Whole blood transcriptomics identifies subclasses of pediatric septic shock.

BACKGROUND: Sepsis is a highly heterogeneous syndrome, which has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine approach aimed at identifying biologically homogenous subgroups of patients with septic shock and critical illnesses. Transcriptomic analysis can identify subclasses derived from differences in underlying pathophysiological processes that may provide the basis for new targeted therapies. The goal of this study was to elucidate pathophysiological pathways and identify pediatric septic shock subclasses based on whole blood RNA expression profiles. METHODS: The subjects were critically ill children with cardiopulmonary failure who were a part of a prospective randomized insulin titration trial to treat hyperglycemia. Genome-wide expression profiling was conducted using RNA sequencing from whole blood samples obtained from 46 children with septic shock and 52 mechanically ventilated noninfected controls without shock. Patients with septic shock were allocated to subclasses based on hierarchical clustering of gene expression profiles, and we then compared clinical characteristics, plasma inflammatory markers, cell compositions using GEDIT, and immune repertoires using Imrep between the two subclasses. RESULTS: Patients with septic shock depicted alterations in innate and adaptive immune pathways. Among patients with septic shock, we identified two subtypes based on gene expression patterns. Compared with Subclass 2, Subclass 1 was characterized by upregulation of innate immunity pathways and downregulation of adaptive immunity pathways. Subclass 1 had significantly worse clinical outcomes despite the two classes having similar illness severity on initial clinical presentation. Subclass 1 had elevated levels of plasma inflammatory cytokines and endothelial injury biomarkers and demonstrated decreased percentages of CD4 T cells and B cells and less diverse T cell receptor repertoires. CONCLUSIONS: Two subclasses of pediatric septic shock patients were discovered through genome-wide expression profiling based on whole blood RNA sequencing with major biological and clinical differences. Trial Registration This is a secondary analysis of data generated as part of the observational CAF-PINT ancillary of the HALF-PINT study (NCT01565941). Registered March 29, 2012.

Whole Blood Transcriptomics Identifies Subclasses of Pediatric Septic Shock.

Background: Sepsis is a highly heterogeneous syndrome, that has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine approach aimed at identifying biologically homogenous subgroups of patients with septic shock and critical illnesses. Transcriptomic analysis can identify subclasses derived from differences in underlying pathophysiological processes that may provide the basis for new targeted therapies. The goal of this study was to elucidate pathophysiological pathways and identify pediatric septic shock subclasses based on whole blood RNA expression profiles. Methods: The subjects were critically ill children with cardiopulmonary failure who were a part of a prospective randomized insulin titration trial to treat hyperglycemia. Genome-wide expression profiling was conducted using RNA-sequencing from whole blood samples obtained from 46 children with septic shock and 52 mechanically ventilated noninfected controls without shock. Patients with septic shock were allocated to subclasses based on hierarchical clustering of gene expression profiles, and we then compared clinical characteristics, plasma inflammatory markers, cell compositions using GEDIT, and immune repertoires using Imrep between the two subclasses. Results: Patients with septic shock depicted alterations in innate and adaptive immune pathways. Among patients with septic shock, we identified two subtypes based on gene expression patterns. Compared with Subclass 2, Subclass 1 was characterized by upregulation of innate immunity pathways and downregulation of adaptive immunity pathways. Subclass 1 had significantly worse clinical outcomes despite the two classes having similar illness severity on initial clinical presentation. Subclass 1 had elevated levels of plasma inflammatory cytokines and endothelial injury biomarkers and demonstrated decreased percentages of CD4 T cells and B cells, and less diverse T-Cell receptor repertoires. Conclusions: Two subclasses of pediatric septic shock patients were discovered through genome-wide expression profiling based on whole blood RNA sequencing with major biological and clinical differences. Trial Registration: This is a secondary analysis of data generated as part of the observational CAF PINT ancillary of the HALF PINT study (NCT01565941). Registered 29 March 2012.

Remission in pediatric Graves' disease treated with antithyroid drug and the risk factors associated with relapse.

PURPOSE: To evaluate the characteristics and frequency of remission in pediatric patients with Graves' disease (GD) treated with antithyroid drug (ATD) and to identify factors that may be associated with relapse. METHODS: Medical records of patients younger than 19 years who presented to the Department of Pediatrics of Queen Elizabeth Hospital Hong Kong with newly diagnosed GD from 1st January 2007 to 31st December 2017 were retrospectively reviewed. Remission was defined as euthyroidism for 12 months or more after discontinuation of ATD treatment and no relapses during the follow-up period. Patients who successfully achieved remission were compared to those who suffered relapse. Factors that may predict occurrence of relapse after ATD treatments were studied, and their odds ratios (ORs) were calculated. RESULTS: A total of 101 patients was included in this study. Eighty-one patients completed one course of ATD. Eighteen patients (17.8%) successfully achieved remission, and 58 patients (57.4%) experienced relapse after discontinuation of ATD. The remission group received a significantly longer course of ATD therapy than the relapse group (median, 28 months; interquartile range [IQR], 18-48 months in remission group vs. median, 21 months; IQR, 17-26; p=0.024). The OR for relapse was 0.971 (95% confidence interval [CI], 0.946-0.997) in univariate analysis and remained significant after adjustments in the multivariate regression model (OR, 0.961; 95% CI, 0.933-0.989; p=0.008). CONCLUSION: The remission rate in pediatric patients with GD treated with ATD was low. A longer ATD course was associated with a greater chance of remission in this population.

Features of partial remission in children with type 1 diabetes using the insulin dose-adjusted A1c definition and risk factors associated with nonremission.

PURPOSE: We sought to evaluate features of partial remission (PR) in children with type 1 diabetes mellitus (T1DM) using the insulin-dose adjusted A1c (IDAA1c) definition and to identify risk factors associated with nonremission. METHODS: Medical records of patients with newly diagnosed T1DM between January 1, 2008, and June 30, 2018, were retrospectively reviewed. Hemoglobin A1c (HbA1c) readings and insulin total daily doses (TDDs) of each patient at each follow-up visit were obtained with IDAA1c values calculated. PR was defined as an IDAA1c score of 9 points or less within 6 months of diagnosis. The trends of HbA1c and TDD within 2 years after diagnosis were compared between remitters and nonremitters. Factors that may predict the occurrence of PR were studied, with their relative risks of nonremission calculated. RESULTS: PR occurred in 26 patients (45.6%), including 8 girls and 18 boys, with a median duration of 8 months. The frequency of remission in male patients was significantly higher (P=0.002) and the relative risk of female sex with nonremission was 2.20 (95% confidence interval [CI], 1.24-3.91), which remained significant when adjusted by multivariate regression modeling. The initial HbA1c level at diagnosis was also significantly higher in the nonremission group (P=0.029), with a relative risk of 1.12 (95% CI, 1.01-1.25). Both HbA1c (P=0.012) and TDD (P=0.006) were significantly lower within 2 years after diagnosis among remitters than in nonremitters. TDD was significantly lower in male patients (P=0.029) during the same period, while there was no significant difference in HbA1c level between male and female patients (P=0.163). CONCLUSION: Both the initial HbA1c level at diagnosis and sex were factors associated with the occurrence of PR. Female sex was an independent risk factor of nonremission, likely resulting from a higher insulin requirement in female T1DM patients.

Rapid PCR-free meat species mitochondrial DNA identification using Electric Field Induced Release and Measurement (EFIRM®).

This work details the usage of EFIRM® (Electric Field Induced Release and Measurement) for PCR-free rapid electrochemical detection of mitochondrial DNA. EFIRM® was able to perform highly sensitive detection of animal species for meat contamination testing without multistep sample lysis, DNA extraction, or PCR amplification steps, demonstrating the capability to detect the presence of foreign meat species that only constituted 0.1% of the total mass of a food sample (achieving sensitivity equivalent to that of PCR). The EFIRM® strategy utilizes surface immobilized nucleic acid probes that complement to mitochondrial sequence of Ovis Aries, Sus Scrofa, and Bos Taurus and are immobilized in a polypyrrole matrix on a 96-electrode array. Quantification was performed through amperometric measurement of oxidation-reduction reactions on a streptavidin-peroxidase enzyme chain that completes the nucleic acid complex. All electrochemical procedures were performed using a high-throughput potentiostat system that allows parallelized electrochemical measurement and interfacing to the 96-electrode array.

Choice of spirometric reference values for compensation assessment.

BACKGROUND AND OBJECTIVE: Two sets of local reference values are available for spirometry in Hong Kong, but it is uncertain how well they work in the assessment of occupational lung diseases. This study examined their relative performance in the compensational assessment of silicosis. METHODS: Local reference values published in 1982 and 2006 were compared in two different populations comprising normal construction/quarry workers and silicosis patients. Only men aged 20-74 years were included. RESULTS: The FVC results of 93 normal workers were significantly higher than those predicted by either the 1982 or the 2006 reference values. Compared with the 1982 reference values, the mean FEV(1)% or FVC% was age-dependent and 5.2% higher in the normal workers. Smoking decreased the forced expiratory ratio, but did not show a major effect on FEV(1) or FVC among asymptomatic subjects. Despite their derivation largely from never-smokers, the 2006 reference values better predicted FEV(1) and FVC among all smoking categories. Among the 357 silicosis patients, the 1982 reference values also gave 8.8% higher FEV(1)% and 7.4% higher FVC%. These spirometric values differed by more than 10% in patients aged 60 years or more. Despite the presence of disease, the mean FVC% was still significantly above 100%. CONCLUSIONS: Both the 1982 and 2006 local reference values underestimated the FVC of normal construction and quarry workers, reflecting possible occupational selection factors. The 2006 reference values outperformed the 1982 ones, especially among older subjects. Careful calibration with similar occupational groups in the same laboratory is highly desirable in the choice of spirometric reference values for compensation assessment. Smoking does not appear to affect this choice.

Risk of active tuberculosis among schoolchildren in Hong Kong.

OBJECTIVE: To estimate the risk of active tuberculosis (TB) and its implication on preventive treatment among BCG-vaccinated schoolchildren. DESIGN: Cohort and case-control designs. SETTING: Community settings in a high-prevalence area. PARTICIPANTS: Children in primary school. The main exposure was their tuberculin response. MAIN OUTCOME MEASURES: Of 94,928 primary schoolchildren tuberculin tested during a routine school revaccination program in 1999, 656 with a tuberculin response at 20 mm or more were followed up prospectively through the territory-wide TB registry up to December 31, 2003, for the development of TB. In a separate case-control analysis, the tuberculin responses of children who subsequently had active TB (at the age of 10-15 years) were compared with those of their sex- and age-matched classmates to ascertain the relative risks of TB for different tuberculin reaction categories. The absolute and relative risks were applied to the 1999 cohort for estimating the incidence of TB among different tuberculin reactors. RESULTS: The annual incidence (95% confidence interval) of active TB was estimated to be 13.4 (5.6-40.6) per 100,000 for the entire cohort and 7.5 (2.4-24.5), 7.5 (1.7-32.0), 16.0 (4.4-57.2), 92.6 (26.6-320.2), and 340.6 (163.3-626.4) per 100,000 for children with a tuberculin reaction at 0 to 4, 5 to 9, 10 to 14, 15 to 19, and 20 mm or more, respectively. By using 10 mm as the cutoff, 482 (95% confidence interval, 163-1391) children have to be treated to prevent a single case of active TB within 5 years. Treatment will cover 17.5% of the cohort, but prevent only 54.1% of all active TB cases. CONCLUSION: It is desirable to reexamine the existing screening method for BCG-vaccinated children from high-prevalence countries.

Initial experience on rifampin and pyrazinamide vs isoniazid in the treatment of latent tuberculosis infection among patients with silicosis in Hong Kong.

OBJECTIVE: To compare the adverse effects and treatment adherence between 2 months of rifampin plus pyrazinamide (2RZ) and 6 months of isoniazid (6H). BACKGROUND: Patients with silicosis in Hong Kong are at high risk of acquiring tuberculosis. A previous study showed that treatment with 6H reduced the risk of silico-tuberculosis by one half. METHOD: Patients with silicosis and a Mantoux skin test reaction > or =10 mm were randomized to receive either 2RZ or 6H daily. Liver function testing was done monthly during the initial 2 months. The adverse effects and treatment adherence were compared between the two regimens. RESULTS: Forty patients (mean age, 61.6 +/- 9.1 years) and 36 patients (mean age, 57.6 +/- 9.7 years) were randomized to the 2RZ and 6H arms, respectively (p > 0.05) [+/- SD]. Baseline characteristics were comparable. Nineteen patients in the 2RZ arm had peak alanine transaminase (ALT) levels > 1.5 times the upper limit of normal (ULN) in comparison with only five study subjects of the 6H arm (47.5% vs 13.9%, p < 0.01). Fourteen patients (35%) in the 2RZ arm and 1 patient (2.8%) in the 6H arm had peak ALT levels more than five times the ULN (p < 0.001). Only seven patients had symptoms suggestive of hepatitis; none of the patients had jaundice. All recovered after withholding treatment. In the 2RZ study arm, none of the baseline characteristics predicted hepatotoxicity. Other adverse effects were generally mild and comparable between both study arms. Treatment was stopped prematurely in 45% and 36.1% of patients in the 2RZ and 6H arms, respectively (p = 0.43). The main reasons were hepatotoxicity for the 2RZ arm and voluntary withdrawal after experiencing other minor adverse effects for the 6H arm. CONCLUSION: A higher incidence of hepatotoxicity was associated with rifampin plus pyrazinamide than isoniazid in the treatment of latent tuberculosis infection among patients with silicosis in Hong Kong.