, respectively. There was an increase in the ratio of self-harm PICU admissions to all-cause PICU admissions per quarter during the pandemic (1.98 [1.43-2.12]) compared with the pre-pandemic period per quarter (1.59 [1.46-1.74]). We also observed a significant decrease in all-cause PICU admissions per quarter early in the pandemic compared with the pre-pandemic period (16,026 [13,721-16,297] vs. 19,607 [18,371-20,581]). CONCLUSIONS: The number of suicide deaths and PICU admissions per quarter for self-harm remained relatively constant during the pandemic, while the number of all-cause PICU admissions per quarter decreased compared with the pre-pandemic period. The resultant higher ratio of self-harm admissions to all-cause PICU admissions may have contributed to the perception that more adolescents required critical care for mental health-related conditions early in the pandemic.

DOTAP: Structure, hydration, and the counterion effect.

The cationic lipid 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) is one of the original synthetic cationic lipids used for the liposomal transfection of oligonucleotides in gene therapy. The key structural element of DOTAP is its quaternary ammonium headgroup that is responsible for interactions with both nucleic acids and target cell membranes. Because these interactions are fundamental to the design of a major class of transfection lipids, it is important to understand the structure of DOTAP and how it interacts with halide counterions. Here, we use x-ray and neutron diffraction techniques to examine the structure of DOTAP and how chloride (Cl-) and iodide (I-) counterions alter the hydration properties of the DOTAP headgroup. A problem of particular interest is the poor solubility of DOTAP/I- in water solutions. Our results show that the poor solubility results from very tight binding of the I- counterion to the headgroup and the consequent expulsion of water. The structural principles we report here are important for assessing the suitability of DOTAP and its quaternary ammonium derivatives for transfection.

Inhibition of human cytomegalovirus replication by interferon alpha can involve multiple anti-viral factors.

The shortcomings of current direct-acting anti-viral therapy against human cytomegalovirus (HCMV) has led to interest in host-directed therapy. Here we re-examine the use of interferon proteins to inhibit HCMV replication utilizing both high and low passage strains of HCMV. Pre-treatment of cells with interferon alpha (IFNα) was required for robust and prolonged inhibition of both low and high passage HCMV strains, with no obvious toxicity, and was associated with an increased anti-viral state in HCMV-infected cells. Pre-treatment of cells with IFNα led to poor expression of HCMV immediate-early proteins from both high and low passage strains, which was associated with the presence of the anti-viral factor SUMO-PML. Inhibition of HCMV replication in the presence of IFNα involving ZAP proteins was HCMV strain-dependent, wherein a high passage HCMV strain was obviously restricted by ZAP and a low passage strain was not. This suggested that strain-specific combinations of anti-viral factors were involved in inhibition of HCMV replication in the presence of IFNα. Overall, this work further supports the development of strategies involving IFNα that may be useful to inhibit HCMV replication and highlights the complexity of the anti-viral response to HCMV in the presence of IFNα.

Multisystem Inflammatory Syndrome in U.S. Children and Adolescents.

BACKGROUND: Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome. METHODS: We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms. RESULTS: We report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki's disease-like features were documented in 74 (40%). Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%). CONCLUSIONS: Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.).

Biallelic variants in OGDH encoding oxoglutarate dehydrogenase lead to a neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities.

PURPOSE: This study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities. METHODS: We performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells. RESULTS: In the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM_002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme α-ketoglutarate dehydrogenase. In silico homology modeling predicts that c.566C>T:p.(Pro189Leu) and c.890C>A:p.(Ser297Tyr) variants interfere with the structure and function of OGDH. Fibroblasts from individual 1 showed that the p.(Ser297Tyr) variant led to a higher degradation rate of the OGDH protein. OGDH protein with p.(Pro189Leu) or p.(Ser297Tyr) variants in HEK293 cells showed significantly lower levels than the wild-type protein. Furthermore, we showed that expression of Drosophila Ogdh (dOgdh) carrying variants homologous to p.(Pro189Leu) or p.(Ser297Tyr), failed to rescue developmental lethality caused by loss of dOgdh. SpliceAI, a variant splice predictor, predicted that the c.935G>A:p.(Arg312Lys)/p.(Phe264_Arg312del) variant impacts splicing, which was confirmed through a mini-gene assay in HEK293 cells. CONCLUSION: We established that biallelic variants in OGDH cause a neurodevelopmental disorder with metabolic and movement abnormalities.

Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals.

PURPOSE: Brain monoamine vesicular transport disease is an infantile-onset movement disorder that mimics cerebral palsy. In 2013, the homozygous SLC18A2 variant, p.Pro387Leu, was first reported as a cause of this rare disorder, and dopamine agonists were efficient for treating affected individuals from a single large family. To date, only 6 variants have been reported. In this study, we evaluated genotype-phenotype correlations in individuals with biallelic SLC18A2 variants. METHODS: A total of 42 affected individuals with homozygous SLC18A2 variant alleles were identified. We evaluated genotype-phenotype correlations and the missense variants in the affected individuals based on the structural modeling of rat VMAT2 encoded by Slc18a2, with cytoplasm- and lumen-facing conformations. A Caenorhabditis elegans model was created for functional studies. RESULTS: A total of 19 homozygous SLC18A2 variants, including 3 recurrent variants, were identified using exome sequencing. The affected individuals typically showed global developmental delay, hypotonia, dystonia, oculogyric crisis, and autonomic nervous system involvement (temperature dysregulation/sweating, hypersalivation, and gastrointestinal dysmotility). Among the 58 affected individuals described to date, 16 (28%) died before the age of 13 years. Of the 17 patients with p.Pro237His, 9 died, whereas all 14 patients with p.Pro387Leu survived. Although a dopamine agonist mildly improved the disease symptoms in 18 of 21 patients (86%), some affected individuals with p.Ile43Phe and p.Pro387Leu showed milder phenotypes and presented prolonged survival even without treatment. The C. elegans model showed behavioral abnormalities. CONCLUSION: These data expand the phenotypic and genotypic spectra of SLC18A2-related disorders.

Unhealthy Food and Beverage Consumption during Childhood and Risk of Cardiometabolic Disease: A Systematic Review of Prospective Cohort Studies.

BACKGROUND: Global consumption of unhealthy foods, including ultra-processed foods (UPFs) and sugar-sweetened beverages (SSBs), has increased substantially among pediatric populations. Suboptimal diet during early life can track into adulthood, alongside risk factors for cardiometabolic disease. OBJECTIVE: To inform the development of updated WHO guiding principles for complementary feeding of infants and young children, this systematic review sought to examine the association between unhealthy food consumption during childhood and cardiometabolic risk biomarkers. METHODS: PubMed (Medline), EMBASE, and Cochrane CENTRAL were systematically searched, with no language restriction, up to 10 March 2022. Inclusion criteria were randomized controlled trials (RCTs), non-RCTs, and longitudinal cohort studies; children aged ≤10.9 y at exposure; studies reporting greater consumption of unhealthy foods and beverages (defined using nutrient- and food-based approaches) than no or low consumption; studies assessing critical nonanthropometric cardiometabolic disease risk outcomes (blood lipid profile, glycemic control, or blood pressure). RESULTS: Of 30,021 identified citations, 11 articles from 8 longitudinal cohort studies were included. Six studies focused on exposure to unhealthy foods or UPF, and 4 focused on SSB only. Methodological heterogeneity was too high across studies to meta-analyze effect estimates. A narrative synthesis of quantitative data revealed that exposure to unhealthy foods and beverages, specifically NOVA-defined UPF, in children of preschool age may be associated with a worse blood lipid and blood pressure profile in later childhood (Grading of Recommendations Assessment, Development, and Evaluation [GRADE]: low and very low certainty, respectively). No associations were evident between SSB consumption and blood lipids, glycemic control, or blood pressure (GRADE: all low certainty). CONCLUSIONS: No definitive conclusion can be made because of quality of the data. More high-quality studies that purposefully assess the effects of unhealthy food and beverage exposure during childhood on cardiometabolic risk outcomes are needed. This protocol was registered at https://www.crd.york.ac.uk/PROSPERO/ as CRD42020218109.

The use of machine learning and artificial intelligence within pediatric critical care.

The field of pediatric critical care has been hampered in the era of precision medicine by our inability to accurately define and subclassify disease phenotypes. This has been caused by heterogeneity across age groups that further challenges the ability to perform randomized controlled trials in pediatrics. One approach to overcome these inherent challenges include the use of machine learning algorithms that can assist in generating more meaningful interpretations from clinical data. This review summarizes machine learning and artificial intelligence techniques that are currently in use for clinical data modeling with relevance to pediatric critical care. Focus has been placed on the differences between techniques and the role of each in the clinical arena. The various forms of clinical decision support that utilize machine learning are also described. We review the applications and limitations of machine learning techniques to empower clinicians to make informed decisions at the bedside. IMPACT: Critical care units generate large amounts of under-utilized data that can be processed through artificial intelligence. This review summarizes the machine learning and artificial intelligence techniques currently being used to process clinical data. The review highlights the applications and limitations of these techniques within a clinical context to aid providers in making more informed decisions at the bedside.

Noninvasive Respiratory Support for Pediatric Acute Respiratory Distress Syndrome: From the Second Pediatric Acute Lung Injury Consensus Conference.

OBJECTIVES: To develop evidence-based recommendations for the Second Pediatric Acute Lung Injury Consensus Conference (PALICC) regarding the effectiveness of noninvasive respiratory support for pediatric acute respiratory distress syndrome (PARDS). These include consideration of the timing and duration of noninvasive ventilation (NIV) and high-flow nasal cannula (HFNC), whether effectiveness varies by disease severity or by characteristics of treatment delivery, and best practices for the use of NIV. DATA SOURCES: MEDLINE (Ovid), Embase (Elsevier), and CINAHL Complete (EBSCOhost). STUDY SELECTION: Searches included all studies involving the use of NIV or HFNC in children with PARDS or hypoxemic respiratory failure. DATA EXTRACTION: Title/abstract review, full-text review, and data extraction using a standardized data extraction form. DATA SYNTHESIS: The Grading of Recommendations Assessment, Development, and Evaluation approach was used to identify and summarize evidence and develop recommendations. Out of 6,336 studies, we identified 187 for full-text review. Four clinical recommendations were generated, related to indications, timing and duration of NIV in patients with PARDS, predictors of NIV failure and need for intubation (signs and symptoms of worsening disease including pulse oximetry saturation/Fio2 ratio), and use of NIV in resource-limited settings. Six good practice statements were generated related to how and where to deliver NIV, the importance of trained experienced staff and monitoring, types of NIV interfaces, the use of sedation, and the potential complications of this therapy. One research statement was generated related to indications of HFNC in patients with PARDS. CONCLUSIONS: NIV is a widely used modality for the treatment of respiratory failure in children and may be beneficial in a subset of patients with PARDS. However, there needs to be close monitoring for worsening disease and NIV failure.

Executive Summary of the Second International Guidelines for the Diagnosis and Management of Pediatric Acute Respiratory Distress Syndrome (PALICC-2).

OBJECTIVES: We sought to update our 2015 work in the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) guidelines for the diagnosis and management of pediatric acute respiratory distress syndrome (PARDS), considering new evidence and topic areas that were not previously addressed. DESIGN: International consensus conference series involving 52 multidisciplinary international content experts in PARDS and four methodology experts from 15 countries, using consensus conference methodology, and implementation science. SETTING: Not applicable. PATIENTS: Patients with or at risk for PARDS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eleven subgroups conducted systematic or scoping reviews addressing 11 topic areas: 1) definition, incidence, and epidemiology; 2) pathobiology, severity, and risk stratification; 3) ventilatory support; 4) pulmonary-specific ancillary treatment; 5) nonpulmonary treatment; 6) monitoring; 7) noninvasive respiratory support; 8) extracorporeal support; 9) morbidity and long-term outcomes; 10) clinical informatics and data science; and 11) resource-limited settings. The search included MEDLINE, EMBASE, and CINAHL Complete (EBSCOhost) and was updated in March 2022. Grading of Recommendations, Assessment, Development, and Evaluation methodology was used to summarize evidence and develop the recommendations, which were discussed and voted on by all PALICC-2 experts. There were 146 recommendations and statements, including: 34 recommendations for clinical practice; 112 consensus-based statements with 18 on PARDS definition, 55 on good practice, seven on policy, and 32 on research. All recommendations and statements had agreement greater than 80%. CONCLUSIONS: PALICC-2 recommendations and consensus-based statements should facilitate the implementation and adherence to the best clinical practice in patients with PARDS. These results will also inform the development of future programs of research that are crucially needed to provide stronger evidence to guide the pediatric critical care teams managing these patients.

HIDEA syndrome is caused by biallelic, pathogenic, rare or founder P4HTM variants impacting the active site or the overall stability of the P4H-TM protein.

HIDEA syndrome is caused by biallelic pathogenic variants in P4HTM. The phenotype is characterized by muscular and central hypotonia, hypoventilation including obstructive and central sleep apneas, intellectual disability, dysautonomia, epilepsy, eye abnormalities, and an increased tendency to develop respiratory distress during pneumonia. Here, we report six new patients with HIDEA syndrome caused by five different biallelic P4HTM variants, including three novel variants. We describe two Finnish enriched pathogenic P4HTM variants and demonstrate that these variants are embedded within founder haplotypes. We review the clinical data from all previously published patients with HIDEA and characterize all reported P4HTM pathogenic variants associated with HIDEA in silico. All known pathogenic variants in P4HTM result in either premature stop codons, an intragenic deletion, or amino acid changes that impact the active site or the overall stability of P4H-TM protein. In all cases, normal P4H-TM enzyme function is expected to be lost or severely decreased. This report expands knowledge of the genotypic and phenotypic spectrum of the disease.

MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia.

The Mediator multiprotein complex functions as a regulator of RNA polymerase II-catalyzed gene transcription. In this study, exome sequencing detected biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome. Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia. Seizures and cataracts were noted in severely affected individuals. Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum. ANN NEUROL 2021;89:828-833.

The conduct and reporting of qualitative evidence syntheses in health and social care guidelines: a content analysis.

BACKGROUND: This paper is part of a broader investigation into the ways in which health and social care guideline producers are using qualitative evidence syntheses (QESs) alongside more established methods of guideline development such as systematic reviews and meta-analyses of quantitative data. This study is a content analysis of QESs produced over a 5-year period by a leading provider of guidelines for the National Health Service in the UK (the National Institute for Health and Care Excellence) to explore how closely they match a reporting framework for QES. METHODS: Guidelines published or updated between Jan 2015 and Dec 2019 were identified via searches of the National Institute for Health and Care excellence (NICE) website. These guidelines were searched to identify any QES conducted during the development of the guideline. Data relating to the compliance of these syntheses against a reporting framework for QES (ENTREQ) were extracted and compiled, and descriptive statistics used to provide an analysis of the of QES conduct, reporting and use by this major international guideline producer. RESULTS: QES contributed, in part, to 54 out of a total of 192 guidelines over the five-year period. Although methods for producing and reporting QES have changed substantially over the past decade, this study found that there has been little change in the number or quality of NICE QESs over time. The largest predictor of quality was the centre or team which undertook the synthesis. Analysis indicated that elements of review methods which were similar to those used in quantitative systematic reviews tended to be carried out well and mostly matched the criteria in the reporting framework, but review methods which were more specific to a QES tended to be carried out less well, with fewer examples of criteria in the reporting framework being achieved. CONCLUSION: The study suggests that use, conduct and reporting of optimal QES methods requires development, as over time the quality of reporting of QES both overall, and by specific centres, has not improved in spite of clearer reporting frameworks and important methodological developments. Further staff training in QES methods may be helpful for reviewers who are more familiar with conventional forms of systematic review if the highest standards of QES are to be achieved. There seems potential for greater use of evidence from qualitative research during guideline development.