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Inhaled anesthetics account for a significant portion of the greenhouse gases generated by perioperative services within the healthcare systems. This cross-sectional study aimed to identify knowledge gaps and practice patterns related to carbon dioxide (CO2) absorbents and intraoperative delivery of fresh gas flows (FGF) for future sustainability endeavors. Secondary aims focused on differences in these knowledge gaps based on the level of training. Surveys were distributed at five large academic medical centers. In addition to site-specific CO2 absorbent use and practice volume and experience, respondents at each institution were queried about individual practice with FGF rates during anesthetic maintenance as well as the cost-effectiveness and environmental impact of different volatile anesthetics. Results were stratified and analyzed by the level of training. In total, 368 (44% physicians, 30% residents, and 26% nurse anesthetists) respondents completed surveys. Seventy-six percent of respondents were unaware or unsure about which type of CO2 absorbent was in use at their hospital. Fifty-nine percent and 48% of respondents used sevoflurane and desflurane with FGF ≥1 L/min, respectively. Most participants identified desflurane as the agent with the greatest environmental impact (89.9%) and a greater proportion of anesthesiologists correctly identified isoflurane as a cost-effective anesthetic (78.3%, p=0.02). Knowledge gaps about in-use CO2 absorbent and optimal FGF usage were identified within the anesthesia care team. Educational initiatives to increase awareness about the carbon emissions from anesthesia and newer CO2 absorbents will impact the environmental and economic cost per case and align anesthesia providers toward healthcare decarbonization.

BackgroundChildren in rural communities often lack access to subspecialty medical care. Telemedicine has the potential to improve access to these services but its effectiveness has not been rigorously evaluated for paediatric patients with endocrine conditions besides diabetes.IntroductionThe purpose of this study was to assess the association between telemedicine and visit attendance among patients who received care from paediatric endocrinologists at an academic medical centre in northern California between 2009-2017.MethodsWe abstracted demographic data, encounter information and medical diagnoses from the electronic health record for patients ≤18 years of age who attended at least one in-person or telemedicine encounter with a paediatric endocrinologist during the study period. We used a mixed effects logistic regression model - adjusted for age, diagnosis and distance from subspecialty care - to explore the association between telemedicine and visit attendance.ResultsA total of 40,941 encounters from 5083 unique patients were included in the analysis. Patients who scheduled telemedicine visits were predominantly publicly insured (97%) and lived a mean distance of 161 miles from the children's hospital. Telemedicine was associated with a significantly higher odds of visit attendance (odds ratio 2.55, 95% confidence interval 2.15-3.02, p

ImportancePediatric referral centers are increasingly using telemedicine to provide consultations to help care for acutely ill children presenting to rural and community emergency departments (EDs). These pediatric telemedicine consultations may help improve physician decision-making and may reduce the frequency of overtriage and interfacility transfers.ObjectiveTo examine the use of pediatric critical care telemedicine vs telephone consultations associated with risk-adjusted transfer rates of acutely ill children from community and rural EDs.Design, setting, and participantsA cluster-randomized crossover trial was conducted between November 18, 2015, and March 26, 2018. Analyses were conducted from January 19, 2018, to July 23, 2022, 2022. Participants included acutely ill children aged 14 years and younger presenting to a participating ED in 15 rural and community EDs in northern California.InterventionsParticipating EDs were randomized to use telemedicine or telephone for consultations with pediatric critical care physicians according to 1 of 4 unbalanced (3 telemedicine:1 telephone) crossover treatment assignment sequences.Main outcomes and measuresIntention-to-treat, treatment-received, and per-protocol analyses were performed to determine the risk of transfer using mixed effects Poisson regression analyses with random intercepts for presenting EDs to account for hospital-level clustering.ResultsA total of 696 children (392 boys [56.3%]; mean [SD] age, 4.2 [4.6] years) were enrolled. Of the 537 children (77.2%) assigned to telemedicine, 251 (46.7%) received the intervention. In the intention-to-treat analysis, patients assigned to the telemedicine arm were less likely to be transferred compared with patients assigned to the telephone arm after adjusting for patient age, severity of illness, and hospital study period (risk rate [RR], 0.93; 95% CI, 0.88-0.99). The adjusted risk of transfer was significantly lower in the telemedicine arm compared with the telephone arm in both the treatment-received analysis (RR, 0.81; 95% CI, 0.71-0.94) and the per-protocol analysis (RR, 0.79; 95% CI, 0.68-0.92).Conclusions and relevanceIn this randomized trial, the use of telemedicine to conduct consultations for acutely ill children in rural and community EDs resulted in less frequent overall interfacility transfers than consultations done by telephone.Trial registrationClinicalTrials.gov Identifier: NCT02877810.

Objectives: Prior research has demonstrated that men and women emergency medicine (EM) residents receive similar numerical evaluations at the beginning of residency, but that women receive significantly lower scores than men in their final year. To better understand the emergence of this gender gap in evaluations we examined discrepancies between numerical scores and the sentiment of attached textual comments.Methods: This multicenter, longitudinal, retrospective cohort study took place at four geographically diverse academic EM training programs across the United States from July 1, 2013–July 1, 2015 using a real-time, mobile-based, direct-observation evaluation tool. We used complementary quantitative and qualitative methods to analyze 11,845 combined numerical and textual evaluations made by 151 attending physicians (94 men and 57 women) during real-time, direct observations of 202 residents (135 men and 67 women).Results: Numerical scores were more strongly positively correlated with positive sentiment of the textual comment for men (r = 0.38, P < 0.001) compared to women (r = −0.26, P < 0.04); more strongly negatively correlated with mixed (r = −0.39, P < 0.001) and negative (r = −0.46, P < 0.001) sentiment for men compared to women (r = −0.13, P < 0.28) for mixed sentiment (r = −0.22, P < 0.08) for negative; and women were around 11% more likely to receive positive comments alongside lower scores, and negative or mixed comments alongside higher scores. Additionally, on average, men received slightly more positive comments in postgraduate year (PGY)-3 than in PGY-1 and fewer mixed and negative comments, while women received fewer positive and negative comments in PGY-3 than PGY-1 and almost the same number of mixed comments.Conclusion: Women EM residents received more inconsistent evaluations than men EM residents at two levels: 1) inconsistency between numerical scores and sentiment of textual comments; and 2) inconsistency in the expected career trajectory of improvement over time. These findings reveal gender inequality in how attendings evaluate residents and suggest that attendings should be trained to provide all residents with feedback that is clear, consistent, and helpful, regardless of resident gender.

BackgroundInhaled anesthetics in the operating room are potent greenhouse gases and are a key contributor to carbon emissions from health care facilities. Real-time clinical decision support (CDS) systems lower anesthetic gas waste by prompting anesthesia professionals to reduce fresh gas flow (FGF) when a set threshold is exceeded. However, previous CDS systems have relied on proprietary or highly customized anesthesia information management systems, significantly reducing other institutions' accessibility to the technology and thus limiting overall environmental benefit.ObjectiveIn 2018, a CDS system that lowers anesthetic gas waste using methods that can be easily adopted by other institutions was developed at the University of California San Francisco (UCSF). This study aims to facilitate wider uptake of our CDS system and further reduce gas waste by describing the implementation of the FGF CDS toolkit at UCSF and the subsequent implementation at other medical campuses within the University of California Health network.MethodsWe developed a noninterruptive active CDS system to alert anesthesia professionals when FGF rates exceeded 0.7 L per minute for common volatile anesthetics. The implementation process at UCSF was documented and assembled into an informational toolkit to aid in the integration of the CDS system at other health care institutions. Before implementation, presentation-based education initiatives were used to disseminate information regarding the safety of low FGF use and its relationship to environmental sustainability. Our FGF CDS toolkit consisted of 4 main components for implementation: sustainability-focused education of anesthesia professionals, hardware integration of the CDS technology, software build of the CDS system, and data reporting of measured outcomes.ResultsThe FGF CDS system was successfully deployed at 5 University of California Health network campuses. Four of the institutions are independent from the institution that created the CDS system. The CDS system was deployed at each facility using the FGF CDS toolkit, which describes the main components of the technology and implementation. Each campus made modifications to the CDS tool to best suit their institution, emphasizing the versatility and adoptability of the technology and implementation framework.ConclusionsIt has previously been shown that the FGF CDS system reduces anesthetic gas waste, leading to environmental and fiscal benefits. Here, we demonstrate that the CDS system can be transferred to other medical facilities using our toolkit for implementation, making the technology and associated benefits globally accessible to advance mitigation of health care-related emissions.

The endocannabinoid system is a highly conserved and ubiquitous signalling pathway with broad-ranging effects. Despite critical pathway functions, gene variants have not previously been conclusively linked to human disease. We identified nine children from eight families with heterozygous, de novo truncating variants in the last exon of DAGLA with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. All children displayed paroxysms of nystagmus or eye deviation accompanied by compensatory head posture and worsened incoordination most frequently after waking. RNA sequencing showed clear expression of the truncated transcript and no differences were found between mutant and wild-type DAGLA activity. Immunofluorescence staining of patient-derived fibroblasts and HEK cells expressing the mutant protein showed distinct perinuclear aggregation not detected in control samples. This report establishes truncating variants in the last DAGLA exon as the cause of a unique paediatric syndrome. Because enzymatic activity was preserved, the observed mislocalization of the truncated protein may account for the observed phenotype. Potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect. To our knowledge, this is the first report directly linking an endocannabinoid system component with human genetic disease and sets the stage for potential future therapeutic avenues.

PurposeDiphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs).MethodsMolecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate-ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants.ResultsDPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2.ConclusionWe provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.

The Genome Empowerment Scale (GEmS), developed as a research tool, assesses perspectives of parents of children with undiagnosed disorders about to undergo exome or genome sequencing related to the process of empowerment. We defined genomic healthcare empowerment as follows: perceived ability to understand and seek new information related to the genomic sequencing, manage emotions related to the diagnostic process and outcomes, and utilize genomic sequencing information to the betterment of the individual/child and family. The GEmS consists of four scales, two are primarily emotion-focused (Meaning of a Diagnosis, and Emotional Management of the Process) and two are action-oriented (Seeking Information and Support, and Implications and Planning). The purpose of this research was to provide a strategy for interpreting results from the GEmS and present illustrative cases. These illustrations should serve to facilitate use of the GEmS in the clinical and research arena, particularly with respect to guiding genetic counseling processes for parents of children with undiagnosed conditions.

PurposePediatric readiness scores may be a useful measure of a hospital's preparedness to care for children. However, there is limited evidence linking these scores with patient outcomes or other metrics, including the need for interfacility transfer. This study aims to determine the association of pediatric readiness scores with the odds of interfacility transfer among a cohort of noninjured children (< 18 years old) presenting to emergency departments (EDs) in small rural hospitals in the state of California.MethodsData from the National Pediatric Readiness Project assessment were linked with the California Office of Statewide Health Planning and Development's ED and inpatient databases to conduct a cross-sectional study of pediatric interfacility transfers. Hospitals were manually matched between these data sets. Logistic regression was performed with random intercepts for hospital and adjustment for patient-level confounders.FindingsA total of 54 hospitals and 135,388 encounters met the inclusion criteria. EDs with a high pediatric readiness score (>70) had lower adjusted odds of transfer (aOR: 0.55, 95% CI: 0.33-0.93) than EDs with a low pediatric readiness score (≤ 70). The pediatric readiness section with strongest association with transfer was the "policies, procedures, and protocols" section; EDs in the highest quartile had lower odds of transfer than EDs in the lowest quartile (aOR: 0.54, 95% CI: 0.31-0.91).ConclusionsPediatric patients presenting to EDs at small rural hospitals with high pediatric readiness scores may be less likely to be transferred. Additional studies are recommended to investigate other pediatric outcomes in relation to hospital ED pediatric readiness.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition in children. Although ADHD is treatable, barriers remain to engagement in treatment, especially among socioeconomically disadvantaged and racial and ethnic minority families. Our goal was to examine the process by which families engage in ADHD treatment and to identify targets for an intervention to improve engagement in care. METHODS: We conducted in-depth semistructured qualitative interviews with 41 parents of diverse youth aged 3 to 17 years old in treatment of ADHD at an urban safety net hospital. Parents were asked about their journey through diagnosis and treatment, community attitudes about ADHD, and other factors influencing treatment access and decision-making. Transcripts were analyzed by using thematic analysis. RESULTS: Of children with ADHD, 69.2% were male, 57.7% were Black or African American, and 38.5% were of Hispanic, Latino, or Spanish origin. Parents were 92.7% female, were 75.6% English speaking, and had a median income of $20 000. Parents described 6 stages to the process of engaging in care for their childs ADHD, which unfolded like a developmental process: (1) normalization and hesitation, (2) fear and stigmatization, (3) action and advocacy, (4) communication and navigation, (5) care and validation, and (6) preparation and transition. Barriers often occurred at points of stage mismatch between parents and providers and/or systems. Difficulty resolving an earlier stage interfered with the progression through subsequent stages. CONCLUSIONS: The 6 stages framework could be used to develop new strategies to measure engagement and to design family-centered interventions to facilitate engagement in ADHD treatment.

ObjectiveTo determine the association between potentially avoidable transfers (PATs) and emergency department (ED) pediatric readiness scores and the score's associated components.Study designThis cross-sectional study linked the 2012 National Pediatric Readiness Project assessment with individual encounter data from California's statewide ED and inpatient databases during the years 2011-2013. A probabilistic linkage, followed by deterministic heuristics, linked pretransfer, and post-transfer encounters. Applying previously published definitions, a transferred child was considered a PAT if they were discharged within 1 day from the ED or inpatient care and had no specialized procedures. Analyses were stratified by injured and noninjured children. We compared PATs with necessary transfers using mixed-effects logistic regression models with random intercepts for hospital and adjustment for patient and hospital covariates.ResultsAfter linkage, there were 6765 injured children (27% PATs) and 18 836 noninjured children (14% PATs) who presented to 283 hospitals. In unadjusted analyses, a 10-point increase in pediatric readiness was associated with lower odds of PATs in both injured (OR 0.93, 95% CI 0.90-0.96) and noninjured children (OR 0.90, 95% CI 0.88-0.93). In adjusted analyses, a similar association was detected in injured patients (aOR 0.92, 95% CI 0.86-0.98) and was not detected in noninjured patients (aOR 0.94, 95% CI 0.88-1.00). Components associated with decreased PATs included having a nurse pediatric emergency care coordinator and a quality improvement plan.ConclusionsHospital ED pediatric readiness is associated with lower odds of a PAT. Certain pediatric readiness components are modifiable risk factors that EDs could target to reduce PATs.

Globally 149 million children under five are estimated to be stunted (length more than 2 standard deviations below international growth standards). Stunting, a form of linear growth faltering, increases risk of illness, impaired cognitive development, and mortality. Global stunting estimates rely on cross-sectional surveys, which cannot provide direct information about the timing of onset or persistence of growth faltering- a key consideration for defining critical windows to deliver preventive interventions. We performed the largest pooled analysis of longitudinal studies in low- and middle-income countries to date (n=32 cohorts, 52,640 children, ages 0-24 months), allowing us to identify the typical age of linear growth faltering onset and to investigate recurrent faltering in early life. The highest incidence of stunting onset occurred from birth to age 3 months. From 0 to 15 months, less than 5% of children per month reversed their stunting status, and among those who did, stunting relapse was common. Early timing and low reversal rates emphasize the importance of preventive intervention delivery within the prenatal and early postnatal phases coupled with continued delivery of postnatal interventions through the first 1000 days of life.

ObjectiveDifferences in the quality of emergency department (ED) care are often attributed to nonclinical factors such as variations in the structure, systems, and processes of care. Few studies have examined these associations among children. We aimed to determine whether process measures of quality of care delivered to patients receiving care in children's hospital EDs were associated with physician-level or hospital-level factors.MethodsWe included children (

Globally 149 million children under five are estimated to be stunted (length more than 2 standard deviations below international growth standards). Stunting, a form of linear growth faltering, increases risk of illness, impaired cognitive development, and mortality. Global stunting estimates rely on cross-sectional surveys, which cannot provide direct information about the timing of onset or persistence of growth faltering- a key consideration for defining critical windows to deliver preventive interventions. We performed the largest pooled analysis of longitudinal studies in low- and middle-income countries to date (n=32 cohorts, 52,640 children, ages 0-24 months), allowing us to identify the typical age of linear growth faltering onset and to investigate recurrent faltering in early life. The highest incidence of stunting onset occurred from birth to age 3 months. From 0 to 15 months, less than 5% of children per month reversed their stunting status, and among those who did, stunting relapse was common. Early timing and low reversal rates emphasize the importance of preventive intervention delivery within the prenatal and early postnatal phases coupled with continued delivery of postnatal interventions through the first 1000 days of life.

Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs∗4]; c.2564_2567dupTGTT [p.Leu856Phefs∗5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects).

ObjectiveTo compare nurse preparedness and quality of patient handoff during interfacility transfers from a pretransfer emergency department to a PICU when conducted over telemedicine versus telephone.DesignCross-sectional nurse survey linked with patient electronic medical record data using multivariable, multilevel analysis.SettingTertiary PICU within an academic children's hospital.ParticipantsPICU nurses who received a patient handoff between October 2017 and July 2018.InterventionsNone.Main results and measurementsAmong 239 eligible transfers, 106 surveys were completed by 55 nurses (44% survey response rate). Telemedicine was used for 30 handoffs (28%), and telephone was used for 76 handoffs (72%). Patients were comparable with respect to age, sex, race, primary spoken language, and insurance, but handoffs conducted over telemedicine involved patients with higher illness severity as measured by the Pediatric Risk of Mortality III score (4.4 vs 1.9; p = 0.05). After adjusting for Pediatric Risk of Mortality III score, survey recall time, and residual clustering by nurse, receiving nurses reported higher preparedness (measured on a five-point adjectival scale) following telemedicine handoffs compared with telephone handoffs (3.4 vs 3.1; p = 0.02). There were no statistically significant differences in both bivariable and multivariable analyses of handoff quality as measured by the Handoff Clinical Evaluation Exercise. Handoffs using telemedicine were associated with increased number of Illness severity, Patient summary, Action list, Situation awareness and contingency planning, Synthesis by receiver components (3.3 vs 2.8; p = 0.04), but this difference was not significant in the adjusted analysis (3.1 vs 2.9; p = 0.55).ConclusionsTelemedicine is feasible for nurse-to-nurse handoffs of critically ill patients between pretransfer and receiving facilities and may be associated with increased perceived and objective nurse preparedness upon patient arrival. Additional research is needed to demonstrate that telemedicine during nurse handoffs improves communication, decreases preventable adverse events, and impacts family and provider satisfaction.

Encoding the slow skeletal muscle isoform of myosin binding protein-C, MYBPC1 is associated with autosomal dominant and recessive forms of arthrogryposis. The authors describe a novel association for MYBPC1 in four patients from three independent families with skeletal muscle weakness, myogenic tremors, and hypotonia with gradual clinical improvement. The patients carried one of two de novo heterozygous variants in MYBPC1, with the p.Leu263Arg variant seen in three individuals and the p.Leu259Pro variant in one individual. Both variants are absent from controls, well conserved across vertebrate species, predicted to be damaging, and located in the M-motif. Protein modeling studies suggested that the p.Leu263Arg variant affects the stability of the M-motif, whereas the p.Leu259Pro variant alters its structure. In vitro biochemical and kinetic studies demonstrated that the p.Leu263Arg variant results in decreased binding of the M-motif to myosin, which likely impairs the formation of actomyosin cross-bridges during muscle contraction. Collectively, our data substantiate that damaging variants in MYBPC1 are associated with a new form of an early-onset myopathy with tremor, which is a defining and consistent characteristic in all affected individuals, with no contractures. Recognition of this expanded myopathic phenotype can enable identification of individuals with MYBPC1 variants without arthrogryposis.

BackgroundTo determine whether telemedicine improves access to outpatient neurology care for underserved patients, we compared appointment completion between urban, in-person clinics and telemedicine clinics held in rural and underserved communities where neurology consultations are provided remotely.MethodsIn this retrospective study, we identified patients scheduled for outpatient care from UCDH pediatric neurologists between January 1, 2009, and July 31, 2017, in person and by telemedicine. Demographic and clinical variables were abstracted from electronic medical records. We evaluated the association between consultation modality and visit completion in overall and matched samples using hierarchical multivariable logistic regression.ResultsWe analyzed 13,311 in-person appointments by 3,831 patients and 1,158 telemedicine appointments by 381 patients. The average travel time to the site of care was 45.8 ± 52.1 minutes for the in-person cohort and 22.3 ± 22.7 minutes for the telemedicine cohort. Telemedicine sites were located at an average travel time of 217.1 ± 114.8 minutes from UCDH. Telemedicine patients were more likely to have nonprivate insurance, lower education, and lower household income. They had different diagnoses and fewer complex chronic conditions. Telemedicine visits were more likely to be completed than either "cancelled" or missed ("no show") compared with in-person visits (OR 1.57, 95% CI: 1.34-1.83; OR 1.66, 95% CI: 1.31-2.10 matched on travel time to the site of care; OR 2.22, 95% CI: 1.66-2.98 matched on travel time to UCDH).ConclusionsThe use of telemedicine for outpatient pediatric neurology visits has high odds of completion and can serve as an equal adjunct to in-person clinic visits.

BackgroundFamily screening of a 48-year-old male with recently diagnosed IgG4-related disease (IgG4-RD) revealed unanticipated elevations in plasma IgG4 in his two healthy teenaged sons.MethodsWe performed gene sequencing, immune cell studies, HLA typing, and analyses of circulating cytotoxic CD4+ T lymphocytes and plasmablasts to seek clues to pathogenesis. DNA from a separate cohort of 99 patients with known IgG4-RD was also sequenced for the presence of genetic variants in a specific gene, FGFBP2.ResultsThe three share a previously unreported heterozygous single base deletion in fibroblast growth factor binding protein type 2 (FGFBP2), which causes a frameshift in the coding sequence. The FGFBP2 protein is secreted by cytotoxic T-lymphocytes and binds fibroblast growth factor. The variant sequence in the FGFBP2 protein is predicted to form a disordered random coil rather than a helical-turn-helix structure, unable to adopt a stable conformation. The proband and the two sons had 5-10-fold higher numbers of circulating cytotoxic CD4 + T cells and plasmablasts compared to matched controls. The three members also share a homozygous missense common variant in FGFBP2 found in heterozygous form in ~40% of the population. This common variant was found in 73% of an independent, well characterized IgG4-RD cohort, showing enrichment in idiopathic IgG4-RD.ConclusionsThe presence of a shared deleterious variant and homozygous common variant in FGFBP2 in the proband and sons strongly implicates this cytotoxic T cell product in the pathophysiology of IgG4-RD. The high prevalence of a common FGFBP2 variant in sporadic IgG4-RD supports the likelihood of participation in disease.

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl-/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl-/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.

Migraines are consistently among the top 20 primary coded diagnoses in emergency departments, constituting 4.5% of all chief complaints. In a significant subset of these, pain arises from the occipital region innervated by the greater (GON) and lesser occipital nerve. In this case series, we present three patients with occipital migraines who received GON blockade with 1% lidocaine. The blockade was performed only after first-line treatment with metoclopramide and possibly additional medications as ordered by triage physician, failed to adequately alleviate pain by 40 minutes after medication administration. Patients were contacted a minimum of seven days following treatment. All three patients experienced significant analgesia and relief of symptoms within 15 minutes of blockade and sustained relief through a seven-day follow-up period.

Interferon regulatory factor 2 binding protein-like (IRF2BPL) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals who carry damaging heterozygous variants in IRF2BPL and are affected with neurological symptoms. Five individuals who carry IRF2BPL nonsense variants resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The IRF2BPL bioinformatics signature based on population genomics is consistent with a gene that is intolerant to variation. We show that the fruit-fly IRF2BPL ortholog, called pits (protein interacting with Ttk69 and Sin3A), is broadly detected, including in the nervous system. Complete loss of pits is lethal early in development, whereas partial knockdown with RNA interference in neurons leads to neurodegeneration, revealing a requirement for this gene in proper neuronal function and maintenance. The identified IRF2BPL nonsense variants behave as severe loss-of-function alleles in this model organism, and ectopic expression of the missense variants leads to a range of phenotypes. Taken together, our results show that IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.

ObjectiveQuality of care delivered to adult patients in the emergency department (ED) is often associated with demographic and clinical factors such as a patient's race/ethnicity and insurance status. We sought to determine whether the quality of care delivered to children in the ED was associated with a variety of patient-level factors.MethodsThis was a retrospective, observational cohort study. Pediatric patients (

Low-grade gliomas can vary widely in disease course and therefore patient outcome. While current characterization relies on both histological and molecular analysis of tissue resected during surgery, there remains high variability within glioma subtypes in terms of response to treatment and outcome. In this study we hypothesized that parameters obtained from magnetic resonance data would be associated with progression-free survival for patients with recurrent low-grade glioma. The values considered were derived from the analysis of anatomic imaging, diffusion weighted imaging, and 1H magnetic resonance spectroscopic imaging data. Metrics obtained from diffusion and spectroscopic imaging presented strong prognostic capability within the entire population as well as when restricted to astrocytomas, but demonstrated more limited efficacy in the oligodendrogliomas. The results indicate that multi-parametric imaging data may be applied as a non-invasive means of assessing prognosis and may contribute to developing personalized treatment plans for patients with recurrent low-grade glioma.

BackgroundOptimal adjuvant management of adult low-grade gliomas is controversial. Recently described tumor classification based on molecular subtype has the potential to individualize adjuvant therapy but has not yet been evaluated as part of a prospective trial.MethodsPatients aged 18 or older with newly diagnosed World Health Organization grade II low-grade gliomas and gross residual disease after surgical resection were enrolled in the study. Patients received monthly cycles of temozolomide for up to 1 year or until disease progression. For patients with available tissue, molecular subtype was assessed based upon 1p/19q codeletion and isocitrate dehydrogenase-1 R132H mutation status. The primary outcome was radiographic response rate; secondary outcomes included progression-free survival (PFS) and overall survival (OS).ResultsOne hundred twenty patients were enrolled with median follow-up of 7.5 years. Overall response rate was 6%, with median PFS and OS of 4.2 and 9.7 years, respectively. Molecular subtype was associated with rate of disease progression during treatment (P

Study objectiveAmong children requiring hospital admission or transfer, we seek to determine whether insurance is associated with the decision to either admit locally or transfer to another hospital.MethodsThis cross-sectional study used Healthcare Cost and Utilization Project 2012 Nationwide Emergency Department Sample. Pediatric patients receiving care in emergency departments (EDs) who were either admitted or transferred were included. Clinical Classifications Software was used to categorize patients into noninjury diagnostic cohorts. Multivariable logistic regression models adjusting for potential confounders, including severity of illness and comorbidities, and incorporating nationally representative weights were used to determine the association between insurance and the odds of transfer relative to admission.ResultsA total of 240,620 noninjury pediatric ED events met inclusion criteria. Patient and hospital characteristics, including older age and nonteaching hospitals, were associated with greater odds of transfer relative to admission. Patients who were uninsured or had self-pay had higher odds of transfer (odds ratio [OR] 3.84; 95% confidence interval [CI] 2.08 to 7.09) relative to admission compared with those with private insurance. Uninsured and self-pay patients also had higher odds of transfer across all 13 diagnostic categories, with ORs ranging from 2.96 to 12.00. Patients with Medicaid (OR 1.05; 95% CI 0.90 to 1.22) and other insurances (OR 1.14; 95% CI 0.87 to 1.48) had similar odds of transfer compared with patients with private insurance.ConclusionChildren without insurance and those considered as having self-pay are more likely to be transferred to another hospital than to be admitted for inpatient care within the same receiving hospital compared with children with private insurance. This study reinforces ongoing concerns about disparities in the provision of pediatric ED and inpatient care.

Study objectiveAmong children requiring hospital admission or transfer, we seek to determine whether insurance is associated with the decision to either admit locally or transfer to another hospital.MethodsThis cross-sectional study used Healthcare Cost and Utilization Project 2012 Nationwide Emergency Department Sample. Pediatric patients receiving care in emergency departments (EDs) who were either admitted or transferred were included. Clinical Classifications Software was used to categorize patients into noninjury diagnostic cohorts. Multivariable logistic regression models adjusting for potential confounders, including severity of illness and comorbidities, and incorporating nationally representative weights were used to determine the association between insurance and the odds of transfer relative to admission.ResultsA total of 240,620 noninjury pediatric ED events met inclusion criteria. Patient and hospital characteristics, including older age and nonteaching hospitals, were associated with greater odds of transfer relative to admission. Patients who were uninsured or had self-pay had higher odds of transfer (odds ratio [OR] 3.84; 95% confidence interval [CI] 2.08 to 7.09) relative to admission compared with those with private insurance. Uninsured and self-pay patients also had higher odds of transfer across all 13 diagnostic categories, with ORs ranging from 2.96 to 12.00. Patients with Medicaid (OR 1.05; 95% CI 0.90 to 1.22) and other insurances (OR 1.14; 95% CI 0.87 to 1.48) had similar odds of transfer compared with patients with private insurance.ConclusionChildren without insurance and those considered as having self-pay are more likely to be transferred to another hospital than to be admitted for inpatient care within the same receiving hospital compared with children with private insurance. This study reinforces ongoing concerns about disparities in the provision of pediatric ED and inpatient care.

ObjectivesTo compare the severity of illness and outcomes among children admitted to a children's hospital PICU from referring emergency departments with and without access to a pediatric critical care telemedicine program.DesignRetrospective cohort study.SettingTertiary academic children's hospital PICU.PatientsPediatric patients admitted directly to the PICU from referring emergency departments between 2010 and 2014.InterventionsNone.MeasurementsDemographic factors, severity of illness, and clinical outcomes among children receiving care in emergency departments with and without access to pediatric telemedicine, as well as a subcohort of children admitted from emergency departments before and after the implementation of telemedicine.Main resultsFive hundred eighty-two patients from 15 emergency departments with telemedicine and 524 patients from 60 emergency departments without telemedicine were transferred and admitted to the PICU. Children admitted from emergency departments using telemedicine were younger (5.6 vs 6.9 yr; p< 0.001) and less sick (Pediatric Risk of Mortality III score, 3.2 vs 4.0; p < 0.05) at admission to the PICU compared with children admitted from emergency departments without telemedicine. Among transfers from emergency departments that established telemedicine programs during the study period, children arrived significantly less sick (mean Pediatric Risk of Mortality III scores, 1.2 units lower; p = 0.03) after the implementation of telemedicine (n = 43) than before the implementation of telemedicine (n = 95). The observed-to-expected mortality ratios of posttelemedicine, pretelemedicine, and no-telemedicine cohorts were 0.81 (95% CI, 0.53-1.09), 1.07 (95% CI, 0.53-1.60), and 1.02 (95% CI, 0.71-1.33), respectively.ConclusionsThe implementation of a telemedicine program designed to assist in the care of seriously ill children receiving care in referring emergency departments was associated with lower illness severity at admission to the PICU. This study contributes to the body of evidence that pediatric critical care telemedicine programs assist referring emergency departments in the care of critically ill children and could result in improved clinical outcomes.

ObjectivesTo compare the severity of illness and outcomes among children admitted to a children's hospital PICU from referring emergency departments with and without access to a pediatric critical care telemedicine program.DesignRetrospective cohort study.SettingTertiary academic children's hospital PICU.PatientsPediatric patients admitted directly to the PICU from referring emergency departments between 2010 and 2014.InterventionsNone.MeasurementsDemographic factors, severity of illness, and clinical outcomes among children receiving care in emergency departments with and without access to pediatric telemedicine, as well as a subcohort of children admitted from emergency departments before and after the implementation of telemedicine.Main resultsFive hundred eighty-two patients from 15 emergency departments with telemedicine and 524 patients from 60 emergency departments without telemedicine were transferred and admitted to the PICU. Children admitted from emergency departments using telemedicine were younger (5.6 vs 6.9 yr; p< 0.001) and less sick (Pediatric Risk of Mortality III score, 3.2 vs 4.0; p < 0.05) at admission to the PICU compared with children admitted from emergency departments without telemedicine. Among transfers from emergency departments that established telemedicine programs during the study period, children arrived significantly less sick (mean Pediatric Risk of Mortality III scores, 1.2 units lower; p = 0.03) after the implementation of telemedicine (n = 43) than before the implementation of telemedicine (n = 95). The observed-to-expected mortality ratios of posttelemedicine, pretelemedicine, and no-telemedicine cohorts were 0.81 (95% CI, 0.53-1.09), 1.07 (95% CI, 0.53-1.60), and 1.02 (95% CI, 0.71-1.33), respectively.ConclusionsThe implementation of a telemedicine program designed to assist in the care of seriously ill children receiving care in referring emergency departments was associated with lower illness severity at admission to the PICU. This study contributes to the body of evidence that pediatric critical care telemedicine programs assist referring emergency departments in the care of critically ill children and could result in improved clinical outcomes.

About 200 cases of blue rubber bleb nevus syndrome (BRBNS) have been reported in the literature. The disorder affects both sexes equally and the occurrence is mostly sporadic except for a few reports of cases with autosomal dominant inheritance pattern. Herein we report an 11-year-old girl with progressive BRBNS and onset at 5 years of age.

Harlequin syndrome (HS) is a rare disorder of the sympathetic nervous system which presents with unilateral decreased sweating and flushing of the face, neck, and chest in response to heat, exercise, or emotional factors. The contralateral side displays a compensatory overreaction to provide normal heat regulation of the face as a whole. In the literature, most of the cases are primary in nature and no underlying cause could be identified. Harlequin sign is used to denote these symptoms in patients who also exhibit associated oculosympathetic paresis, such as Horner syndrome, Adie syndrome, and Ross syndrome.We report a rare case of a 13-year-old boy who presented with complaints of flushing and sweating of the left side of the face after exertion, while the right side remained dry and maintained its normal color. No structural abnormality was identified on detailed work up. Thus, diagnosis of classic idiopathic HS was made. Despite the rarity of this syndrome, dermatologists should be acquainted with this distinctive entity and should refer the patient for complete ophthalmological and neurological examination.

BackgroundAlcoholic steatohepatitis (ASH) is caused in part by the effects of ethanol (EtOH) on hepatic methionine metabolism.MethodsTo investigate the phenotypic and epigenetic consequences of altered methionine metabolism in this disease, we studied the effects of 4-week intragastric EtOH feeding with and without the methyl donor betaine in cystathionine beta synthase (CβS) heterozygous C57BL/6J mice.ResultsThe histopathology of early ASH was induced by EtOH feeding and prevented by betaine supplementation, while EtOH feeding reduced and betaine supplementation maintained the hepatic methylation ratio of the universal methyl donor S-adenosylmethionine (SAM) to the methyltransferase inhibitor S-adenosylhomocysteine (SAH). MethylC-seq genomic sequencing of heterozygous liver samples from each diet group found 2 to 4% reduced methylation in gene bodies, but not promoter regions of all autosomes of EtOH-fed mice, each of which were normalized in samples from mice fed the betaine-supplemented diet. The transcript levels of nitric oxide synthase (Nos2) and DNA methyltransferase 1 (Dnmt1) were increased, while those of peroxisome proliferator receptor-α (Pparα) were reduced in EtOH-fed mice, and each was normalized in mice fed the betaine-supplemented diet. DNA pyrosequencing of CβS heterozygous samples found reduced methylation in a gene body of Nos2 by EtOH feeding that was restored by betaine supplementation and was correlated inversely with its expression and positively with SAM/SAH ratios.ConclusionsThe present study has demonstrated relationships among EtOH induction of ASH with aberrant methionine metabolism that was associated with gene body DNA hypomethylation in all autosomes and was prevented by betaine supplementation. The data imply that EtOH-induced changes in selected gene transcript levels and hypomethylation in gene bodies during the induction of ASH are a result of altered methionine metabolism that can be reversed through dietary supplementation of methyl donors.

Griscelli Syndrome (GS) is a rare autosomal recessive disorder characterized by pigmentary dilution of the hair and skin (partial albinism). Three different types (1-3) caused by mutation in three different genes have been described. Patients with GS type 1 have primary central nervous system dysfunction; type 2 patients commonly develop hemophagocytic lymphohistiocytosis and type 3 patients present with partial albinism only. Two siblings discussed here had silvery hair, eyebrows and eyelashes since birth with no features suggestive of immunodeficiency or neurological impairment, making it an even rarer presentation of Griscelli Syndrome, type 3. Diagnosis was confirmed on light microscopy (LM) of hair shafts. Both GS1 and GS2 have been described earlier. However, extensive search of the literature failed to reveal a similar presentation from Indian origin. This is the first ever report of GS-3 in non-identical siblings from India.