Strategic combination of bacteriophages with highly susceptible cells for enhanced intestinal settlement and resistant cell killing.

Avian pathogenic Escherichia coli (APEC) causes enormous economic losses and is a primary contributor to the emergence of multidrug resistance (MDR)-related problems in the poultry industry. Bacteriophage (phage) therapy has been successful in controlling MDR, but phage-resistant variants have rapidly emerged through the horizontal transmission of diverse phage defense systems carried on mobile genetic elements. Consequently, while multiple phage cocktails are recommended for phage therapy, there is a growing need to explore simpler and more cost-effective phage treatment alternatives. In this study, we characterized two novel O78-specific APEC phages, φWAO78-1 and φHAO78-1, in terms of their morphology, genome, physicochemical stability and growth kinetics. Additionally, we assessed the susceptibility of thirty-two O78 APEC strains to these phages. We analyzed the roles of highly susceptible cells in intestinal settlement and fecal shedding (susceptible cell-assisted intestinal settlement and shedding, SAIS) of phages in chickens via coinoculation with phages. Furthermore, we evaluated a new strategy, susceptible cell-assisted resistant cell killing (SARK), by comparing phage susceptibility between resistant cells alone and a mixture of resistant and highly susceptible cells in vitro. As expected, high proportions of O78 APEC strains had already acquired multiple phage defense systems, exhibiting considerable resistance to φWAO78-1 and φHAO78-1. Coinoculation of highly susceptible cells with phages prolonged phage shedding in feces, and the coexistence of susceptible cells markedly increased the phage susceptibility of resistant cells. Therefore, the SAIS and SARK strategies were demonstrated to be promising both in vivo and in vitro.

Artificial Intelligence-Enhanced Neurocritical Care for Traumatic Brain Injury : Past, Present and Future.

In neurointensive care units (NICU), particularly in cases involving traumatic brain injury (TBI), swift and accurate decision-making is critical because of rapidly changing patient conditions and the risk of secondary brain injury. The use of artificial intelligence (AI) in NICU can enhance clinical decision support and provide valuable assistance in these complex scenarios. This article aims to provide a comprehensive review of the current status and future prospects of AI utilization in the NICU, along with the challenges that must be overcome to realize this. Presently, the primary application of AI in NICU is outcome prediction through the analysis of pre-admission and high-resolution data during admission. Recent applications include augmented neuromonitoring via signal quality control and real-time event prediction. In addition, AI can integrate data gathered from various measures and support minimally invasive neuromonitoring to increase patient safety. However, despite the recent surge in AI adoption within the NICU, the majority of AI applications have been limited to simple classification tasks, thus leaving the true potential of AI largely untapped. Emerging AI technologies, such as generalist medical AI and digital twins, harbor immense potential for enhancing advanced neurocritical care through broader AI applications. If challenges such as acquiring high-quality data and ethical issues are overcome, these new AI technologies can be clinically utilized in the actual NICU environment. Emphasizing the need for continuous research and development to maximize the potential of AI in the NICU, we anticipate that this will further enhance the efficiency and accuracy of TBI treatment within the NICU.

Effects of G and SH Truncation on the Replication, Virulence, and Immunogenicity of Avian Metapneumovirus.

Four mutants varying the length of the G and SH genes, including a G-truncated mutant (ΔG) and three G/SH-truncated mutants (ΔSH/G-1, ΔSH/G-2, and ΔSH/G-3), were generated via serially passaging the avian metapneumovirus strain SNU21004 into the cell lines Vero E6 and DF-1 and into embryonated chicken eggs. The mutant ΔG particles resembled parental virus particles except for the variance in the density of their surface projections. G and G/SH truncation significantly affected the viral replication in chickens' tracheal ring culture and in infected chickens but not in the Vero E6 cells. In experimentally infected chickens, mutant ΔG resulted in the restriction of viral replication and the attenuation of the virulence. The mutants ΔG and ΔSH/G-1 upregulated three interleukins (IL-6, IL-12, and IL-18) and three interferons (IFNα, IFNß, and IFNγ) in infected chickens. In addition, the expression levels of innate immunity-related genes such as Mda5, Rig-I, and Lgp2, in BALB/c mice were also upregulated when compared to the parental virus. Immunologically, the mutant ΔG induced a strong, delayed humoral immune response, while the mutant ΔSH/G-1 induced no humoral immune response. Our findings indicate the potential of the mutant ΔG but not the mutant ΔSH/G-1 as a live attenuated vaccine candidate.

Clinical Outcome of Patients with Poor-Grade Aneurysmal Subarachnoid Hemorrhage with Bundled Treatments: A Propensity Score-Matched Analysis.

BACKGROUND: Poor-grade aneurysmal subarachnoid hemorrhage (aSAH), defined as Hunt and Hess (HH) grades IV and V, is a challenging disease because of its high mortality and poor functional outcomes. The effectiveness of bundled treatments has been demonstrated in critical diseases. Therefore, poor-grade aSAH bundled treatments have been established. This study aims to evaluate whether bundled treatments can improve long-term outcomes and mortality in patients with poor-grade aSAH. METHODS: This is a comparative study using historical control from 2008 to 2022. Bundled treatments were introduced in 2017. We compared the rate of favorable outcomes (modified Rankin Scale score 0-2) at 6 months and mortality before and after the introduction of the bundled treatments. To eliminate confounding bias, the propensity score matching method was used. RESULTS: A total of 90 consecutive patients were evaluated. Forty-three patients received bundled treatments, and 47 patients received conventional care. The proportion of patients with HH grade V was higher in the bundle treatment group (41.9% vs. 27.7%). Conversely, the proportion of patients with fixed pupils on the initial examination was higher in the conventional group (30.2% vs. 38.3%). After 1:1 propensity score matching, 31 pairs were allocated to each group. The proportion of patients with 6-month favorable functional outcomes was significantly higher in the bundled treatments group (46.4% vs. 20.7%, p = 0.04). The 6-month mortality rate was 14.3% in the bundled treatments group and 27.3% in the conventional group (p = 0.01). Bundled treatments (odd ratio 14.6 [95% confidence interval 2.1-100.0], p < 0.01) and the presence of an initial pupil reflex (odd ratio 12.0 [95% confidence interval 1.4-104.6], p = 0.02) were significantly associated with a 6-month favorable functional outcome. CONCLUSIONS: The bundled treatments improve 6-month functional outcome and mortality in patients with poor-grade aSAH.

Tracing the Evolutionary Pathways of Serogroup O78 Avian Pathogenic Escherichia coli.

Avian pathogenic E. coli (APEC) causes severe economic losses in the poultry industry, and O78 serogroup APEC strains are prevalent in chickens. In this study, we aimed to understand the evolutionary pathways and relationships between O78 APEC and other E. coli strains. To trace these evolutionary pathways, we classified 3101 E. coli strains into 306 subgenotypes according to the numbers and types of single nucleotide polymorphisms (RST0 to RST63-1) relative to the consensus sequence (RST0) of the RNA polymerase beta subunit gene and performed network analysis. The E. coli strains showed four apparently different evolutionary pathways (I-1, I-2, I-3, and II). The thirty-two Korean O78 APEC strains tested in this study were classified into RST4-4 (45.2%), RST3-1 (32.3%), RST21-1 (12.9%), RST4-5 (3.2%), RST5-1 (3.2%), and RST12-6 (3.2%), and all RSTs except RST21-1 (I-2) may have evolved through the same evolutionary pathway (I-1). A comparative genomic study revealed the highest relatedness between O78 strains of the same RST in terms of genome sequence coverage/identity and the spacer sequences of CRISPRs. The early-appearing RST3-1 and RST4-4 prevalence among O78 APEC strains may reflect the early settlement of O78 E. coli in chickens, after which these bacteria accumulated virulence and antibiotic resistance genes to become APEC strains. The zoonotic risk of the conventional O78 APEC strains is low at present, but the appearance of genetically distinct and multiple virulence gene-bearing RST21-1 O78 APEC strains may alert us to a need to evaluate their virulence in chickens as well as their zoonotic risk.

Significant Reduction in External Ventricular Drain-Related Infections After Introducing a Novel Bundle Protocol: A Before and After Trial.

BACKGROUND: External ventricular drain (EVD)-related infection (ERI) is a serious complication in neurosurgical patients. The estimated ERI rates range from 5 to 20 cases per 1,000 EVD catheter days. The pathophysiology of ERI is similar to central line-associated bloodstream infections (CLABSIs) stemming from skin-derived bacterial colonization. The use of bundle management can reduce CLABSI rates. Due to the pathogenic similarities between infections related to the two devices, we developed and evaluated the effectiveness of an ERI-bundle protocol based on CLABSI bundles. METHODS: From November 2016 to November 2021, we conducted a study to evaluate the effectiveness of an ERI-bundle protocol. This study adopted a before-and-after trial, comparing the ERI rates for the 2 years before and 3 years after the introduction of the newly developed ERI-bundle protocol. We also analyzed the contributing factors to ERI using logistic regression analysis. RESULTS: A total of 183 patients with 2,381 days of catheter use were analyzed. The ERI rate decreased significantly after the ERI-bundle protocol from 16.7% (14 of 84; 14.35 per 1,000 catheter days) to 4.0% (4 of 99; 3.21 per 1,000 catheter days) (P = 0.004). CONCLUSION: Introduction of the ERI-bundle protocol was very effective in reducing ERI.

Protein Requirement Changes According to the Treatment Application in Neurocritical Patients.

Objective: Exploring protein requirements for critically ill patients has become prominent. On the other hand, considering the significant impact of coma therapy and targeted temperature management (TTM) on the brain as well as systemic metabolisms, protein requirements may plausibly be changed by treatment application. However, there is currently no research on protein requirements following the application of these treatments. Therefore, the aim of this study is to elucidate changes in patients' protein requirements during the application of TTM and coma therapy. Methods: This study is a retrospective analysis of prospectively collected data from March 2019 to May 2022. Among the patients admitted to the intensive care unit, those receiving coma therapy and TTM were included. The patient's treatment period was divided into two phases (Phase 1: application and maintenance of coma therapy and TTM; Phase 2: tapering and cessation of treatment). In assessing protein requirements, the Urine Urea Nitrogen (UUN) method was employed to estimate the nitrogen balance, offering insight into protein utilization within the body. The patient's protein requirement for each phase was defined as the amount of protein required to achieve a nitrogen balance within ±5, based on the 24-hour collection of UUN. Changes in protein requirements between phases were analyzed. Results: Out of 195 patients, 107 patients with a total of 214 UUN values were included. The mean protein requirement for the entire treatment period was 1.84 ± 0.62 g/kg/day, which is higher than the generally recommended protein supply of 1.2 g/kg/day. As the treatment was tapered, there was a statistically significant increase in the protein requirement from 1.49 ± 0.42 to 2.18 ± 0.60 in phase 2 (p < 0.001). Conclusion: Our study revealed a total average protein requirement of 1.84 ± 0.62g during the treatment period, which falls within the upper range of the preexisting guidelines. Nevertheless, a notable deviation emerged when analyzing the treatment application period separately. Hence, it is recommended to incorporate considerations for the type and timing of treatment, extending beyond the current guideline, which solely accounts for the 'severity by disease.

The Unique Relationship between Neuro-Critical Care and Critical Illness-Related Corticosteroid Insufficiency : Implications for Neurosurgeons in Neuro-Critical Care.

The brain houses vital hormonal regulatory structures such as the hypothalamus and pituitary gland, which may confer unique susceptibilities to critical illness-related corticosteroid insufficiency (CIRCI) in patients with neurological disorders. In addition, the frequent use of steroids for therapeutic purposes in various neurological conditions may lead to the development of steroid insufficiency. This abstract aims to highlight the significance of understanding these relationships in the context of patient care and management for physicians. Neurological disorders may predispose patients to CIRCI due to the role of the brain in hormonal regulation. Early recognition of CIRCI in the context of neurological diseases is essential to ensure prompt and appropriate intervention. Moreover, the frequent use of steroids for treating neurological conditions can contribute to the development of steroid insufficiency, further complicating the clinical picture. Physicians must be aware of these unique interactions and be prepared to evaluate and manage patients with CIRCI and steroid insufficiency in the context of neurological disorders. This includes timely diagnosis, appropriate steroid administration, and careful monitoring for potential adverse effects. A comprehensive understanding of the interplay between neurological disease, CIRCI, and steroid insufficiency is critical for optimizing patient care and outcomes in this complex patient population.

The effect of audiovisual feedback of monitor/defibrillators on percentage of appropriate compression depth and rate during cardiopulmonary resuscitation.

BACKGROUND: High quality cardiopulmonary resuscitation (CPR) is one of the key elements of the survival chain in cardiac arrest. Audiovisual feedback of chest compressions have been suggested to be beneficial by increasing the quality of CPR in the simulated cardiac arrests. METHODS: A prospective before and after study was performed to investigate the effect of a real-time audiovisual feedback system on CPR quality during in-hospital cardiac arrest in intensive care units from November 2018 to February 2022. In the feedback period, CPR was performed with the aid of the real-time audiovisual feedback system. The primary outcome was the percentage of compressions with both adequate depth (5.0-6.0 cm) and rate (100-120/minute). RESULTS: A total of 27,295 compressions in 30 cardiac arrests in the no-feedback period and 27,965 compressions in 30 arrests in the feedback period were analyzed. The percentage of compressions with both adequate depth and rate was 11.8% in the feedback period and 16.8% in the no-feedback period (P < 0.01). The percentage of compressions with adequate rate in the feedback period was lower than that in the no-feedback period (67.3% vs. 75.5%, P < 0.01). The percentage of beyond-target depth with the feedback was significantly higher than that without feedback (64.2% vs. 51.4%, P < 0.01). CONCLUSION: Real-time audiovisual feedback system did not increase CPR quality and was associated with a higher percentage of compression depth deeper than the recommended 5.0-6.0 cm. It is essential to explore more effective ways of implementing feedback in real clinical settings to improve of the quality of CPR. TRIAL REGISTRATION: NCT03902873 (study start: Nov. 2018, initial release April 2019, retrospectively registered).

Identification of bacterial pathogens in brain abscesses by metagenomic approach using nanopore 16S amplicon sequencing.

Brain abscess is medically challenging. In this study, we applied nanopore sequencing for 16S rRNA analysis and investigated its efficacy and diagnostic value for patients with brain abscesses. Genomic DNA was extracted from the pus samples (n = 27) of brain abscess, and 16S rRNA genes were amplified by PCR. Sequencing libraries were generated using a rapid barcoding kit, and the generated reads were analyzed using the EPI2ME16S workflow. A conventional culture study was performed. More sensitive identification of pathogens was made by 16S sequencing, faster than the culture study. The proportion of anaerobic bacteria identified by 16S sequencing was higher (75%) than that obtained by culturing (32%). Polymicrobial infections were identified in 10 cases (40%) by 16S sequencing, while the culture study identified multiple bacteria in only 2 cases (8%). 16S sequencing was useful for identifying the composition of polymicrobial infections, including rare pathogens, and for the initial diagnosis of space-occupying lesions.

Receptor binding motif surrounding sites in the spike 1 protein of infectious bronchitis virus have high susceptibility to mutation related to selective pressure.

BACKGROUND: To date, various genotypes of infectious bronchitis virus (IBV) have co-circulated and in Korea, GI-15 and GI-19 lineages were prevailing. The spike protein, particularly S1 subunit, is responsible for receptor binding, contains hypervariable regions and is also responsible for the emerging of novel variants. OBJECTIVE: This study aims to investigate the putative major amino acid substitutions for the variants in GI-19. METHODS: The S1 sequence data of IBV isolated from 1986 to 2021 in Korea (n = 188) were analyzed. Sequence alignments were carried out using Multiple alignment using Fast Fourier Transform of Geneious prime. The phylogenetic tree was generated using MEGA-11 (ver. 11.0.10) and Bayesian analysis was performed by BEAST v1.10.4. Selective pressure was analyzed via online server Datamonkey. Highlights and visualization of putative critical amino acid were conducted by using PyMol software (version 2.3). RESULTS: Most (93.5%) belonged to the GI-19 lineage in Korea, and the GI-19 lineage was further divided into seven subgroups: KM91-like (Clade A and B), K40/09-like, QX-like (I-IV). Positive selection was identified at nine and six residues in S1 for KM91-like and QX-like IBVs, respectively. In addition, several positive selection sites of S1-NTD were indicated to have mutations at common locations even when new clades were generated. They were all located on the lateral surface of the quaternary structure of the S1 subunits in close proximity to the receptor-binding motif (RBM), putative RBM motif and neutralizing antigenic sites in S1. CONCLUSIONS: Our results suggest RBM surrounding sites in the S1 subunit of IBV are highly susceptible to mutation by selective pressure during evolution.

Long-Term Surgical Outcome of Indirect Bypass Surgery in Young Children With Moyamoya Disease.

BACKGROUND: The prognosis of moyamoya disease (MMD) in young children (younger than 4 years) is worse than that of older adults. The effectiveness of surgery is still inconclusive. OBJECTIVE: To evaluate long-term outcomes after indirect bypass in young children with MMD. METHODS: A total of 1417 MMD children underwent indirect bypass from August 1988 to October 2020. This study included 135 patients who were younger than 4 years at the time of surgery. The clinical features and surgical outcomes of these patients were assessed. We analyzed the long-term outcome of 102 children who were followed up for more than 5 years (mean: 18.8 years, range: 5-27.3 years). Cross-sectional analysis was performed to evaluate overall outcomes based on the Lansky Play Performance Scale (LPS). The annual risk of symptomatic stroke after surgery was calculated with a person-year method, and the event-free survival rate was evaluated using the Kaplan-Meier method. RESULTS: The overall clinical outcome was favorable (LPS ≥ 80) in 88% of the patients. The overall postoperative adverse event rate was 15%, including 1 death. At the last follow-up, 86% of patients who had seizures at diagnosis were seizure-free. During the follow-up, there were 3 symptomatic infarctions on the operated hemisphere (postoperative 3, 3, and 10 months each). There was no hemorrhagic event. The annual infarction rate was 0.16% per person-year. The 20-year event-free survival rates for symptomatic infarction were 97%. CONCLUSION: Indirect bypass could provide a satisfactory long-term outcome and prevent recurrent stroke in young children with MMD.

Nutrition Therapy for Patients With Traumatic Brain Injury: A Narrative Review.

Traumatic brain injury (TBI) is a global health and socio-economic problem, resulting in significant disability and mortality. Malnutrition is common in TBI patients and is associated with increased vulnerability to infection, higher morbidity and mortality rates, as well as longer stays in the intensive care unit and hospital. Following TBI, various pathophysiological mechanisms, such as hypermetabolism and hypercatabolism, affect patient outcomes. It is crucial to provide adequate nutrition therapy to prevent secondary brain damage and promote optimal recovery. This review includes a literature review and discusses the challenges encountered in clinical practice regarding nutrition in TBI patients. The focus is on determining energy requirements, timing and methods of nutrition delivery, promoting enteral tolerance, providing enteral nutrition to patients receiving vasopressors, and implementing trophic enteral nutrition. Enhancing our understanding of the current evidence regarding appropriate nutrition practices will contribute to improving overall outcomes for TBI patients.

Recent Updates on Controversies in Decompressive Craniectomy and Cranioplasty: Physiological Effect, Indication, Complication, and Management.

Decompressive craniectomy (DCE) and cranioplasty (CP) are surgical procedures used to manage elevated intracranial pressure (ICP) in various clinical scenarios, including ischemic stroke, hemorrhagic stroke, and traumatic brain injury. The physiological changes following DCE, such as cerebral blood flow, perfusion, brain tissue oxygenation, and autoregulation, are essential for understanding the benefits and limitations of these procedures. A comprehensive literature search was conducted to systematically review the recent updates in DCE and CP, focusing on the fundamentals of DCE for ICP reduction, indications for DCE, optimal sizes and timing for DCE and CP, the syndrome of trephined, and the debate on suboccipital CP. The review highlights the need for further research on hemodynamic and metabolic indicators following DCE, particularly in relation to the pressure reactivity index. It provides recommendations for early CP within three months of controlling increased ICP to facilitate neurological recovery. Additionally, the review emphasizes the importance of considering suboccipital CP in patients with persistent headaches, cerebrospinal fluid leakage, or cerebellar sag after suboccipital craniectomy. A better understanding of the physiological effects, indications, complications, and management strategies for DCE and CP to control elevated ICP will help optimize patient outcomes and improve the overall effectiveness of these procedures.

Optimizing Mannitol Use in Managing Increased Intracranial Pressure: A Comprehensive Review of Recent Research and Clinical Experiences.

Mannitol, derived from mannose sugar, is crucial in treating patients with elevated intracranial pressure (ICP). Its dehydrating properties at the cellular and tissue levels increase plasma osmotic pressure, which is studied for its potential to reduce ICP through osmotic diuresis. While clinical guidelines support mannitol use in these cases, the best approach for its application continues to be debated. Important aspects needing further investigation include: 1) bolus administration versus continuous infusion, 2) ICP-based dosing versus scheduled bolus, 3) identifying the optimal infusion rate, 4) determining the appropriate dosage, 5) establishing fluid replacement plans for urinary loss, and 6) selecting monitoring techniques and thresholds to assess effectiveness and ensure safety. Due to the lack of adequate high-quality prospective research data, a comprehensive review of recent studies and clinical trials is crucial. This assessment aims to bridge the knowledge gap, improve understanding of effective mannitol use in elevated ICP patients, and provide insights for future research. In conclusion, this review aspires to contribute to the ongoing discourse on mannitol application. By integrating the latest findings, this review will offer valuable insights into the function of mannitol in decreasing ICP, thereby informing better therapeutic approaches and enhancing patient outcomes.

Intracranial Pressure Monitoring for Acute Brain Injured Patients: When, How, What Should We Monitor.

While there is no level I recommendation for intracranial pressure (ICP) monitoring, it is typically indicated for patients with severe traumatic brain injury (TBI) with a Glasgow Coma Scale (GCS) score of 3-8 (class II). Even for moderate TBI patients with GCS 9-12, ICP monitoring should be considered for risk of increased ICP. The impact of ICP monitoring on patient outcomes is still not well-established, but recent studies reported a reduction of early mortality (class III) in TBI patients. There is no standard protocol for the application of ICP monitoring. In cases where cerebrospinal fluid drainage is required, an external ventricular drain is commonly used. In other cases, parenchymal ICP monitoring devices are generally employed. Subdural or non-invasive forms are not suitable for ICP monitoring. The mean value of ICP is the parameter recommended for observation in many guidelines. In TBI, values above 22 mmHg are associated with increased mortality. However, recent studies proposed various parameters including cumulative time with ICP above 20 mmHg (pressure-time dose), pressure reactivity index, ICP waveform characteristics (pulse amplitude of ICP, mean ICP wave amplitude), and the compensatory reserve of the brain (reserve-amplitude-pressure), which are useful in predicting patient outcomes and guiding treatment. Further research is required for validation of these parameters compared to simple ICP monitoring.

The Unique Relationship between Neuro-Critical Care and Critical Illness-Related Corticosteroid Insufficiency : Implications for Neurosurgeons in Neuro-Critical Care.

The brain houses vital hormonal regulatory structures such as the hypothalamus and pituitary gland, which may confer unique susceptibilities to critical illness-related corticosteroid insufficiency (CIRCI) in patients with neurological disorders. In addition, the frequent use of steroids for therapeutic purposes in various neurological conditions may lead to the development of steroid insufficiency. This abstract aims to highlight the significance of understanding these relationships in the context of patient care and management for physicians. Neurological disorders may predispose patients to CIRCI due to the role of the brain in hormonal regulation. Early recognition of CIRCI in the context of neurological diseases is essential to ensure prompt and appropriate intervention. Moreover, the frequent use of steroids for treating neurological conditions can contribute to the development of steroid insufficiency, further complicating the clinical picture. Physicians must be aware of these unique interactions and be prepared to evaluate and manage patients with CIRCI and steroid insufficiency in the context of neurological disorders. This includes timely diagnosis, appropriate steroid administration, and careful monitoring for potential adverse effects. A comprehensive understanding of the interplay between neurological disease, CIRCI, and steroid insufficiency is critical for optimizing patient care and outcomes in this complex patient population.

Genome-wide association study identifies novel susceptibilities to adult moyamoya disease.

Genome-wide association study has limited to discover single-nucleotide polymorphisms (SNPs) in several ethnicities. Here, we investigated an initial GWAS to identify genetic modifiers predicting with adult moyamoya disease (MMD) in Koreans. GWAS was performed in 216 patients with MMD and 296 controls using the large-scale Asian-specific Axiom Precision Medicine Research Array. A subsequent fine-mapping analysis was conducted to assess the causal variants associated with adult MMD. A total of 489,966 out of 802,688 SNPs were subjected to quality control analysis. Twenty-one SNPs reached a genome-wide significance threshold (p = 5 × 10-8) after pruning linkage disequilibrium (r2 < 0.8) and mis-clustered SNPs. Among these variants, the 17q25.3 region including TBC1D16, CCDC40, GAA, RNF213, and ENDOV genes was broadly associated with MMD (p = 3.1 × 10-20 to 4.2 × 10-8). Mutations in RNF213 including rs8082521 (Q1133K), rs10782008 (V1195M), rs9913636 (E1272Q), rs8074015 (D1331G), and rs9674961 (S2334N) showed a genome-wide significance (1.9 × 10-8 < p < 4.3 × 10-12) and were also replicated in the East-Asian populations. In subsequent analysis, RNF213 mutations were validated in a fine-mapping outcome (log10BF > 7). Most of the loci associated with MMD including 17q25.3 regions were detected with a statistical power greater than 80%. This study identifies several novel and known variations predicting adult MMD in Koreans. These findings may good biomarkers to evaluate MMD susceptibility and its clinical outcomes.

Prediction of Serious Intracranial Hypertension from Low-Resolution Neuromonitoring in Traumatic Brain Injury: An Explainable Machine Learning Approach.

There is a strong association between intracranial hypertension (IH) that occurs following the acute phase of traumatic brain injury (TBI) and negative outcomes. This study proposes a pressure-time dose (PTD)-based parameter that may specify a possible serious IH (SIH) event and develops a model to predict SIH. The minute-by-minute signals of arterial blood pressure (ABP) and intracranial pressure (ICP) of 117 TBI patients were utilized as the internal validation dataset. The SIH event was explored through the prognostic power of the IH event variables for the outcome after 6 months, and an IH event with thresholds that included an ICP of 20 mmHg and PTD > 130 mmHg * minutes was considered an SIH event. The physiological characteristics of normal, IH and SIH events were investigated. LightGBM was employed to forecast an SIH event from various time intervals using physiological parameters derived from the ABP and ICP. Training and validation were conducted on 1,921 SIH events. External validation was performed on two multi-center datasets containing 26 and 382 SIH events. The SIH parameters could be used to predict mortality (AUROC = 0.893, p < 0.001) and favorability (AUROC = 0.858, p < 0.001). The trained model robustly forecasted SIH after 5 and 480 minutes with an accuracy of 86.95% and 72.18% in internal validation. External validation also revealed a similar performance. This study demonstrated that the proposed SIH prediction model has reasonable predictive capacities. A future intervention study is required to investigate whether the definition of SIH is maintained in multi-center data and to ensure the effects of the predictive system on TBI patient outcomes at the bedside.