A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases.

Newborn screening (NBS) dramatically improves outcomes in severe childhood disorders by treatment before symptom onset. In many genetic diseases, however, outcomes remain poor because NBS has lagged behind drug development. Rapid whole-genome sequencing (rWGS) is attractive for comprehensive NBS because it concomitantly examines almost all genetic diseases and is gaining acceptance for genetic disease diagnosis in ill newborns. We describe prototypic methods for scalable, parentally consented, feedback-informed NBS and diagnosis of genetic diseases by rWGS and virtual, acute management guidance (NBS-rWGS). Using established criteria and the Delphi method, we reviewed 457 genetic diseases for NBS-rWGS, retaining 388 (85%) with effective treatments. Simulated NBS-rWGS in 454,707 UK Biobank subjects with 29,865 pathogenic or likely pathogenic variants associated with 388 disorders had a true negative rate (specificity) of 99.7% following root cause analysis. In 2,208 critically ill children with suspected genetic disorders and 2,168 of their parents, simulated NBS-rWGS for 388 disorders identified 104 (87%) of 119 diagnoses previously made by rWGS and 15 findings not previously reported (NBS-rWGS negative predictive value 99.6%, true positive rate [sensitivity] 88.8%). Retrospective NBS-rWGS diagnosed 15 children with disorders that had been undetected by conventional NBS. In 43 of the 104 children, had NBS-rWGS-based interventions been started on day of life 5, the Delphi consensus was that symptoms could have been avoided completely in seven critically ill children, mostly in 21, and partially in 13. We invite groups worldwide to refine these NBS-rWGS conditions and join us to prospectively examine clinical utility and cost effectiveness.

Evaluation of autofluorescence and image of oral pathogens and the tooth.

PURPOSE: To test the applicability of autofluorescence (AF) spectrum and image in the detection and identification of oral pathogens. METHODS: Oral pathogens (Candida albicans, Porphyromonas gingivalis, Streptococcus mutans) and teeth were used. To induce AF, the 405 nm laser was used as a light source, and AF was obtained and observed using a spectrometer, fluorescence camera, and microscope, respectively. RESULTS: The tested oral pathogens had similar spectral distributions, but their peak intensities and peak ratios were different. Their peak positions and spectral patterns were different from those of the tested sound and carious teeth. These differences were also found from the other referenced oral mucosa. Fluorescence image could localize the existence of oral bacteria. Oral pathogens could be imaged by fluorescence, but identification of each pathogen by image was not probable. CLINICAL SIGNIFICANCE: Oral pathogens can be observed and identified from the lesion if autofluorescence spectrum and fluorescence images are combined.

Changes in Cortical Activation During Dual-Task Walking in Individuals With and Without Visual Vertigo.

BACKGROUND AND PURPOSE: Persons with vestibular disorders are known to have slower gait speed with greater imbalance and veering during dual-task walking than healthy individuals, but the cerebral mechanisms are unknown. The purpose of this study was to determine whether individuals with visual vertigo (VV) have different cerebral activation during dual-task walking compared with control subjects. METHODS: Fourteen individuals with VV and 14 healthy controls (CON) were included (mean 39 years old, 85% women). A cross-sectional experimental study consisting of 4 combinations of 2 surfaces (even and uneven) and 2 task conditions (single- and dual-task) was performed. Participants walked over an even (level flooring) or uneven (wood prisms underneath carpeting) surface, either quietly or while reciting every other letter of the alphabet. Changes in cerebral activation over the bilateral prefrontal cortices were recorded using functional near-infrared spectroscopy during 4 task conditions relative to quiet standing. Gait speed and cognitive performance were recorded. RESULTS: There were no between-group differences in cognitive performance. Both groups slowed when walking on an uneven surface or performing a dual-task; participants in the VV group walked more slowly than those in the CON group in all conditions. Participants with VV had decreased cerebral activation in the bilateral prefrontal regions in comparison to CON participants in all conditions. DISCUSSION AND CONCLUSIONS: Participants with VV had lower prefrontal cortex activation than CON participants during dual-task walking. Lower cortical activity in those with VV may be due to shifted attention away from the cognitive task to prioritize maintenance of dynamic balance.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A303).

Favorable outcomes of culture-based Helicobacter pylori eradication therapy in a region with high antimicrobial resistance.

BACKGROUND: The eradication rate of Helicobacter pylori has declined, mainly due to antimicrobial resistance. To overcome resistance-associated treatment failure, the efficacy of culture-based, susceptibility-guided therapy was demonstrated as the first-line eradication therapy for H pylori infection. AIMS: To evaluate the efficacy of culture-based therapy as the first-line eradication therapy in regions with high levels of antimicrobial resistance. METHODS: Helicobacter pylori-positive patients without previous eradication treatment history were recommended to undergo culture to determine the minimal inhibitory concentration (MIC). If they consented, 7-day clarithromycin-containing PPI triple; 7-day esomeprazole, moxifloxacin, and amoxicillin (MEA) therapy; or 7- or 14-day esomeprazole, bismuth, metronidazole, and tetracycline (quadruple) therapy were administered based on the agar dilution-determined MIC. Eradication, treatment compliance, and adverse events were examined. RESULTS: In total, 74 patients were enrolled, and 69 patients completed the protocols. The overall resistance rates to amoxicillin, clarithromycin, metronidazole, and moxifloxacin were 6.7%, 31.0%, 41.8%, and 39.2%, respectively. The patients were allocated to the PPI triple (n = 50), MEA (n = 8) or quadruple (n = 16) therapy. The eradication rate in the intention-to-treat analysis was 93.1% (69 of 74 patients). The eradication rates in the per-protocol analysis were 100.0% (69 of 69 patients). Epigastric pain, nausea, and vomiting were less common than those of other empirical therapies. CONCLUSIONS: Culture-based, susceptibility-guided therapy is effective first-line eradication therapy, especially in regions with high levels of antimicrobial resistance.

Ultimate eradication rate of Helicobacter pylori after first, second, or third-line therapy in Korea.

BACKGROUND AND AIMS: Resistance rates of Helicobacter pylori to clarithromycin, metronidazole, and quinolone are over 30% in South Korea. The aim of this prospective study was to evaluate the ultimate eradication rate of H. pylori after first, second, or third-line therapy in Korea. METHODS: A cohort of 2202 patients with H. pylori was treated with proton pump inhibitor (PPI)-based triple therapy for seven days. In case of treatment failure or recurrence, moxifloxacin-based triple therapy (MA) or bismuth-based quadruple therapy (QUAD) was randomly given. When the second-line treatment failed or H. pylori recurred, the unused MA or QUAD was used as a third-line treatment. RESULTS: Eighty-six patients had recurrence at least once during consecutive lines of treatments. Among 2116 patients (intention-to-treat [ITT]) without recurrence, 1644 (77.7%, per-protocol [PP]) completely followed our treatment flow. The ITT and PP rates of first-line treatment were 69.8% and 89.3%. After second line, they reached 78.4% (ITT) and 98.4% (PP). The "final" eradication rate up to third line treatment were 80.0% (1692/2116) and 99.8% (1641/1644), respectively. Resistance to clarithromycin showed significantly lower eradication rate (OR 0.358, P < 0.001) than those with susceptible strains in multivariate analysis. However in PP analysis, there was no significant difference in ultimate success rate regarding resistance pattern. CONCLUSION: Final success rate of PP was high, 99.8% in Korea in spite of high antibiotic resistance rates. However, high rate of refusal of further treatment and follow-up loss made ITT eradication rate low. Proper strategy to improve the treatment adherence is needed.

Safety and Effectiveness of SB2 (Infliximab Biosimilar) in Adult Patients with Immune-Mediated Inflammatory Diseases: A Post-Marketing Surveillance in Korea.

INTRODUCTION: SB2 is a biosimilar of infliximab (IFX), which is approved for rheumatoid arthritis (RA), ankylosing spondylitis (AS), adult and pediatric Crohn's disease (CD), adult and pediatric ulcerative colitis (UC), psoriatic arthritis (PsA), and plaque psoriasis (PsO). The drug approval process in Korea includes post-marketing surveillance (PMS) studies to re-examine the safety and effectiveness of approved new medications. METHODS: This was a prospective, multi-center, open-label, observational, phase 4 PMS study of IFX-naïve patients or patients switched from reference IFX or another IFX-biosimilar to SB2 in all approved indications. The primary endpoint was to evaluate the safety of SB2 reported as adverse events (AEs) and adverse drug reactions (ADRs). The secondary endpoint was to evaluate the effectiveness measured as investigators' overall effectiveness assessment, categorized as improved, stable, or worsened. Furthermore, disease-specific activity scores were collected for each indication [28-joint Modified Disease Activity Score (DAS28) for RA, Korean Bath Ankylosing Spondylitis Disease Activity Index (KBASDAI), Crohn's Disease Activity Index (CDAI), and Full Mayo Score for UC]. RESULTS: In the safety and effectiveness analysis, 180 and 128 patients were included, respectively. Most patients (83.9%) were IFX-naïve patients and 16.1% were switched patients. RA (48.9%) and AS (31.1%) were the most frequent indications. Overall, 23 (12.8%) patients reported AEs and 14 (7.8%) patients reported ADRs. Serious adverse events (SAEs) were reported by 3 (1.7%) patients. As per investigators' overall effectiveness assessments, SB2 was effective in 94.6% (105/111) of IFX-naïve patients and 82.4% (14/17) of switched patients. In IFX-naïve patients, disease activity scores decreased significantly from baseline to week 30 (week 24 for AS); mean (SD) changes of disease scores for each indication were DAS28 - 1.9 (0.79) for RA, KBASDAI - 3.8 (1.68) for AS, CDAI - 200.4 (112.47) for CD, and Full Mayo Score - 6.6 (2.92) for UC. The persistence rate of SB2 treatments was 88.3% with median treatment duration of 30.1 weeks. CONCLUSION: This PMS study of the IFX-biosimilar SB2 in Korea confirmed the safety and effectiveness of SB2 in major indications.

An automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases.

While many genetic diseases have effective treatments, they frequently progress rapidly to severe morbidity or mortality if those treatments are not implemented immediately. Since front-line physicians frequently lack familiarity with these diseases, timely molecular diagnosis may not improve outcomes. Herein we describe Genome-to-Treatment, an automated, virtual system for genetic disease diagnosis and acute management guidance. Diagnosis is achieved in 13.5 h by expedited whole genome sequencing, with superior analytic performance for structural and copy number variants. An expert panel adjudicated the indications, contraindications, efficacy, and evidence-of-efficacy of 9911 drug, device, dietary, and surgical interventions for 563 severe, childhood, genetic diseases. The 421 (75%) diseases and 1527 (15%) effective interventions retained are integrated with 13 genetic disease information resources and appended to diagnostic reports ( https://gtrx.radygenomiclab.com ). This system provided correct diagnoses in four retrospectively and two prospectively tested infants. The Genome-to-Treatment system facilitates optimal outcomes in children with rapidly progressive genetic diseases.