The morbid genome of ciliopathies: an update.

PURPOSE: Ciliopathies are highly heterogeneous clinical disorders of the primary cilium. We aim to characterize a large cohort of ciliopathies phenotypically and molecularly. METHODS: Detailed phenotypic and genomic analysis of patients with ciliopathies, and functional characterization of novel candidate genes. RESULTS: In this study, we describe 125 families with ciliopathies and show that deleterious variants in previously reported genes, including cryptic splicing variants, account for 87% of cases. Additionally, we further support a number of previously reported candidate genes (BBIP1, MAPKBP1, PDE6D, and WDPCP), and propose nine novel candidate genes (CCDC67, CCDC96, CCDC172, CEP295, FAM166B, LRRC34, TMEM17, TTC6, and TTC23), three of which (LRRC34, TTC6, and TTC23) are supported by functional assays that we performed on available patient-derived fibroblasts. From a phenotypic perspective, we expand the phenomenon of allelism that characterizes ciliopathies by describing novel associations including WDR19-related Stargardt disease and SCLT1- and CEP164-related Bardet-Biedl syndrome. CONCLUSION: In this cohort of phenotypically and molecularly characterized ciliopathies, we draw important lessons that inform the clinical management and the diagnostics of this class of disorders as well as their basic biology.

Toxoplasma and Toxocara seropositivity in juvenile idiopathic arthritis and its relation to disease activity and type of therapies.

Juvenile idiopathic arthritis (JIA) is the most frequently encountered autoimmune rheumatic disease in children. To our knowledge, this is the first study aimed to estimate the frequency of Toxoplasma gondii (T. gondii) and Toxocara seropositivity in JIA and assess its relation to the disease activity, IL-10 levels, and type of the received therapies. This study was conducted on 43 JIA patients and 50 cases as a control group. All participants were evaluated by disease activity score (JADAS-27), and the presence of specific IgG and IgM antibodies against T. gondii and IgG against Toxocara species using an enzyme-linked immunosorbent assay. IL-10 serum levels were measured using an ELISA kit. The results show that JIA patients have significantly higher seropositivity for anti-T. gondii IgG compared to control subjects (p = 0.02) and a non-significant difference for Toxocara seropositivity (p = 0.41). All participants were negative for IgM anti-Toxoplasma gondii. Demographic parameters did not significantly affect these seroprevalence frequencies (p > 0.05). IL-10 was significantly higher among JIA patients compared to controls (p = 0.007) and seropositive anti-T. gondii JIA exhibited significantly higher IL-10 levels compared to seronegative ones (p = 0.03). Seropositive anti-T. gondii IgG JIA patients had a significantly higher disease activity score (JADAS-27) than seronegative anti-T. gondii IgG cases (p = 0.02). There was a significant positive correlation between anti-T. gondii IgG and JADAS-27 score (p = 0.009). A significant association was detected between T. gondii infection and DMARDs including the biological therapies (p < 0.05). Overall, this study supports a possible association between T. gondii infection and JIA, IL-10, disease activity score, and DMARDs therapies. It is possible that IL-10 plays a role in the development of JIA and contributes to persistent asymptomatic infection with T. gondii in JIA patients. As a result, a recommendation for screening tests for T. gondii infection among JIA patients is crucial before and during commencing DMARDs therapies and closely monitoring early signs of infection.

Randomised trial estimating length of endotracheal tube insertion using gestational age or nasal-tragus length in newborns: a study protocol.

INTRODUCTION: Endotracheal tube (ETT) insertion depth estimation is important for optimal placement of ETT tip and balanced ventilation of the lungs. Various methods are available to determine the ETT insertion depth. The Neonatal Resuscitation Programme recommends the gestational age and nasal-tragus length (NTL) methods for estimating ETT insertion depth during cardiopulmonary resuscitation. However, the prospective data comparing these two methods is lacking. METHODS AND ANALYSIS: This is an open-label multi-centre randomised controlled trial, where gestational age and NTL methods will be used to determine the initial ETT insertion depth in term and preterm infants that are less than 28 days old, requiring oral intubation in the delivery room or neonatal intensive care unit (NICU). SITES AND SAMPLE SIZE: The trial is aimed to recruit 454 infants over 3 years across tertiary level NICUs. OUTCOMES: The primary outcome includes an optimally positioned ETT, defined as an ETT tip between the upper border of the first thoracic vertebra and the lower border of the second thoracic vertebra. The outcome is assessed by a paediatric radiologist, who will be masked to the group assignment. Secondary outcomes are malpositioned ETT tips, pneumothorax, ETT repositioning, chronic lung disease, invasive ventilation days, and death. ANALYSIS: Data will be analysed using the intention-to-treat principle. The primary and categorical secondary outcomes will be compared using the χ2 test. Adjusted risk ratios of outcomes will be calculated along with 95% CIs through multivariable logistic regression analysis, including covariates deemed biologically to influence the outcomes. ETHICS AND DISSEMINATION: The study has been approved by the PNU Research Ethics Board (20-0148) and the respective ethical review boards of the participating centres. The results will be disseminated through conference meetings, social media platforms, and publications in scientific journals. TRIAL REGISTRATION NUMBER: NCT04393337.

Association of Low Umbilical Cord pH and Hypoglycemia in Healthy Term Newborns: Should it Be a Part of Postnatal Screening?

Hypoglycemia may lead to neurological impairment; therefore, high-risk newborns are screened postnatally. However, hypoglycemia monitoring protocols often do not include cord blood acidosis as a risk factor. The study aimed to find an association between asymptomatic cord blood acidosis and hypoglycemia. All healthy term infants born at McMaster Children Hospital, Hamilton, Canada, between October 2013 and September 2014, who had umbilical cord blood pH <7.0 or base excess <12 mmol/L were studied. Infants with evidence of hypoxic-ischemic encephalopathy, birth weights outside of 10th to 95th percentiles for gestation, mothers with preeclampsia, diabetes or taking a -blockers at the time of the birth were excluded. Hypoglycemia was defined as blood glucose <2.6 mmol/L in the first two hours of life. One hundred sixtysix infants met the cord blood gas criteria, but only 16 had hypoglycemia. Although infants with mild perinatal depression are at risk for hypoglycemia, a significant association could not be proved.

Minimum Duration of Antibiotic Treatment Based on Blood Culture in Rule Out Neonatal Sepsis.

BACKGROUND: Neonatologists usually wait 48 hours for blood culture results before deciding to discontinue antibiotics. The objective of the study was to analyze time to positive blood culture in rule out sepsis and estimate the minimum duration of antibiotics. METHODS: Retrospective analysis of blood culture at the Neonatal Intensive Care Unit, McMaster Children's Hospital (January 2004 to December 2013) using BacT/Alert® 3D microbial system was conducted. We calculated average time taken for blood culture samples to emit a positive signal and compared it between Gram-positive and Gram-negative organisms. Kaplan-Meier curves for time to detect positive culture were generated. A Cox proportional hazard regression model with the outcome variable "time to detect positive blood culture" and predictor variables "early-onset sepsis (EOS) versus late-onset sepsis (LOS)", "Gram-positive versus Gram-negative" and "definite versus possible pathogen versus contaminant" was generated. RESULTS: Of 7,480 blood cultures performed in 9,254 neonates, 885 samples grew microorganisms. 845 culture reports from 627 neonates were analyzed. Definite or opportunistic pathogens caused 815 (96%) infections (54 EOS and 791 LOS) and the rest were contaminants. Gram-negative organisms grew significantly faster than Gram-positive (P < 0.001). Cultures from EOS were positive significantly earlier than LOS (P = 0.032). Gram-negative status was an independent predictor of early detection of a positive culture (hazard ratio 3.5 [95% CI, 2.7-4.5] P < 0.001). CONCLUSION: The probability of positive blood culture beyond 24 hours for a Gram-negative organism is small. Empiric antimicrobial treatment can be reduced after 24 hours to target only Gram-positive organisms in LOS and can be stopped in EOS unless clinical or laboratory parameters strongly suggest sepsis.