Korean Clinical Practice Guidelines: Current Status of Adherence to the RIGHT Checklist.

BACKGROUND: The Korean Academy of Medical Sciences (KAMS) has been utilizing AGREE II to audit the quality of clinical practice guidelines (CPGs) developed in Korea. Monitoring the RIGHT Checklist adherence could help monitor the quality status and discover areas for improvement of CPG development. METHODS: We included 129 CPGs from the past 5 years and assessed each item of the RIGHT Checklist. STATA version 15.0 was used for statistical analysis. RESULTS: Among the seven sections of the RIGHT checklist, sections with a full compliance rate over 60% were 'basic information' (65%) and 'background' (66%). The other sections' mean full compliance rates were 'Evidence' 52%, 'Recommendation' 35%, 'Review and quality assurance' 25% and 'Funding, declaration and management of interest' 17%. Sections with a partial compliance rate over 60% were 'Recommendation' (60%) and 'Funding, declaration and management of interest' (70%). Non-compliance was highest in the 'Review and quality assurance' (17%) domain. In comparison between groups 1 (under median group) and 2 (over median group), group 2 showed a tendency to have multi-stakeholder involvement and present sufficient information on financial resources and conflict of interest declarations. For the CPGs developmental methodology aspect, group 2 provided more pertinent information than group 1 about supporting evidence-making and the process from evidence to recommendation. CONCLUSION: This study evaluated adherence to the RIGHT Checklist of CPGs developed in Korea. It can provide helpful information to develop strategic plans for enhancing the capabilities of developing CPGs in Korea.

What We Should Consider in Point of Care Blood Glucose Test; Current Quality Management Status of a Single Institution.

Background and Objectives: Point of care test (POCT) is generally performed by non-laboratory staff who often lack an understanding on the quality control and quality assurance programs. The purpose of this study was to understand the current status of quality management of point of care (POC) blood glucose testing in a single institution where non-laboratory staff perform the tests. Materials and Methods: From July to August 2020, management status of glucometer, test strips, quality control (QC) materials, quality assurance program, and operators' response to processing of displayed results was monitored in all Soonchunhyang University Bucheon hospital departments that performed POC blood glucose test. Results of the POC blood glucose test conducted from January 2019 to May 2020 were analyzed retrospectively. Results: A total 124 glucometers were monitored in 47 departments. Insufficient management of approximately 50% of blood sugar, test strips, and QC materials was observed. Although daily QC was conducted by 95.7% of the departments, the QC records were inaccurate. The method of recording test results varied with departments and operators. Various judgments and troubleshooting were performed on the unexpected or out of measurable range results, including some inappropriate processes. In POC blood glucose test results review, 4568 atypical results were identified from a total of 572,207 results. Conclusions: Sufficient training of the non-laboratory staff and ongoing assessment of competency through recertification is needed to maintain acceptable levels of POCT quality. In this study, various problems were identified in glucometer and reagent management, QC and post-analytic phase. We believe that these results provide meaningful basal information for planning effective operators' training and competency evaluation, and the development of an efficient POCT quality management system.

Differences in Perspectives of Medical Device Adverse Events: Observational Results in Training Program Using Virtual Cases.

BACKGROUND: Medical device adverse event reporting is an essential activity for mitigating device-related risks. Reporting of adverse events can be done by anyone like healthcare workers, patients, and others. However, for an individual to determine the reporting, he or she should recognize the current situation as an adverse event. The objective of this report is to share observed individual differences in the perception of a medical device adverse event, which may affect the judgment and the reporting of adverse events. METHODS: We trained twenty-three participants from twelve Asia-Pacific Economic Cooperation (APEC) member economies about international guidelines for medical device vigilance. We developed and used six virtual cases and six questions. We divided participants into six groups and compared their opinions. We also surveyed the country's opinion to investigate the beginning point of 'patient use'. The phases of 'patient use' are divided into: 1) inspecting, 2) preparing, and 3) applying medical device. RESULTS: As for the question on the beginning point of 'patient use,' 28.6%, 35.7%, and 35.7% of participants provided answers regarding the first, second, and third phases, respectively. In training for applying international guidelines to virtual cases, only one of the six questions reached a consensus between the two groups in all six virtual cases. For the other five questions, different judgments were given in at least two groups. CONCLUSION: From training courses using virtual cases, we found that there was no consensus on 'patient use' point of view of medical devices. There was a significant difference in applying definitions of adverse events written in guidelines regarding the medical device associated incidents. Our results point out that international harmonization effort is needed not only to harmonize differences in regulations between countries but also to overcome diversity in perspectives existing at the site of medical device use.

Risk of Interval Cancer in Fecal Immunochemical Test Screening Significantly Higher During the Summer Months: Results from the National Cancer Screening Program in Korea.

OBJECTIVES: This study aimed to evaluate the impact of seasonal variations in climate on the performance of the fecal immunochemical test (FIT) in screening for colorectal cancer in the National Cancer Screening Program in Korea. METHODS: Data were extracted from the National Cancer Screening Program databases for participants who underwent FIT between 2009 and 2010. We compared positivity rates, cancer detection rates, interval cancer rates, positive predictive value, sensitivity, and specificity for FIT during the spring, summer, fall, and winter seasons in Korea. RESULTS: In total, 4,788,104 FIT results were analyzed. FIT positivity rate was lowest during the summer months. In the summer, the positive predictive value of FIT was about 1.1 times (adjusted odds ratio (aOR) 1.08, 95% confidence interval (CI) 1.00-1.16) higher in the overall FIT group and about 1.3 times (aOR 1.29, 95% CI 1.10-1.50) higher in the quantitative FIT group, compared to those in the other seasons. Cancer detection rates, however, were similar regardless of season. Interval cancer risk was significantly higher in the summer for both the overall FIT group (aOR 1.16, 95% CI 1.07-1.27) and the quantitative FIT group (aOR 1.31, 95% CI 1.12-1.52). In addition, interval cancers in the rectum and distal colon were more frequently detected in the summer and autumn than in the winter. CONCLUSIONS: The positivity rate of FIT was lower in the summer, and the performance of the FIT screening program was influenced by seasonal variations in Korea. These results suggest that more efforts to reduce interval cancer during the summer are needed in population-based screening programs using FIT, particularly in countries with high ambient temperatures.

Higher satisfaction with an alternative collection device for stool sampling in colorectal cancer screening with fecal immunochemical test: a cross-sectional study.

BACKGROUND: Identifying preferences for stool collection devices may help increase uptake rates for colorectal cancer screening via fecal immunochemical test (FIT). This study surveyed satisfaction with different devices utilized to collect stool samples for FIT: a conventional container and a sampling bottle (Eiken OC-Sensor). METHODS: This cross-sectional study was conducted at the National Cancer Center, Korea. Participants aged 50-74 years who used either a conventional container or a sampling bottle to collect a stool sample for FIT were asked to complete a questionnaire designed to survey their satisfaction with the stool collection process and their intentions to undergo FIT in subsequent screening rounds. In total, 1657 participants (1224 conventional container, 433 sampling bottle) were included for analysis. RESULTS: Satisfaction with the sampling bottle was higher than that with the conventional container (79.9% vs.73.0%, p = 0.005, respectively; aOR = 1.52, 95% CI: 1.16-2.00). Participants satisfied with the sampling bottle were more likely to be female, be of younger age (50-64 years old), have higher household income, and have prior experience with FIT. Intentions to undergo subsequent screening were stronger among those given the sampling bottle than those given the conventional container (aOR = 1.78, 95% CI: 1.28-2 .48). CONCLUSIONS: Satisfaction with the stool collection process was higher with the sampling bottle. However, additional studies are needed to validate whether the increased satisfaction and stronger intentions to undergo subsequent screening with the sampling bottle could actually lead to increased uptake in subsequent rounds, along with analysis of the device's cost effectiveness.

Effect of the Standardization of Diagnostic Tests on the Prevalence of Diabetes Mellitus and Impaired Fasting Glucose.

BACKGROUND: Without standardization of medical laboratory's testing practices, there is an increase in false diagnoses when relying on test results. However, the effect of test standardization is difficult to assess numerically. This study's purpose is to quantify the effect of the standardization level of a laboratory on the prevalence of diabetes mellitus (DM) and impaired fasting glucose (IFG). METHODS: Laboratories were classified into three levels: 'highly-standardized laboratory,' 'basically-standardized laboratory,' and 'non-standardized laboratory.' Based on the results of Korean External Quality Assessment Scheme (KEQAS), the cutoff values for diagnosis of DM and IFG were recalculated, given false positive and false negative rates. RESULTS: The prevalence of DM and IFG in the population as a whole was estimated using the 2013 Korea National Health and Nutrition Examination Survey (KNHANES) database. When the prevalence of DM from KNHANES was 11.88% (95% confidence interval [CI], 10.59%-13.17%), the proportion with a systematic false error ranged from 10.91% (95% CI, 9.65%-12.17%) to 13.09% (95% CI, 11.74%-14.45%). The prevalence of IFG varied from 13.59% (95% CI, 12.25%-14.91%) to 40.49% (95% CI, 38.54%-42.43%), in contrast to 24.58% (95% CI, 22.85%-26.31%) of the reference value. The prevalence of DM and IFG tended to be over- and under-estimated more as the laboratory standardization level became lower, respectively. CONCLUSION: Our study proved that standardization of clinical laboratory tests is an important factor affecting the prevalence estimation of national disease statistics based on the simulation using KNHANES data.

Pyridoxine-derived bicyclic amido-, ureido-, and carbamato-pyridinols: synthesis and antiangiogenic activities.

We recently developed an efficient and practical synthesis for a novel series of pyridoxine-derived 6-amido-2,4,5-trimethylpyridin-3-ols and found that this novel scaffold has outstanding activity to inhibit angiogenesis measured by the quantitative chick embryo chorioallantoic membrane (CAM) assay. As an effort to extend the scope of the amidopyridinol scaffold, we here report the synthesis and antiangiogenic activities of a series of bicyclic versions of the amidopyridinol including five- and six-membered cyclic amide-, cyclic urea-, and cyclic carbamate-fused pyridinols. The six membered bicyclic derivatives were prepared by the reported procedures, and the five-membered ring-fused ones were synthesized by new synthetic methods developed in this study. CAM assays showed that both six- and five-membered lactam-fused pyridinols have activities comparable to sunitinib malate, the positive control, in inhibition of vascular endothelial growth factor-induced angiogenesis. On the other hand, the urea and the carbamate derivatives showed modest to moderate antiangiogenic activities. In summary, some bicyclic aminopyridinols can provide a good platform for structural exploitation in future medicinal chemistry work.

Improving the reliability of clinical practice guideline appraisals: effects of the Korean AGREE II scoring guide.

The Korean translated Appraisal of Guidelines for Research and Evaluation II (Korean AGREE II) instrument was distributed into Korean medical societies in 2011. However, inter-rater disagreement issues still exist. The Korean AGREE II scoring guide was therefore developed to reduce inter-rater differences. This study examines the effects of the Korean AGREE II scoring guide to reduce inter-rater differences. Appraisers were randomly assigned to two groups (Scoring Guide group and Non-Scoring Guide group). The Korean AGREE II instrument was provided to both groups. However, the scoring guide was offered to Scoring Guide group only. Total 14 appraisers were participated and each guideline was assessed by 8 appraisers. To evaluate the reliability of the Korean AGREE II scoring guide, correlation of scores among appraisers and domain-specific intra-class correlation (ICC) were compared. Most scores of two groups were comparable. Scoring Guide group showed higher reliability at all guidelines. They showed higher correlation among appraisers and higher ICC values at almost all domains. The scoring guide reduces the inter-rater disagreement and improves the overall reliability of the Korean-AGREE II instrument.

Developing a scoring guide for the Appraisal of Guidelines for Research and Evaluation II instrument in Korea: a modified Delphi consensus process.

Korea has a relatively short history in the development and use of clinical practice guidelines (CPGs). Additionally, it has been difficult to employ the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument due to the lack of consensus and the presence of differences in Korean medical settings and in the Korean socio-cultural environment. An AGREE II scoring guide was therefore developed to reduce differences among evaluators using the same tool. In consideration of the importance of using a quantitative measure of satisfaction with the elements described in the AGREE II manual, a final draft was developed through a Delphi consensus process. Ninety-two draft scoring guides for anchor points 1, 3, 5, and 7 (full score) in 23 items were developed. Consensus was defined as agreement among at least 70% of the raters. Agreement on 88 draft scoring guidelines was reached in the first Delphi round, and agreement for the remaining four was achieved in the second round. The development of an AGREE II scoring guide in this study is expected to contribute to improving the CPG environment.

A comparison of qualitative and quantitative fecal immunochemical tests in the Korean national colorectal cancer screening program.

OBJECTIVE: The National Cancer Screening Program (NCSP) has since 2004 provided annual colorectal cancer screening using the fecal immunochemical test (FIT) for individuals aged 50 years or older. The aim of this study was to examine the positivity and detection rates of the FIT and to compare the detection rates of the qualitative and quantitative FITs in participants in the 2009 NCSP. METHODS: We analyzed positivity and detection rates according to FIT type (qualitative and quantitative). We used a multinomial logistic regression to analyze the odds ratio of "benign" or "suspicious cancer and cancer" compared to "normal," adjusted for gender, age, health insurance type, region of residence, hospital type, and FIT type. RESULTS: Of the 1,181,904 participants, 72.8% received a qualitative and 27.2% a quantitative FIT. The positivity rates were 8.1% for the qualitative and 2.5% for the quantitative FIT. The detection rate was 5.2% for the qualitative and 14.4% for the quantitative FIT. The odds ratio of a "suspicious cancer and cancer" versus a "normal" result was 2.73 (95% CI = 2.22-3.35) for the quantitative compared to qualitative FIT, after adjustment. CONCLUSIONS: The positivity rate of the qualitative FIT was around three times higher than that of the quantitative FIT. However, the odds ratio for detection of "suspicious cancer and cancer" versus "normal" of the quantitative FIT was about three times higher than that of the qualitative FIT. These findings suggest that quality control may be important, particularly for the qualitative FIT.

Which Health Impacts of Medical Device Adverse Event Should Be Reported Immediately in Korea?

OBJECTIVE: Immediate medical device adverse event (MDAE) reporting indications of Korea include death, life-threatening, hospitalization (initial or prolonged), disability or permanent damage, and congenital malformation or abnormalities. With the advent of new codes from the International Medical Device Regulators Forum, a study was undertaken to explore the applicability of health impact codes as immediate MDAE reporting indications in the Republic of Korea. METHOD: This domestic cross-sectional survey study was conducted for members from Medical Device Safety Information Monitoring Center in November 2019. For the annex F (health impact) codes defining health impact of an MDAE, we checked whether each code matched with the current indication and asked experts whether they agreed with each code as an indication of immediate reporting. Consensus was reached when ≥70% of experts agreed. RESULTS: A total of 28 experts from 19 centers responded to the survey. Of a total of 64 codes, 29 matched with the current indication. However, in an expert survey, 17 of 29 codes were not agreed for immediate reporting and 5 codes were found to be unmatched codes. For these 5 codes, experts agreed that they would need reporting immediately. Finally, only 17 codes achieved consensus for immediate reporting. CONCLUSIONS: There is a discrepancy between the code matched to the current immediate MDAE reporting indication and experts' consensus. Sufficient discussion and agreement would be needed to apply health impact codes for immediate reporting.

Improving the blood collection process using the active-phlebotomist phlebotomy system.

BACKGROUND: Because the number of patients requiring phlebotomy varies significantly at different times throughout the day, it is difficult to control wait times during peak times. We tried to solve this problem by changing from the conventional fixed-phlebotomist phlebotomy system (CFPPS), in which the phlebotomist waits for patients at a fixed location to the active-phlebotomist phlebotomy system (APPS), in which a phlebotomist goes to patients actively. We compared the productivity of these two systems. METHODS: After changing the system at our hospital, we measured the waiting time before seeing phlebotomy staff and compared it to a comparable hospital that uses CFPPS. We reviewed the phlebotomy count recorded in the laboratory information system before and after the system change. RESULTS: After the system change, the average waiting time for phlebotomy was 2.34 min (median 1 min) and the waiting time was less than 5 min in all time slots, except 7:00 to 7:30 a.m. The new system significantly decreased the waiting time. In addition, the maximum number of patients seen by a phlebotomist during the peak time was higher in the APPS. CONCLUSION: The APPS enhanced the productivity of the phlebotomist and reduced waiting time with limited human resources in a Korean hospital.

The establishment of the Korean medical device safety information monitoring center: Reviewing ten years of experience.

Medical devices may revolutionize healthcare delivery but can lead to serious adverse events for treated patients and users. While reporting of adverse events related to medical devices is an essential starting point for post-market surveillance, underreporting of medical device adverse events is a global problem. Korea introduced a voluntary medical device adverse event reporting system in 2010, called the Medical Device Safety Information Monitoring Center, which has led to an increase in adverse event reports. For 10 years, the Medical Device Safety Information Monitoring Center has analyzed medical device adverse events systematically and has provided active feedback to the manufacturers and education on safe use. Recently, the Medical Device Safety Information Monitoring Center contributed to harmonization of international medical device vigilance through the sharing of adverse events. This experience of Korea might contribute to improvements in medical device vigilance, which is a critical prerequisite for improving medical device policies and regulations.

Preliminary feasibility assessment of CDM-based active surveillance using current status of medical device data in medical records and OMOP-CDM.

In recent years, there has been an emerging interest in the use of claims and electronic health record (EHR) data for evaluation of medical device safety and effectiveness. In Korea, national insurance electronic data interchange (EDI) code has been used as a medical device data source for common data model (CDM). This study performed a preliminary feasibility assessment of CDM-based vigilance. A cross-sectional study of target medical device data in EHR and CDM was conducted. A total of 155 medical devices were finally enrolled, with 58.7% of them having EDI codes. Femoral head prosthesis was selected as a focus group. It was registered in our institute with 11 EDI codes. However, only three EDI codes were converted to systematized nomenclature of medicine clinical terms concept. EDI code was matched in one-to-many (up to 104) with unique device identifier (UDI), including devices classified as different global medical device nomenclature. The use of UDI rather than EDI code as a medical device data source is recommended. We hope that this study will share the current state of medical device data recorded in the EHR and contribute to the introduction of CDM-based medical device vigilance by selecting appropriate medical device data sources.

Modulation of cytokine and nitric oxide by mesenchymal stem cell transfer in lung injury/fibrosis.

BACKGROUND: No effective treatment for acute lung injury and fibrosis currently exists. Aim of this study was to investigate the time-dependent effect of bone marrow-derived mesenchymal stem cells (BMDMSCs) on bleomycin (BLM)-induced acute lung injury and fibrosis and nitric oxide metabolites and inflammatory cytokine production. METHODS: BMDMSCs were transferred 4 days after BLM inhalation. Wet/dry ratio, bronchoalveolar lavage cell profiles, histologic changes and deposition of collagen were analyzed. RESULTS: Nitrite, nitrate and cytokines were measured weekly through day 28. At day 7, the wet/dry ratio, neutrophilic inflammation, and amount of collagen were elevated in BLM-treated rats compared to sham rats (p = 0.05-0.002). Levels nitrite, nitrate, IL-1beta, IL-6, TNF-alpha, TGF-beta and VEGF were also higher at day 7 (p < 0.05). Degree of lymphocyte and macrophage infiltration increased steadily over time. BMDMSC transfer significantly reduced the BLM-induced increase in wet/dry ratio, degree of neutrophilic infiltration, collagen deposition, and levels of the cytokines, nitrite, and nitrate to those in sham-treated rats (p < 0.05). Fluorescence in situ hybridization localized the engrafted cells to areas of lung injury. CONCLUSION: Systemic transfer of BMDMSCs effectively reduced the BLM-induced lung injury and fibrosis through the down-regulation of nitric oxide metabolites, and proinflammatory and angiogenic cytokines.

Reporting Quality of Diagnostic Accuracy Studies in Laboratory Medicine: Adherence to Standards for Reporting of Diagnostic Accuracy Studies (STARD) 2015.

BACKGROUND: Poor reporting quality in diagnostic accuracy studies hampers an adequate judgment of the validity of the study. The Standards for Reporting of Diagnostic Accuracy Studies (STARD) statement was published to improve the reporting quality of diagnostic accuracy studies. This study aimed to evaluate the adherence of diagnostic accuracy studies published in Annals of Laboratory Medicine (ALM) to STARD 2015 and to identify directions for improvement in the reporting quality of these studies. METHODS: Two independent authors assessed articles published in ALM between 2012-2018 for compliance with 30 STARD 2015 checklist items to identify all eligible diagnostic accuracy studies published during this period. We included 66 diagnostic accuracy studies. A total of the fulfilled STARD items were calculated, and adherence was analyzed on an individual-item basis. RESULTS: The overall mean±SD number of STARD items reported for the included studies was 11.2±2.7. Only five (7.6%) studies adhered to more than 50% of the 30 items. No study satisfied more than 80% of the items. Large variability in adherence to reporting standards was detected across items, ranging from 0% to 100%. CONCLUSIONS: Adherence to STARD 2015 is suboptimal among diagnostic accuracy studies published in ALM. Our study emphasizes the necessity of adherence to STARD to improve the reporting quality of future diagnostic accuracy studies to be published in ALM.

Clinical, biochemical, and genetic analysis of a Korean neonate with hereditary tyrosinemia type 1.

BACKGROUND: Hereditary tyrosinemia type 1 (HT1; MIM 276700) is caused by mutations in the fumarylaceto-acetate hydrolase (FAH) gene, and is the most severe disorder associated with the tyrosine catabolic pathway. HT1 is a very rare disorder and no genetically confirmed case of HT1 in Korea has yet been reported. In this study, we present a Korean neonate with clinical and biochemical features of HT1. METHODS: A female neonate was admitted to our hospital for further work-up of an abnormal newborn screening test. We analyzed amino acids and organic acids in the patient's blood and urine. To confirm the presence of the genetic abnormality, all the coding exons of the FAH gene and the flanking introns were amplified by polymerase chain reaction (PCR). RESULTS: The patient's newborn screening test revealed increased concentrations of methionine and tyrosine. Subsequent urine organic acid analysis showed increased urinary excretion of 4-hydroxyphenyllactate, 4-hydroxyphenylpyruvate, succinate, and succinylacetone. Gap-PCR and sequence analysis of the FAH gene revealed a homozygous large deletion mutation encompassing exons 12-14. The patient's parents were not consanguineous but were heterozygous carriers of the same mutation. CONCLUSIONS: The patient had a novel, large deletion mutation of FAH and is the first report of genetically confirmed HT1 in Korea.

Dose Estimation Curves Following In Vitro X-ray Irradiation Using Blood From Four Healthy Korean Individuals.

Cytogenetic dosimetry is useful for evaluating the absorbed dose of ionizing radiation based on analysis of radiation-induced chromosomal aberrations. We created two types of in vitro dose-response calibration curves for dicentric chromosomes (DC) and translocations (TR) induced by X-ray irradiation, using an electron linear accelerator, which is the most frequently used medical device in radiotherapy. We irradiated samples from four healthy Korean individuals and compared the resultant curves between individuals. Aberration yields were studied in a total of 31,800 and 31,725 metaphases for DC and TR, respectively, obtained from 11 X-ray irradiation dose-points (0, 0.05, 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4, and 5 Gy). The dose-response relationship followed a linear-quadratic equation, Y=C+αD+ßD², with the coefficients C=0.0011 for DC and 0.0015 for TR, α=0.0119 for DC and 0.0048 for TR, and ß=0.0617 for DC and 0.0237 for TR. Correlation coefficients between irradiation doses and chromosomal aberrations were 0.971 for DC and 0.6 for TR, indicating a very strong and a moderate correlation, respectively. This is the first study implementing cytogenetic dosimetry following exposure to ionizing X-radiation.

Mutation analysis of PAH gene and characterization of a recurrent deletion mutation in Korean patients with phenylketonuria.

Phenylketonuria (PKU; MIM 261600) is an autosomal recessive metabolic disorder caused by a deficiency of phenylalanine hydroxylase (PAH; EC 1.14.16.1). Point mutations in the PAH gene are known to cause PKU in various ethnic groups, and large deletions or duplications account for up to 3% of the PAH mutations in some ethnic groups. However, a previous study could not identify approximately 14% of the mutant alleles by sequence analysis in Korean patients with PKU, which suggests that large deletions or duplication might be frequent causes of PKU in Koreans. To test this hypothesis, we performed multiplex ligation-dependent probe amplification (MLPA) for the identification of uncharacterized mutant alleles after PAH sequence analysis of 33 unrelated Korean patients with PKU. Bi-directional sequencing of the PAH exons and flanking intronic regions revealed 27 different mutations, including four novel mutations (two missense and two deletion mutations), comprising 57/66 (86%) mutant alleles. MLPA identified a large deletion that encompassed exons 5 and 6 in four patients, another large deletion that extended from exon 4 to exon 7 in one patient, and a duplication of exon 4 in one patient. Chromosomal walking characterized the deletion breakpoint of the most common large deletion that involved exons 5 and 6 (c.456_706+138del). The present study shows that the allelic frequency of exon deletion or duplication is 9% (6/66) in Korean PKU patients, which suggests that these mutations may be frequent causes of PKU in Korean subjects.

Mutation of Glu78 of the AVP-NPII gene impairs neurophysin as a carrier protein for arginine vasopressin in a family with neurohypophyseal diabetes insipidus.

Familial neurohypophyseal diabetes insipidus (FNDI; OMIM 192340) is a rare inherited disorder with an autosomal dominant inheritance pattern. It is characterized by persistent polydipsia and polyuria induced by deficient or absent secretion of arginine vasopressin (AVP). We report a Korean kindred in whom FNDI is associated with a novel deletion mutation in exon 2 of the AVP-NPII gene encoding the neurophysin II moiety. An 18-yr-old man with polyuria and polydipsia was shown to have central diabetes insipidus by using the water deprivation test. Four family members were suspected to have symptomatic vasopressin-deficient diabetes insipidus. Direct sequencing of the AVP-NPII gene showed a heterozygous GAG deletion mutation in exon 2, which results in in-frame deletion of glutamic acid (c.232_234delGAG; p.Glu78del). The mutation was predicted to yield an abnormal AVP precursor lacking Glu78 (E78) in its neurophysin II moiety. Because Glu78 is essential for neurophysin II molecules to form a salt bridge with AVP, the function of neurophysin as a carrier protein for AVP would be impaired. The proband's mother and sister have the same mutation. Presence of this mutation suggests that the portion of the neurophysin peptide encoded by this sequence is important for the appropriate expression of vasopressin.