The Application of Knowledge-Based Clinical Decision Support Systems to Detect Antibiotic Allergy.

Prevention of drug allergies is important for patient safety. The objective of this study was to evaluate the outcomes of antibiotic allergy-checking clinical decision support system (CDSS), K-CDSTM. A retrospective chart review study was performed in 29 hospitals and antibiotic allergy alerts data were collected from May to August 2022. A total of 15,535 allergy alert cases from 1586 patients were reviewed. The most frequently prescribed antibiotics were cephalosporins (48.5%), and there were more alerts of potential cross-reactivity between beta-lactam antibiotics than between antibiotics with the same ingredients or of the same class. Regarding allergy symptoms, dermatological disorders were the most common (38.8%), followed by gastrointestinal disorders (28.4%). The 714 cases (4.5%) of immune system disorders included 222 cases of anaphylaxis and 61 cases of severe cutaneous adverse reactions. Alerts for severe symptoms were reported in 6.4% of all cases. This study confirmed that K-CDS can effectively detect antibiotic allergies and prevent the prescription of potentially allergy-causing antibiotics among patients with a history of antibiotic allergies. If K-CDS is expanded to medical institutions nationwide in the future, it can prevent an increase in allergy recurrence related to drug prescriptions through cloud-based allergy detection CDSSs.

Efficacy and Safety of Topical Corticosteroid Treatment under Occlusion for Severe Alopecia Areata in Children. A single-center retrospective analysis.

BACKGROUND: Alopecia areata (AA) has a poor clinical course in children. There are no reliable therapeutic options for children with severe AA, including alopecia totalis (AT) and alopecia universalis (AU). AIM: We evaluated the efficacy and adverse effects of a potent topical corticosteroid (TCS) under occlusion in pediatric patients with severe AA. METHODS: We reviewed records of 23 patients under the age of 10 years with AT or AU treated with a potent TCS (0.05% clobetasol propionate or 0.3% diflucortolone valerate) for 8 hours under occlusion with a plastic film. We used the Severity of Alopecia Tool (SALT) to measure clinical improvement. The primary endpoint was a Severity of Alopecia Tool (SALT) score of 20 or less at six months. We analyzed the change in cortisol levels to identify the long-term safety of TCS therapy on the hypothalamus-pituitary-adrenal axis. RESULTS: Nineteen patients reached SALT 20 or less at the 6-month treatment. Six patients relapsed over the 6-month follow-up period. Four patients were suspected of adrenal insufficiency. However, the cortisol level of the patients recovered to normal at least 1-month after lowering TCS potency or changing to non-steroidal treatments. LIMITATIONS: Retrospective design and small sample size. CONCLUSION: This study shows that a potent TCS occlusion may be a safe treatment option in pediatric patients with severe AA. Further long-term studies are required to evaluate the safety and recurrence of TCS occlusion therapy for pediatric AA.

Exploring the Genetic Causes for Postnatal Growth Failure in Children Born Non-Small for Gestational Age.

The most common causes of short stature (SS) in children are familial short stature (FSS) and idiopathic short stature (ISS). Recently, growth plate dysfunction has been recognized as the genetic cause of FSS or ISS. The aim of this study was to investigate monogenic growth failure in patients with ISS and FSS. Targeted exome sequencing was performed in patients categorized as ISS or FSS and the subsequent response to growth hormone (GH) therapy was analyzed. We found 17 genetic causes involving 12 genes (NPR2, IHH, BBS1, COL1A1, COL2A1, TRPS1, MASP1, SPRED1, PTPTN11, ADNP, NADSYN1, and CERT1) and 2 copy number variants. A genetic cause was found in 45.5% and 35.7% of patients with FSS and ISS, respectively. The genetic yield in patients with syndromic and non-syndromic SS was 90% and 23.1%, respectively. In the 11 genetically confirmed patients, a gain in height from -2.6 to -1.3 standard deviations after 2 years of GH treatment was found. The overall diagnostic yield in this study was 41.7%. We identified several genetic causes involving paracrine signaling, the extracellular matrix, and basic intracellular processes. Identification of the causative gene may provide prognostic evidence for the use of GH therapy in non-SGA children.

The Impact of International Conservation Agreements on Protected Areas: Empirical Findings from the Convention on Biological Diversity Using Causal Inference.

Although 30 years have passed since the Convention on Biological Diversity (CBD) was adopted in 1992, few attempts have been made to evaluate its impact on protected areas. This study investigates the relationship between participation in the CBD and conservation effort in member countries, using an original dataset of 169 countries from 1992 to 2015. Our measure of conservation effort is the percentage of a country's terrestrial area under protection, which is the primary mechanism for achieving the CBD's conservation as distinct from its sustainable use or access and benefit-sharing objectives. We consider how protected area expansion relates to membership of the CBD, and a set of socio-economic and political variables that measure both the opportunity cost of conservation and national responsiveness to the demand for public goods. We find a positive and significant relationship between the area under protection, membership of the CBD, and a dummy for the Aichi biodiversity targets-Nagoya protocol. We also find that the area under protection is negatively related to measures of economic development and education (proxies for the opportunity cost of conservation), and positively associated with forest area (a proxy for species richness and endemism). We conclude that, at least for this measure of conservation effort, the CBD has had a significant impact, albeit moderated in predictable ways by the opportunity cost of conservation.

Prevalence of asthma in preterm and associated risk factors based on prescription data from the Korean National Health Insurance database.

We retrospectively analyzed National Health Insurance claims data (January 2002-December 2018) to determine the asthma prevalence and risk factors among preterm infants born in Korea. Patients with asthma were defined as those with a history of asthma medication prescriptions at least twice per year with International Classification of Diseases, Tenth Edition codes J45 and J46. We enrolled 99,139 preterm infants. The prevalence of asthma among preterm and term infants was 32.7% and 26.9%, 21.2% and 19.1%, 6.7% and 5.9%, 2.0%, and 1.6%, and 2.4% and 1.6% at 2, 5, 10, 15, and 16 years of age, respectively. The relative risk (RR) of asthma in preterm infants was 1.1-fold that in female preterm infants. The RR of asthma medication prescriptions for infants with extreme prematurity was 1.92-fold that of infants with moderate/late pre-term status. Among preterm with bronchopulmonary dysplasia (BPD) and respiratory distress syndrome (RDS) without comorbidities, the RRs for the number of asthma medication prescriptions were 1.34 and 1.06, respectively. This study revealed a higher prevalence of asthma among preterm infants than that in term infants. Male sex, extreme prematurity, BPD, and RDS were identified as risk factors for asthma medication prescriptions in preterm infants.

Shared Interoperable Clinical Decision Support Service for Drug-Allergy Interaction Checks: Implementation Study.

BACKGROUND: Clinical decision support (CDS) can improve health care with respect to the quality of care, patient safety, efficiency, and effectiveness. Establishing a CDS system in a health care setting remains a challenge. A few hospitals have used self-developed in-house CDS systems or commercial CDS solutions. Since these in-house CDS systems tend to be tightly coupled with a specific electronic health record system, the functionality and knowledge base are not easily shareable. A shared interoperable CDS system facilitates the sharing of the knowledge base and extension of CDS services. OBJECTIVE: The study focuses on developing and deploying the national CDS service for the drug-allergy interaction (DAI) check for health care providers in Korea that need to introduce the service but lack the budget and expertise. METHODS: To provide the shared interoperable CDS service, we designed and implemented the system based on the CDS Hooks specification and Health Level Seven (HL7) Fast Healthcare Interoperability Resources (FHIR) standard. The study describes the CDS development process. The system development went through requirement analysis, design, implementation, and deployment. In particular, the concept architecture was designed based on the CDS Hooks structure. The MedicationRequest and AllergyIntolerance resources were profiled to exchange data using the FHIR standard. The discovery and DAI check application programming interfaces and rule engine were developed. RESULTS: The CDS service was deployed on G-Cloud, a government cloud service. In March 2021, the CDS service was launched, and 67 health care providers participated in the CDS service. The health care providers participated in the service with 1,008,357 DAI checks for 114,694 patients, of which 33,054 (3.32%) cases resulted in a "warning." CONCLUSIONS: Korea's Ministry of Health and Welfare has been trying to build an HL7 FHIR-based ecosystem in Korea. As one of these efforts, the CDS service initiative has been conducted. To promote the rapid adoption of the HL7 FHIR standard, it is necessary to accelerate practical service development and to appeal to policy makers regarding the benefits of FHIR standardization. With the development of various case-specific implementation guides using the Korea Core implementation guide, the FHIR standards will be distributed nationwide, and more shared interoperable health care services will be introduced in Korea.

Evaluation of users' level of satisfaction for an artificial intelligence-based diagnostic program in pediatric rare genetic diseases.

The artificial intelligence (AI)-based genetic diagnostic program has been applied to genome sequencing to facilitate the diagnostic process. The objective of the current study was to evaluate the experience and level of satisfaction of participants using an AI-based diagnostic program for rare pediatric genetic diseases. The patients with neurodevelopmental disorders or hearing impairments, their guardians, and their physicians from 16 tertiary general hospitals were enrolled. The study period was from April 2020 to March 2021. A survey was designed to assess their experience and level of satisfaction. A total of 30 physicians and 243 patients and guardians (199 neurodevelopmental disorders and 44 hearing impairments) completed the survey. DNA samples of the subjects were collected through buccal swabs or blood collection: 211 subjects (86.8%) through buccal swab and 29 subjects (11.9%) through blood collection. Average turnaround time for result receipt was 57.54 ± 32.42 days. For the sampling method, 193 patients and guardians (81.1%) and 28 physicians (93.3%) preferred buccal swab. The level of satisfaction of the 2 groups participating in the AI-based diagnostic program was 8.31 ± 1.71 out of 10 in the patient and guardian group and 8.42 ± 1.23 in the physician group. Clinicians, patients, and guardians are satisfied with the AI-based diagnostic program in general. With an increase in AI-based precision medicine solutions, the evaluation of the user's satisfaction with appropriate provision will help improve personal health care.

Digital Health Profile of South Korea: A Cross Sectional Study.

(1) Backgroud: For future national digital healthcare policy development, it is vital to collect baseline data on the infrastructure and services of medical institutions' information and communication technology (ICT). To assess the state of medical ICT across the nation, we devised and administered a comprehensive digital healthcare survey to medical institutions across the nation. (2) Methods: From 16 November through 11 December 2020, this study targeted 42 tertiary hospitals, 311 general hospitals, and 1431 hospital locations countrywide. (3) Results: Since 2015, most hospitals have implemented electronic medical record (EMR) systems (90.5 percent of hospitals, which is the smallest unit, and 100 percent of tertiary hospitals). The rate of implementation of personal health records (PHRs) varied significantly between 61.9 percent and 2.4 percent, depending on the size of the hospital. Hospitals have implemented around three to seven government-sponsored information/data transmission and receiving systems for statistical or investigative objectives. For secondary usage of medical data, more than half of tertiary hospitals have implemented a clinical data warehouse or shared data model. However, new service establishments utilizing modern medical technologies such as artificial intelligence or lifelogging were scarce and in the planning stages. (4) Conclusion: This study shows that the level of digitalization in Korean medical institutions is significant, despite the fact that the development and spending in ICT infrastructure and services provided by individual institutions imposes a significant cost. This illustrates that, in the face of a pandemic, strong government backing and policymaking are essential to activate ICT-based medical services and efficiently use medical data.

Diagnostic performance of automated, streamlined, daily updated exome analysis in patients with neurodevelopmental delay.

BACKGROUND: The diagnostic yield of whole-exome sequencing (WES) varies from 30%-50% among patients with mild to severe neurodevelopmental delay (NDD)/intellectual disability (ID). Routine retrospective reanalysis of undiagnosed patients has increased the total diagnostic yield by 10-15%. Here, we performed proband-only WES of 1065 patients with NDD/ID and applied a prospective, daily reanalysis automated pipeline to patients without clinically significant variants to facilitate diagnoses. METHODS: The study included 1065 consecutive patients from 1056 nonconsanguineous unrelated families from 10 multimedical centers in South Korea between April 2018 and August 2021. WES data were analyzed daily using automatically updated databases with variant classification and symptom similarity scoring systems. RESULTS: At the initial analysis, 402 patients from 1056 unrelated families (38.0%, 402/1,056 families) had a positive genetic diagnosis. Daily prospective, automated reanalysis resulted in the identification of 34 additional diagnostic variants in 31 patients (3%), which increased our molecular diagnostic yield to 41% (433/1056 families). Among these 31 patients, 26 were diagnosed with 23 different diseases that were newly discovered after 2019. The time interval between the first analysis and the molecular diagnosis by reanalysis was 1.2 ± 0.9 years, which was shorter in the patients enrolled during the latter part of the study period. CONCLUSION: Daily updated databases and reanalysis systems enhance the diagnostic performance in patients with NDD/ID, contributing to the rapid diagnosis of undiagnosed patients by applying the latest molecular genetic information.

Association of Early Pubertal Onset in Female Rats With Inhalation of Lavender Oil.

BACKGROUND: Central precocious puberty (CPP) is caused by early activation of the hypothalamic-pituitary-gonadal axis but its major cause remains unclear. Studies have indicated an association between chronic environmental exposure to endocrine-disrupting chemicals and pubertal onset. Essential oil is widely used in homes worldwide for relief of respiratory symptoms, stress, and/or sleep disturbance. METHODS: To evaluate this association, we compared the hormone levels and timing of vaginal opening (VO) in female rats exposed to lavender oil (LO) through different routes (study groups: control, LO nasal spray [LS], and indoor exposure to LO [LE]) during the prepubertal period. The body weights of the animals were also compared every 3 days until the day of VO, at which time gonadotropin levels and internal organ weights were assessed. RESULTS: The LS group showed early VO at 33.8 ± 1.8 days compared with the control (38.4 ± 2.9 days) and LE (36.6 ± 1.5 days) groups. Additionally, luteinizing hormone levels were significantly higher in the LE and LS groups than those in the control group. Body weights did not differ significantly among the groups. CONCLUSION: Inhalation exposure to an exogenic simulant during the prepubertal period might trigger early pubertal onset in female rats. Further evaluation of exposure to other endocrine-disrupting chemicals capable of inducing CPP through the skin, orally, and/or nasally is warranted.

Phenotypic and molecular spectra of patients with switch/sucrose nonfermenting complex-related intellectual disability disorders in Korea.

BACKGROUND: The switch/sucrose nonfermenting (SWI/SNF) complex is an adenosine triphosphate-dependent chromatin-remodeling complex associated with the regulation of DNA accessibility. Germline mutations in the components of the SWI/SNF complex are related to human developmental disorders, including the Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. These disorders are collectively referred to as SWI/SNF complex-related intellectual disability disorders (SSRIDDs). METHODS: Whole-exome sequencing was performed in 564 Korean patients with neurodevelopmental disorders. Twelve patients with SSRIDDs (2.1%) were identified and their medical records were retrospectively analyzed. RESULTS: ARID1B, found in eight patients, was the most frequently altered gene. Four patients harbored pathogenic variants in SMARCA4, SMARCB1, ARID2, and SMARCA2. Ten patients were diagnosed with CSS, and one patient without a typical phenotype was diagnosed with ARID1B-related nonsyndromic intellectual disability. Another patient harboring the SMARCA2 pathogenic variant was diagnosed with NCBRS. All pathogenic variants in ARID1B were truncating, whereas variants in SMARCA2, SMARCB1, and SMARCA4 were nontruncating (missense). Frequently observed phenotypes were thick eyebrows (10/12), hypertrichosis (8/12), coarse face (8/12), thick lips (8/12), and long eyelashes (8/12). Developmental delay was observed in all patients, and profound speech delay was also characteristic. Agenesis or hypoplasia of the corpus callosum was observed in half of the patients (6/12). CONCLUSIONS: SSRIDDs have a broad disease spectrum, including NCBRS, CSS, and ARID1B-related nonsyndromic intellectual disability. Thus, SSRIDDs should be considered as a small but important cause of human developmental disorders.

Pancreatic involvement in patients with inborn errors of metabolism.

BACKGROUND: Repeated inflammation of the pancreas can cause pancreatitis or diabetes. It is well recognized that the organic acidemias may be complicated by pancreatitis but less recognized are other metabolic disorders in which pancreatitis can occur. This study shows that long-term follow-up of patients with various metabolic disorders in Korea revealed several with episodes of isolated pancreatitis or diabetes concomitantly with pancreatitis. RESULTS AND DISCUSSION: In this study, two patients with methylmalonic aciduria (MMA), two with propionic acidemia (PPA), one with fatty acid oxidation disorder (FAOD), and one with hyperornithinemia, gyrate atrophy, and juvenile onset diabetes mellitus (DM) were clinically followed for up to 10 - 21 years. Two Korean siblings with MMA showed recurrent pancreatitis from the age of 15 and 19, respectively. The frequency of admission due to pancreatitis was up to 11 times. One patient with MMA developed diabetes mellitus at the age of 20. The other patient with MMA developed recurrent pancreatitis at 4 years and diabetes at 8 years of age. One of the patients with PPA presented with diabetic ketoacidosis. The other PPA patient died of cardiac arrest at age 10. The patient with FAOD presented with pancreatitis at 10 years and died at the age of 15 years due to cardiac arrest. A 35-year-old woman with hyperornithinemia/gyrate atrophy was diagnosed with juvenile onset diabetes at the age of 7 years. No pancreatitis occurred during the follow-up period. CONCLUSIONS: We conclude that various metabolic disorders can trigger acute or chronic pancreatitis. Proper and prompt multidisciplinary management of metabolic derangement is crucial for preventing pancreatic damage. Further clinical and investigational studies are required to elucidate the pathogenesis of pancreatitis and diabetes mellitus in patients with inborn errors in metabolism.

The GBA p.G85E mutation in Korean patients with non-neuronopathic Gaucher disease: founder and neuroprotective effects.

BACKGROUND: Gaucher disease (GD) is caused by a deficiency of ß-glucocerebrosidase, encoded by GBA. Haplotype analyses previously demonstrated founder effects for particular GBA mutations in Ashkenazi Jewish and French-Canadian populations. This study aimed to investigate the clinical characteristics and mutation spectrum of GBA in Korean GD patients and to identify founder effect of GBA p.G85E in non-neuronopathic GD patients. RESULTS: The study cohort included 62 GD patients from 58 unrelated families. Among them, 18 patients from 17 families harbored the p.G85E mutation. Haplotype analysis was performed for 9 probands and their parents for whom DNA samples were available. In 58 unrelated probands, the GBA mutation p.L483P was the most common (30/116 alleles, 26%), followed by p.G85E (16%), p.F252I (13%), and p.R296Q (9%). The median age at diagnosis of the 18 patients harboring the p.G85E mutation was 3.8 (range 1.2-57) years. No patients developed neurological symptoms during follow-up periods of 2.2-20.3 (median 13.9) years. The size of the shared haplotype containing GBA p.G85E was 732 kbp, leading to an estimated age of 3075 years. CONCLUSION: The GBA p.G85E mutation, which appears to be neuroprotective despite producing distinctive visceromegaly and skeletal symptoms, exhibited a potential founder effect in Korean GD patients.

Environmental and economic effectiveness of the Kyoto Protocol.

This study investigates the environmental and economic impacts of the Kyoto Protocol on Annex I parties through an impact assessment by combining the propensity score matching and the difference-in-difference methods. We establish a country-level panel data set including CO2 emissions, gross domestic product (GDP), and other socioeconomic data for 1997-2008 and 2005-2008. Based on the impact evaluation, we conduct the simulation predicting the impacts of the Protocol to capture the differences of marginal damage cost of carbon emissions between the actual and counterfactual situations. The results suggest that participating as an Annex I party has a significant positive impact on CO2 emission reductions, but a negative impact on the GDP of the participants in the long run. The predicted marginal benefit of the Protocol based on the marginal damage cost of carbon emissions shows that the marginal benefit of emission reductions mitigates a limited portion of the GDP loss. Future global climate change frameworks should focus on balancing the impact on economic and environmental performance in order to ensure sustainable development, especially for developing countries that have low capacity to mitigate emissions.

Fatal outcome of autosomal recessive polycystic kidney disease in neonates with recessive PKHD1 mutations.

Autosomal recessive polycystic kidney disease (ARPKD) is the most common inherited childhood-onset renal disease, with underlying ciliopathy, and varies widely in clinical severity. The aim of this study was to describe the most severe form of ARPKD, with a fatal clinical course, and its association with mutations in polycystic kidney and hepatic disease 1 (fibrocystin) (PKHD1). Clinical, imaging, pathological, and molecular genetic findings were reviewed in patients prenatally affected with ARPKD and their families.Five unrelated Korean families, including 9 patients, were analyzed. Among the 9 patients, 2 fetuses died in utero, 6 patients did not survive longer than a few days, and 1 patient survived for 5 months with ventilator support and renal replacement therapy. A total of 6 truncating mutations (all nonsense) and 4 missense mutations were detected in a compound heterozygous state, including 4 novel mutations. The most severe phenotypes were shared among all affected patients in each family, irrespective of mutation types.Our data suggest a strong genotype-phenotype relationship in ARPKD, with minimal intra-familial heterogeneity. These findings are important for informing future reproductive planning in affected families.

Successful rapid weight reduction and the use of liraglutide for morbid obesity in adolescent Prader-Willi syndrome.

Prader-Willi syndrome (PWS), an imprinting disorder, results from the loss of expression of a paternal gene on chromosome 15q11-q13. Progressive obesity and its associated complications lead to increased morbidity and early death in PWS patients. The management techniques available for morbid obesity in adolescents and adults with PWS are limited. Herein, we report successful weight reduction in an adolescent PWS case showing morbid obesity and respiratory failure. An 18-year-old girl with PWS presented with diffuse cellulitis and dyspnea due to severe obesity. Her body weight had increased from 146 to 161 kg despite dietary restriction to 800 kcal/day, and a mechanical ventilator was required for dyspnea. During mechanical ventilation, the patient was managed using diuretics and by restricting fluid intake; her daily calorie intake was reduced to 200 kcal. This aggressive calorie and water restriction continued for 3 weeks and reduced her body weight to 118.6 kg. After transfer to the general ward, the patient was provided with growth hormone therapy and intensive aquatic rehabilitation and was administered liraglutide; as a result, her weight further decreased to 104 kg (body mass index [BMI], 50.8 kg/m2), and she was discharged. Following discharge, she maintained her BMI and adapted to 1,000 kcal/day for 1 year. Aggressive water and calorie restriction were observed as an effective method for rapid weight reduction in PWS patients, and liraglutide appeared useful in maintaining weight reduction in adolescent and adult PWS.