Transition database for rare diseases and its use for clinical documentation.

Patients with rare diseases commonly suffer from severe symptoms as well as chronic and sometimes life-threatening effects. Not only the rarity of the diseases but also the poor documentation of rare diseases often leads to an immense delay in diagnosis. One of the main problems here is the inadequate coding with common classifications such as the International Statistical Classification of Diseases and Related Health Problems. Instead, the ORPHAcode enables precise naming of the diseases. So far, just few approaches report in detail how the technical implementation of the ORPHAcode is done in clinical practice and for research. We present a concept and implementation of storing and mapping of ORPHAcodes. The Transition Database for Rare Diseases contains all the information of the Orphanet catalog and serves as the basis for documentation in the clinical information system as well as for monitoring Key Performance Indicators for rare diseases at the hospital. The five-step process (especially using open source tools and the DataVault 2.0 logic) for set-up the Transition Database allows the approach to be adapted to local conditions as well as to be extended for additional terminologies and ontologies.

A scoping review of the toxicity and health impact of IQOS.

This work aims to summarize the current evidence on the toxicity and health impact of IQOS, taking into consideration the data source. On 1 June 2022, we searched PubMed, Web of Science, and Scopus databases using the terms: 'heated tobacco product', 'heat-not-burn', 'IQOS', and 'tobacco heating system'. The search was time-restricted to update a previous search conducted on 8 November 2021, on IQOS data from 2010-2021. The data source [independent, Philip Morris International (PMI), or other manufacturers] was retrieved from relevant sections of each publication. Publications were categorized into two general categories: 1) Toxicity assessments included in vitro, in vivo, and systems toxicology studies; and 2) The impact on human health included clinical studies assessing biomarkers of exposure and biomarkers of health effects. Generally, independent studies used classical in vitro and in vivo approaches, but PMI studies combined these with modeling of gene expression (i.e. systems toxicology). Toxicity assessment and health impact studies covered pulmonary, cardiovascular, and other systemic toxicity. PMI studies overall showed reduced toxicity and health risks of IQOS compared to cigarettes, but independent data did not always conform with this conclusion. This review highlights some discrepancies in IQOS risk assessment regarding methods, depth, and breadth of data collection, as well as conclusions based on the data source.

Sex-related DNA methylation is associated with inflammation and gene expression in the lungs of healthy individuals.

Lung cancer exhibits sex-biased molecular characteristics and epidemiological trends, suggesting a need for sex-specific approaches to understanding its etiology and treatment. DNA methylation alterations play critical roles in lung carcinogenesis and may serve as valuable biomarkers for precision medicine strategies. We employed the Infinium MethylationEPIC array to identify autosomal sex-related differentially methylated CpG sites (DM-CpGs) in lung epithelium of healthy individuals (32 females and 37 males) while controlling for age, BMI, and tobacco use. We correlated DM-CpGs with gene expression in lung epithelium and immune responses in bronchoalveolar lavage. We validated these DM-CpGs in lung tumors and adjacent normal tissue from The Cancer Genome Atlas (TCGA). Among 522 identified DM-CpGs, 61% were hypermethylated in females, predominantly located in promoter regions. These DM genes were implicated in cell-to-cell signaling, cellular function, transport, and lipid metabolism. Correlation analysis revealed sex-specific patterns between DM-CpGs and gene expression. Additionally, several DM-CpGs were correlated significantly with cytokines (IL-1ß, IL-4, IL-12p70, and IFN-γ), macrophage, and lymphocyte counts. Also, some DM-CpGs were observed in TCGA lung adenocarcinoma, squamous cell carcinoma, and adjacent normal tissues. Our findings highlight sex-specific DNA methylation patterns in healthy lung epithelium and their associations with lung gene expression and lung immune biomarkers. These findings underscore the potential role of lung sex-related CpGs as epigenetic predispositions influencing sex disparities in lung cancer risk and outcomes, warranting further investigation for personalized lung cancer management strategies.

Variable Syndromic Immunodeficiency in Patients with Biallelic PRIM1 Mutations.

Mutations in genes of the DNA polymerase complex have been linked to impaired immunological function next to distinct syndromic features. Biallelic mutations in PRIM1 are associated with a primordial dwarfism syndrome with variable hypogammaglobulinemia. The disease is mostly lethal in infancy due to pulmonary infections as well as hepatic cirrhosis. We studied 3 novel patients with PRIM1-deficiency with a focus on immunological consequences. All three shared dysmorphic features including a prominent forehead, triangular face and bilateral cryptorchidism. P1 carried the novel homozygous PRIM1 splice variant c.103+2T>G, allowing residual protein expression and associated with a mild clinical phenotype. P2 and P3 carried the known homozygous variant c.638+36C>G and died in infancy. Paradoxically, B cell lymphopenia was most pronounced in P1. No other significant lymphocyte abnormalities were detected. Interestingly, all 3 patients showed variable, but intermittently excessive Type I interferon signatures. In summary, the B-cell deficiency in PRIM1-deficiency is markedly variable and the severity of syndromic manifestations is not predictive of the immunological phenotype. We highlight a potential contribution of pathological type I interferon activation to disease pathogenesis which warrants further investigations.

Aberrant RNA sensing in regulatory T cells causes systemic autoimmunity.

Chronic and aberrant nucleic acid sensing causes type I IFN-driven autoimmune diseases, designated type I interferonopathies. We found a significant reduction of regulatory T cells (Tregs) in patients with type I interferonopathies caused by mutations in ADAR1 or IFIH1 (encoding MDA5). We analyzed the underlying mechanisms using murine models and found that Treg-specific deletion of Adar1 caused peripheral Treg loss and scurfy-like lethal autoimmune disorders. Similarly, knock-in mice with Treg-specific expression of an MDA5 gain-of-function mutant caused apoptosis of peripheral Tregs and severe autoimmunity. Moreover, the impact of ADAR1 deficiency on Tregs is multifaceted, involving both MDA5 and PKR sensing. Together, our results highlight the dysregulation of Treg homeostasis by intrinsic aberrant RNA sensing as a potential determinant for type I interferonopathies.

A rare manifestation of STING-associated vasculopathy with onset in infancy: a case report.

BACKGROUND: STING-associated vasculopathy with onset in infancy (SAVI) is a rare type I interferonopathy caused by heterozygous variants in the STING gene. In SAVI, STING variants confer a gain-of-function which causes overactivation of type I interferon (IFN) signaling leading to autoinflammation and various degrees of immunodeficiency and autoimmunity. CASE PRESENTATION: We report the case of a 5 year old child and his mother, both of whom presented with systemic inflammatory symptoms yet widely varying organ involvement, disease course and therapeutic response. Genetic testing revealed a heterozygous STING variant, R281Q, in the child and his mother that had previously been associated with SAVI. However, in contrast to previously reported SAVI cases due to the R281Q variant, our patients showed an atypical course of disease with alopecia totalis in the child and a complete lack of lung involvement in the mother. CONCLUSIONS: Our findings demonstrate the phenotypic breadth of clinical SAVI manifestations. Given the therapeutic benefit of treatment with JAK inhibitors, early genetic testing for SAVI should be considered in patients with unclear systemic inflammation involving cutaneous, pulmonary, or musculoskeletal symptoms, and signs of immunodeficiency and autoimmunity.

Absence of Type I Interferon Autoantibodies or Significant Interferon Signature Alterations in Adults With Post-COVID-19 Syndrome.

Genetic defects in the interferon (IFN) system or neutralizing autoantibodies against type I IFNs contribute to severe COVID-19. Such autoantibodies were proposed to affect post-COVID-19 syndrome (PCS), possibly causing persistent fatigue for >12 weeks after confirmed SARS-CoV-2 infection. In the current study, we investigated 128 patients with PCS, 21 survivors of severe COVID-19, and 38 individuals who were asymptomatic. We checked for autoantibodies against IFN-α, IFN-ß, and IFN-ω. Few patients with PCS had autoantibodies against IFNs but with no neutralizing activity, indicating a limited role of type I IFNs in PCS pathogenesis. In a subset consisting of 28 patients with PCS, we evaluated IFN-stimulated gene activity and showed that it did not correlate with fatigue. In conclusion, impairment of the type I IFN system is unlikely responsible for adult PCS.

Disrupted degradative sorting of TLR7 is associated with human lupus.

Hyperactive TLR7 signaling has long been appreciated as driver of autoimmune disease in mouse models. Recently, gain-of-function mutations in TLR7 were identified as a monogenic cause of human lupus. TLR7 is an intracellular transmembrane receptor, sensing RNA breakdown products within late endosomes. Here, we show that endosome dysfunction leads to unrestricted TLR7 signaling and is associated with human lupus. The late endosomal BORC complex together with the small GTPase Arl8b controls intracellular TLR7 levels by regulating receptor turnover. This requires a direct interaction between the TLR7-associated trafficking factor Unc93b1 and Arl8b. We identified an UNC93B1 mutation in a patient with childhood-onset lupus, which results in reduced BORC interaction and endosomal TLR7 accumulation. Therefore, a failure to control TLR7 turnover is sufficient to break immunological tolerance to nucleic acids. Our results highlight the importance of an intact endomembrane system in preventing pathological TLR7 signaling and autoimmune disease.

UNC93B1 variants underlie TLR7-dependent autoimmunity.

UNC93B1 is critical for trafficking and function of nucleic acid-sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self-nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype-specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.

Tissue factor binds to and inhibits interferon-α receptor 1 signaling.

Tissue factor (TF), which is a member of the cytokine receptor family, promotes coagulation and coagulation-dependent inflammation. TF also exerts protective effects through unknown mechanisms. Here, we showed that TF bound to interferon-α receptor 1 (IFNAR1) and antagonized its signaling, preventing spontaneous sterile inflammation and maintaining immune homeostasis. Structural modeling and direct binding studies revealed binding of the TF C-terminal fibronectin III domain to IFNAR1, which restricted the expression of interferon-stimulated genes (ISGs). Podocyte-specific loss of TF in mice (PodΔF3) resulted in sterile renal inflammation, characterized by JAK/STAT signaling, proinflammatory cytokine expression, disrupted immune homeostasis, and glomerulopathy. Inhibiting IFNAR1 signaling or loss of Ifnar1 expression in podocytes attenuated these effects in PodΔF3 mice. As a heteromer, TF and IFNAR1 were both inactive, while dissociation of the TF-IFNAR1 heteromer promoted TF activity and IFNAR1 signaling. These data suggest that the TF-IFNAR1 heteromer is a molecular switch that controls thrombo-inflammation.

Uncommon Mechanism of Mangled Extremity; Three Cases of Rope Entanglement Injury of the Lower Leg

Rope entanglement injury is a rare entity. Previous reported studies mainly consisted of finger-related injuries. We describe three cases of rope entanglement injury of the lower leg. In the first patient, a belowthe- knee amputation was performed as the primary treatment for unilateral amputated lower limb. In the second patient, a below-the-knee amputation and perineal wound management were simultaneously performed. The third patient had vascular injury combined with internal soft tissue injury without related bone fracture. He suffered serious sequelae from a delay in transfer from a local hospital. Rope entanglement injuries of the lower leg do not present in a consistent manner, and the treatment of accompanying injuries should be considered from an early stage. Care should be taken to ensure that there are no internal injuries missed because the exterior appears to be stable.

Impact of Angiotensin Receptor Blockers, Beta Blockers,Calcium Channel Blockers and Thiazide Diuretics on Survivalof Ovarian Cancer Patients / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#We investigated the impact of four types of antihypertensive medications, angiotensinreceptor blockers (ARBs), beta blockers (BBs; both selective and non-selective), calciumchannel blockers (CCBs), and thiazide diuretics (TDs) on survival outcomes in epithelial ovariancancer (EOC). @*Materials and Methods@#A single-institutional retrospective chart review of 878 patients with EOC was performed.Survival was compared according to use of the four antihypertensive medications duringprimary treatment. Propensity score matching (ratio 1:3) was performed to control possibleassociated covariates, such as age, International Federation of Gynecology and Obstetricsstage, residual status after primary debulking surgery, and co-morbidity. @*Results@#Among 878 patients, 56 patients (6.4%) were ARB users, 62 (7.1%) were BB users, 107(12.2%) were CCBs users and 32 (3.6%) used TDs. Median progression-free survival (PFS)for ARB, BB, and CCB users was 37.8, 27.2, and 23.6 months compared with 33.6 monthsfor non-users. ARB was associated with 35% decreased risk of disease progression (hazardratio [HR], 0.65; 95% confidence interval [CI], 0.42 to 0.99; p=0.046) in multivariate analysis.After propensity score matching, median PFS for ARB users was 37.8 months and ARBuse remained to be associated with lower recurrence rate in univariate (p=0.035) and multivariateanalysis (HR, 0.60; 95% CI, 0.39 to 0.93; p=0.022). @*Conclusion@#In this study, ARBs use during primary treatment is associated with lower recurrence in EOCpatients. However, CCBs, BBs, and TDs did not show beneficial impact.

Antibiotic use in patients with abdominal injuries: guideline by the Korean Society of Acute Care Surgery

PURPOSE: A task force appointed by the Korean Society of Acute Care Surgery reviewed previously published guidelines on antibiotic use in patients with abdominal injuries and adapted guidelines for Korea. METHODS: Four guidelines were assessed using the Appraisal of Guidelines for Research and Evaluation II instrument. Five topics were considered: indication for antibiotics, time until first antibiotic use, antibiotic therapy duration, appropriate antibiotics, and antibiotic use in abdominal trauma patients with hemorrhagic shock. RESULTS: Patients requiring surgery need preoperative prophylactic antibiotics. Patients who do not require surgery do not need antibiotics. Antibiotics should be administered as soon as possible after injury. In the absence of hollow viscus injury, no additional antibiotic doses are needed. If hollow viscus injury is repaired within 12 hours, antibiotics should be continued for ≤ 24 hours. If hollow viscus injury is repaired after 12 hours, antibiotics should be limited to 7 days. Antibiotics can be administered for ≥7 days if hollow viscus injury is incompletely repaired or clinical signs persist. Broad-spectrum aerobic and anaerobic coverage antibiotics are preferred as the initial antibiotics. Second-generation cephalosporins are the recommended initial antibiotics. Third-generation cephalosporins are alternative choices. For hemorrhagic shock, the antibiotic dose may be increased twofold or threefold and repeated after transfusion of every 10 units of blood until there is no further blood loss. CONCLUSION: Although this guideline was drafted through adaptation of other guidelines, it may be meaningful in that it provides a consensus on the use of antibiotics in abdominal trauma patients in Korea.

Comparison of Quality of Life among Patients with Mangled Trauma

PURPOSE: Mangled injury is defined as severe injury, including three or more tissues such as bones, nerves, vessels, muscles, and tendons in the upper or lower extremities. The choice of treatment results in different cosmetic and functional outcomes for mangled injury. In this study, we estimated patients' quality of life after treatment with the future intention of having patients make proper decisions at the time of injury. METHODS: Twenty patients were treated at Asan Medical Center from January, 2009 to November, 2011, and 11 patients were included who agreed with the questionnaire. We used 36-item short form health survey (SF-36) for estimating quality of life after treatments. RESULTS: Subjective satisfaction of cosmetic and functional aspects was higher in the reconstruction group than in the amputation group. However, in the estimation of specified satisfaction using SF-36, the amputation group was more satisfied than the reconstruction group. CONCLUSION: Among the many treatment considerations at the time of injury, expected cosmetic and functional outcomes were important parts determining the decision. In our study, the amputation group showed a better satisfaction level. This result could help patients make more appropriate decisions in the case of mangled injury.

The Effect of Educational Intervention of Human Tissue Donation on Nurses' Knowledge, Attitudes and Self-efficacy / 한국간호교육학회지

PURPOSE: This study was conducted to examine the effects of an intervention program for human tissue donation with nurses, modified from the Korea Foundation for Human Tissue Donation, to promote human tissue donation via nurses' knowledge and attitudes toward human tissue donation, and self-efficacy for teaching tissue donation. METHODS: A non-equivalent control group quasi-experimental design was adopted, and data were collected from 82 nurses (41 of each group: experimental and comparison) working at a general hospital in Inchon, South Korea. RESULTS: In a multivariate analysis (MANOVA), the integrative effect on outcome variables from the intervention program was statistically significant (p<.001). Accordingly, an ANOVA was performed to determine which individual outcome variable showed a significant effect with intervention, and it was found that the effects of intervention on all the outcome variables (knowledge and attitude, and self-efficacy for teaching human tissue donation) were significant (p<.001). CONCLUSION: The results of the study showed that the intervention had positive effects on knowledge and attitudes toward tissue donation, and self-efficacy for teaching tissue donation among nurses. These outcome variables derived from the intervention might be essential for eliciting positive behavior toward human tissue donation.

Rapidly growing pediatric trampoline-related injuries in Korea: a 10-year single center retrospective study / 소아과

PURPOSE: Several published policy statements have warned against the risks associated with trampoline use and recommended safety guidelines. However, few studies have focused on trampoline-related injuries in Korea. This study aimed to assess the incidence and characteristics of pediatric trampoline-related injuries presented to Ulsan University Hospital. METHODS: We retrospectively reviewed the medical records of children aged <16 years with trampoline-related injuries who visited our Emergency Department between 2008 and 2017. RESULTS: Over the 10-year period, 178 trampoline-related injuries were reported, which represented a significant increase (P=0.016). Most (87.6%) of the injuries occurred during the last 5 study years, and a rapid increase in injuries was observed in children aged <6 years. Lower extremity injuries (62.4%) were the most common, followed by injuries of the upper extremities, head and face, and trunk, including injuries to the neck and spine. Sixty-seven children (37.6%) had fractures, and proximal tibia fractures were the most common. Fractures were significantly more common in younger children (<6 years old) than in older children (P=0.026). CONCLUSION: In Korea, the mechanism of trampoline injury is similar to that of injuries incurred in indoor trampoline parks but is characterized by smaller spaces and multiple users. Trampoline use and the incidence of trampoline-related injuries in children aged <6 years are increasing rapidly. Prohibiting the use of trampolines for children aged <6 years, restricting simultaneous use by multiple children, and ensuring adult supervision should be strictly emphasized. Public awareness and policy guidelines are needed to reduce the incidence of trampoline-related injuries.

Central Line-Associated Bloodstream Infection Prevention by Central Venous Catheter Management Staff in the Surgical Intensive Care Unit

PURPOSE: Patients in the intensive care unit (ICU) are more susceptible to nosocomial infections, including central line-associated bloodstream infection (CLABSI), surgical site infection, urinary tract infection or ventilator-associated pneumonia. This study is a comparative analysis of how central venous catheter (CVC) management staff affects CLABSI. METHODS: We performed a two-phase review of all patients transferred to the surgical ICU (SICU) from January 2013 to June 2014. CVC management staff was introduced in October 2013. Electronic medical records provided the data for a comparative analysis of incidence rates and risks of CLABSI, as well as the subjects' general characteristics. RESULTS: This study included 248 patients before the introduction of a CVC management staff member and 196 patients after the introduction. General patient characteristics before and after the CVC management staff was in place did not differ significantly. The CLABSI rate decreased by 4.61 cases/1,000 device days after the introduction (6.26 vs. 1.65; odds ratio, 4.47; 95% confidence interval, 1.39~14.37; p=0.009). However, the mortality rate and length of ICU stay did not change after CVC management staff was in place (12.9% vs. 10.7%, p=0.480; 16.00±24.89 vs. 15.87±18.80, p=0.954; respectively). CONCLUSION: In this study, the introduction of CVC management staff effectively reduced CLABSI rates in current ICU system.

The Role of Whole-Body Computed Tomography in Severely Injured Patients Retrospective Single Center Cohort Study

PURPOSE: To assess the effects of whole-body computed tomography (WBCT) on severely injured trauma patients. METHODS: After the installation of a WBCT scanner, we compared 48 patients who underwent the WBCT (WBCT cohort) with 40 patients prior to the WBCT (pre-WBCT cohort). We evaluated the number of CT, radiation exposure, time interval to decision and clinical outcomes such as length of intensive care unit stay, ventilation period, and acute kidney injury rates. RESULTS: In the WBCT cohort, the number of CT scans was significantly less (3.5 times) than in the pre-WBCT cohort (5.5 times; p<0.001). The radiation exposure was significantly lower in the WBCT cohort (24.5 mSv) than in the pre-WBCT cohort (31.3 mSv; p=0.040). The amount of radio-contrast used differed between the groups, but not significantly. Although there were fewer acute kidney injuries in the WBCT cohort (27.1%) than in pre-WBCT cohort (37.5%; p=0.296), especially severe injuries (stage 3 Acute Kidney Injury [AKI] Network: 17.5% in pre-WBCT vs. 6.3% in WBCT; p=0.059), the difference did not reach statistical significance. The hospital length of stay was significantly shorter in the WBCT cohort (21.42 days) than in the pre-WBCT cohort (32.38 days, p=0.019). However, there were no significant differences in the time interval to decision, intensive care unit stay, ventilation days, and mortality. CONCLUSION: The WBCT decreased the number of CT scans and subsequent less use of radio-contrast amount. It also tended to reduce severe AKI.

Posterior Reversible Encephalopathy Syndrome in a Critically Ill Postoperative Patient / 대한구급학회지

Posterior reversible encephalopathy syndrome (PRES) is a transient condition characterized by altered mental status, seizure, headache, and visual disturbance with typical neuro-imaging findings in the bilateral parieto-occipital regions. Clinicians should be aware of this syndrome because delayed diagnosis and treatment result in irreversible neurologic deficits. We present the case of a 77-year-old male diagnosed with PRES in the setting of postoperative critical illness caused by small-bowel strangulation.

Management of Cardiac Arrest following Anaphylactic Reaction to Cisatracurium Using Extracorporeal Membrane Oxygenation / 대한구급학회지

Anaphylactic reaction during the perioperative period typically exhibits rapid onset, varying clinical manifestations, and an expected mortality rate of 1.5-9%. Neuromuscular blocking agents are the leading cause of perioperative anaphylaxis. Here, we report a severe case of anaphylaxis that developed in a 66-year-old man due to cisatracurium administration. And he was successfully managed by extracorporeal membrane oxygenation. Cardiopulmonary resuscitation was performed by extracorporeal membrane oxygenation, and the patient was successfully weaned off 24 hours later.