Primary cilia function as critical sensory organelles that mediate multiple signaling pathways, including the Hedgehog (Hh) pathway, which is essential for organ patterning and morphogenesis. Disruptions in Hh signaling have been implicated in supernumerary tooth formation and molar fusion in mutant mice. Cilk1, a highly conserved serine/threonine-protein kinase localized within primary cilia, plays a critical role in ciliary transport. Loss of Cilk1 results in severe ciliopathy phenotypes, including polydactyly, edema, and cleft palate. However, the role of Cilk1 in tooth development remains unexplored. In this study, we investigated the role of Cilk1 in tooth development. Cilk1 was found to be expressed in both the epithelial and mesenchymal compartments of developing molars. Cilk1 deficiency resulted in altered ciliary dynamics, characterized by reduced frequency and increased length, accompanied by downregulation of Hh target genes, such as Ptch1 and Sostdc1, leading to the formation of diastemal supernumerary teeth. Furthermore, in Cilk1^-/-;PCS1-MRCS1^△/△ mice, which exhibit a compounded suppression of Hh signaling, we uncovered a novel phenomenon: diastemal supernumerary teeth can be larger than first molars. Based on these findings, we propose a progressive model linking Hh signaling levels to sequential changes in tooth patterning: initially inducing diastemal supernumerary teeth, then enlarging them, and ultimately leading to molar fusion. This study reveals a previously unrecognized role of Cilk1 in controlling tooth morphology via Hh signaling and highlights how Hh signaling levels shape tooth patterning in a gradient-dependent manner.
Animals ; Hedgehog Proteins/physiology* ; Mice ; Signal Transduction/physiology* ; Tooth, Supernumerary ; Molar ; Cilia/physiology* ; Odontogenesis/physiology* ; Patched-1 Receptor ; Protein Serine-Threonine Kinases/physiology* ; Mice, Knockout ; Adaptor Proteins, Signal Transducing

Background: Latency in transferring patients from intensive care units (ICUs) to general wards impedes the optimal allocation of ICU resources, underscoring the urgency of initiatives to reduce it. This study evaluates the extent of ICU transfer latency and assesses the potential benefits of minimizing it. Methods: Transfer latency was measured as the time between the first transfer request and the actual ICU discharge at a single-center tertiary hospital in 2021. Computer-based simulations and cost analyses were performed to examine how reducing transfer latency could affect average hourly ICU bed occupancy, the proportion of time ICU occupancy exceeds 80%, and hospital costs. The first analysis evaluated all ICU admissions, and the second analysis targeted a subset of ICU admissions with longer transfer latency, those requiring infectious precautions. Results: A total of 7,623 ICU admissions were analyzed, and the median transfer latency was 5.7 hours. Eliminating transfer latency for all ICU admissions would have resulted in a 32.8% point decrease in the proportion of time ICU occupancy exceeded 80%, and a potential annual savings of $6.18 million. Eliminating transfer latency for patients under infectious precautions would have decreased the time ICU occupancy exceeded 80% by 13.5% points, and reduced annual costs by a potential $1.26 million. Conclusions Transfer latency from ICUs to general wards might contribute to high ICU occupancy. Efforts to minimize latency for all admissions, or even for a subset of admissions with particularly long transfer latency, could enable more efficient use of ICU resources.

Background: Acute deterioration of patients in general wards often leads to major adverse events (MAEs), including unplanned intensive care unit transfers, cardiac arrest, or death. Traditional early warning scores (EWSs) have shown limited predictive accuracy, with frequent false positives. We conducted a prospective observational external validation study of an artificial intelligence (AI)-based EWS, the VitalCare - Major Adverse Event Score (VC-MAES), at a tertiary medical center in the Republic of Korea. Methods: Adult patients from general wards, including internal medicine (IM) and obstetrics and gynecology (OBGYN)—the latter were rarely investigated in prior AI-based EWS studies—were included. The VC-MAES predictions were compared with National Early Warning Score (NEWS) and Modified Early Warning Score (MEWS) predictions using the area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC), and logistic regression for baseline EWS values. False-positives per true positive (FPpTP) were assessed based on the power threshold. Results: Of 6,039 encounters, 217 (3.6%) had MAEs (IM: 9.5%, OBGYN: 0.26%). Six hours prior to MAEs, the VC-MAES achieved an AUROC of 0.918 and an AUPRC of 0.352, including the OBGYN subgroup (AUROC, 0.964; AUPRC, 0.388), outperforming the NEWS (0.797 and 0.124) and MEWS (0.722 and 0.079). The FPpTP was reduced by up to 71%. Baseline VC-MAES was strongly associated with MAEs (P<0.001). Conclusions The VC-MAES significantly outperformed traditional EWSs in predicting adverse events in general ward patients. The robust performance and lower FPpTP suggest that broader adoption of the VC-MAES may improve clinical efficiency and resource allocation in general wards.

Background: TP53 mutations are associated with poor prognosis in myelodysplastic neoplasm (MDS) and AML. The updated 5th WHO classification and International Consensus Classification (ICC) categorize TP53-mutated MDS and AML as unique entities. We conducted a multicenter study in Korea to investigate the characteristics of TP53-mutated MDS and AML, focusing on diagnostic aspects based on updated classifications. Methods: This study included patients aged ≥ 18 yrs who were diagnosed as having MDS(N = 1,244) or AML (N = 2,115) at six institutions. The results of bone marrow examination, cytogenetic studies, and targeted next-generation sequencing, including TP53, were collected and analyzed. Results: TP53 mutations were detected in 9.3% and 9.2% of patients with MDS and AML, respectively. Missense mutation was the most common, with hotspot codons R248/ R273/G245/Y220/R175/C238 accounting for 25.4% of TP53 mutations. Ten percent of patients had multiple TP53 mutations, and 78.4% had a complex karyotype. The median variant allele frequency (VAF) of TP53 mutations was 41.5%, with a notable difference according to the presence of a complex karyotype. According to the 5th WHO classification and ICC, the multi-hit TP53 mutation criteria were met in 58.6% and 75% of MDS patients, respectively, and the primary determinants were a TP53 VAF > 50% for the 5th WHO classification and the presence of a complex karyotype for the ICC. Conclusions Collectively, we elucidated the molecular genetic characteristics of patients with TP53-mutated MDS and AML, highlighting key factors in applying TP53 mutation-related criteria in updated classifications, which will aid in establishing diagnostic strategies.

Background: Ensuring reference material (RM) commutability is crucial for evaluating measurement traceability in order to standardize laboratory tests. However, commutability assessment is not routinely performed. We assessed whether RMs prepared following CLSI C37-A guidelines could be used without assessing commutability by evaluating their commutability for four lipid measurements using the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and CLSI EP14 protocols. Methods: We analyzed total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in frozen sera from 20 individuals and 11 RMs, prepared by the Korea Disease Control and Prevention AgencyLaboratory Standardization Project (per CLSI C37-A), using six routine measurement procedures (MPs). Regression equations and 95% prediction intervals derived from single-donor sera were analyzed following CLSI EP14. The IFCC protocol was used to assess differences in inter-MP biases between RM and clinical samples. The effect of the TG concentration on commutability was evaluated by analyzing biases between MP results and reference procedure-assigned values. Results: RMs were commutable for most MP pairs for TC and TG. Commutability for HDL-C and LDL-C varied across RMs, with RM10 and RM11 showing higher TG levels (2.38 and 2.95 mmol/L, respectively) and lower commutability. Increased bias percentages from assigned values were observed for RMs with higher TG levels. Conclusions RMs prepared per CLSI C37-A were commutable with most MP pairs for TC and TG. Elevated TG levels affected HDL-C and LDL-C commutability, highlighting the need to consider TG concentrations during RM preparation and assess commutability to standardize laboratory tests.

Background: An international reference measurement laboratory network for creatinine (Cr) is lacking; therefore, Korea developed an independent evaluation and certification system. The in vitro diagnostics (IVD) certification program, launched in 2017, formed part of a broader Cr standardization initiative intended to enhance accuracy at the manufacturing stage. Methods: The program was designed to evaluate analytical systems, including all reagent lots, calibrators, and instrument models, twice annually. Bias, imprecision, total error (TE), and linearity were evaluated based on established acceptance criteria. A post-certification process allows submission for a second challenge and validation of corrective actions. Results: Between 2017 and 2023, 489 analytical systems were evaluated. Average acceptance rates for bias, imprecision, TE, and linearity were 70.8%, 95.9%, 87.7%, and 87.8%, respectively. The lowest acceptance rate for bias evaluation was 8.7% for the kinetic Jaffe method without compensation in 2018. Over the 7-year period, the mean absolute percentage bias (absBias%), coefficient of variation (CV), and TE were 4.62%, 1.37%,and 7.29%, respectively. The highest absBias% (7.94%) was observed in the 0.0 ≤ Cr < 1.0target value range. Since 2019, a consistent reduction in absBias% has been observed. Conclusions This program is a pioneering response to the absence of a global certification program for Cr assays. It offers significant advantages, including comprehensive evaluations, fee-free participation, and a robust post-certification process. Continuous participation and improvement efforts by manufacturers have contributed to enhanced accuracy in Cr assays.

Purpose: This study investigated the impact of nusinersen on health-related quality of life (HRQoL), functional performance, and caregiver burden in patients with infantile-onset spinal muscular atrophy (SMA), addressing a growing interest in disease-modifying treatments. Methods: A 14-month observational study was conducted to evaluate changes in HRQoL and functional performance using the Pediatric Quality of Life Inventory (PedsQL) Infant Scales and the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT). Caregiver burden was assessed through the Assessment of Caregiver Experience with Neuromuscular Disease (ACEND). Motor function was evaluated using the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Correlations between CHOP INTEND scores, functional performance, and caregiver burden were analyzed. Results: Eight patients with infantile-onset SMA and their caregivers participated, with a median treatment initiation age of 4.6 months (range, 1.1 to 15.1). CHOP INTEND scores showed significant improvement (P<0.001), whereas all PedsQL Infant Scale scores declined. Conversely, the PEDI-CAT revealed significant enhancements in daily activities, mobility, and social-cognitive domains (all P<0.001). Caregiver burden lessened across most dimensions (P<0.001), with the exception of the time-related burden (P=0.731). Higher CHOP INTEND scores correlated with improvements in PEDI-CAT domains and a reduction in caregiver burden related to sitting/play and transfer activities. Conclusion The study demonstrates the positive effects of nusinersen on functional performance and caregiver burden in patients with infantile-onset SMA. However, discrepancies were observed in HRQoL outcomes, suggesting a need for further research that includes SMA-specific outcome measures to comprehensively assess the treatment's impact on patients' lives.

Purpose: This study aimed to develop a comprehensive practical guide for enteral nutrition (EN) designed to enhance patient safety and reduce complications in Korea. Under the leadership of the Korean Society for Parenteral and Enteral Nutrition (KSPEN), the initiative sought to standardize EN procedures, improve decision-making, and promote effective multidisciplinary communication. Methods: The KSPEN EN committee identified key questions related to EN practices and organized them into seven sections such as prescribing, delivery route selection, formula preparation, administration, and quality management. Twenty-one experts, selected based on their expertise, conducted a thorough literature review to formulate evidence-based recommendations. Drafts underwent peer review both within and across disciplines, with final revisions completed by the KSPEN Guideline Committee. The guide, which will be published in three installments, addresses critical elements of EN therapy and safety protocols. Results: The practical guide recommends that EN orders include detailed elements and advocates the use of electronic medical records for communication. Standardized prescription forms and supplementary safety measures are outlined. Review frequency is adjusted according to patient condition—daily for critically ill or unstable patients and as dictated by institutional protocols for stable patients. Evidence indicates that adherence to these protocols reduces mortality, complications, and prescription errors. Conclusion The KSPEN practical guide offers a robust framework for the safe delivery of EN tailored to Korea’s healthcare context. It emphasizes standardized protocols and interdisciplinary collaboration to improve nutritional outcomes, patient safety, and operational efficiency. Rigorous implementation and monitoring of adherence are critical for its success.

Purpose: This study investigated the impact of nusinersen on health-related quality of life (HRQoL), functional performance, and caregiver burden in patients with infantile-onset spinal muscular atrophy (SMA), addressing a growing interest in disease-modifying treatments. Methods: A 14-month observational study was conducted to evaluate changes in HRQoL and functional performance using the Pediatric Quality of Life Inventory (PedsQL) Infant Scales and the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT). Caregiver burden was assessed through the Assessment of Caregiver Experience with Neuromuscular Disease (ACEND). Motor function was evaluated using the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Correlations between CHOP INTEND scores, functional performance, and caregiver burden were analyzed. Results: Eight patients with infantile-onset SMA and their caregivers participated, with a median treatment initiation age of 4.6 months (range, 1.1 to 15.1). CHOP INTEND scores showed significant improvement (P<0.001), whereas all PedsQL Infant Scale scores declined. Conversely, the PEDI-CAT revealed significant enhancements in daily activities, mobility, and social-cognitive domains (all P<0.001). Caregiver burden lessened across most dimensions (P<0.001), with the exception of the time-related burden (P=0.731). Higher CHOP INTEND scores correlated with improvements in PEDI-CAT domains and a reduction in caregiver burden related to sitting/play and transfer activities. Conclusion The study demonstrates the positive effects of nusinersen on functional performance and caregiver burden in patients with infantile-onset SMA. However, discrepancies were observed in HRQoL outcomes, suggesting a need for further research that includes SMA-specific outcome measures to comprehensively assess the treatment's impact on patients' lives.