Search

Neurocritical care has emerged as a specialized field addressing the complex needs of patients with acute neurological disorders, such as stroke, brain tumor and traumatic brain injury. The clinical management of these patients necessitates precise, individualized nutritional support due to the significant variability in neurological deficits and resting energy expenditure (REE) based on factors including stroke phase, type (hemorrhagic or ischemic), and intracranial pressure and activity of neuronal cells. This emphasizes the need for accurate, patient-specific nutritional recommendations, achievable through indirect calorimetry. Traditional predictive equations may not accurately capture the diverse nutritional requirements of neurocritical patients. Indirect calorimetry offers a more reliable, personalized approach to determining patients' nutritional needs, crucial for this heterogeneous population. Furthermore, clinical practice often inadequately addresses nutritional needs in neurocritical patients, highlighting the importance of optimizing nutritional support to enhance patient outcomes. Indirect calorimetry also plays a critical role in assessing patients with non-normal body temperatures. Hypothermia affects the body's metabolic rate and overall energy expenditure, making it challenging to evaluate energy requirements during hypothermia treatment. Indirect calorimetry can provide more accurate assessments under such conditions. In conclusion, employing indirect calorimetry in neurocritical care is essential for accurate, individualized nutritional support. By accounting for factors such as stroke type, location, intracranial pressure and body temperature, indirect calorimetry offers valuable insights and improved patient care, emphasizing its indispensability in managing neurocritical patients.

Remote cerebellar hemorrhage (RCH) is a rare complication of neurosurgical procedures and is characterized by a typical bleeding pattern defined as the “zebra sign.” Only few cases of RCH have been reported in the English literature, and its pathophysiology remains unclear. In this report, we present the cases of three patients with RCH after three different procedures: burr-hole trephination and chronic subdural hematoma evacuation of bilateral cerebral convexity with subsequent subdural drain insertion, lumbar drainage for cerebrospinal fluid divergence for thoracic endovascular aortic repair, and combined bypass surgery for moyamoya disease.

Impaired cerebral autoregulation (CA) can cause negative outcomes in neurological conditions. Real-time CA monitoring can predict and thereby help prevent postoperative complications for neurosurgery patients, especially those suffering from moyamoya disease (MMD). We applied the concept of moving average to the correlation between mean arterial blood pressure (MBP) and cerebral oxygen saturation (SCO2) to monitor CA in real time, revealing optimal window size for the moving average. The experiment was conducted with 68 surgical vital-sign records containing MBP and SCO2. To evaluate CA, the cerebral oximetry index (COx) and coherence obtained from transfer function analysis (TFA) were calculated and compared between patients with postoperative infarction and those who without. For real-time monitoring, the moving average was applied to COx and coherence to determine the differences between groups, and the optimal moving-average window size was identified. The average COx and coherence within the very-low-frequency (VLF) range (0.02-0.07 Hz) during the entire surgery were significantly different between the groups (COx: AUROC = 0.78 , p = 0.003 ; coherence: AUROC = 0.69 , p = 0.029 ). For the case of real-time monitoring, COx showed a reasonable performance ( AUROC > 0.74 ) with moving-average window sizes larger than 30 minutes. Coherence showed an AUROC > 0.7 for time windows of up to 60 minutes; however, for windows larger than this threshold, the performance became unstable. With an appropriate window size, COx showed stable performance as a predictor of postoperative infarction in MMD patients.

Objective: Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating cerebrovascular event; patients are routinely admitted to the intensive care unit (ICU) for initial management. Because complications may be delayed, unplanned ICU readmissions can occur. Therefore, in this study we evaluate the rate of and factors associated with readmission after aSAH and identify if readmission is associated with poor clinical outcomes.Methods: We retrospectively reviewed the medical records of all patients receiving surgical or endovascular treatment for aSAH and admitted to the ICU between January 2008 and December 2019. We categorized patients by readmission and analyzed their clinical parameters.Results: Of the 345 patients who transferred to ward-level care after an initial ICU stay (Group 2), 27 (7.3%) were readmitted to the ICU (Group 1). History of hypertension (HTN), initial Glasgow Coma Scale (GCS) score, modified Fisher grade, and vasospasm therapy during first ICU stay were significantly different between the groups. The most common reason for readmission was delayed cerebral ischemia (DCI; 70.3%; OR 5.545; 95% CI 1.25−24.52; p=0.024). Comorbid HTN (OR 5.311; 95% CI 1.75−16.12; p=0.03) and vasospasm therapy during first ICU stay (OR 7.234; 95% CI 2.41−21.7; p＜0.01) also were associated with readmission. Readmitted patients had longer hospital stay and lower GCS scores at discharge (p＜0.01).Conclusions: DCI was the most common cause of ICU readmission in patients with aSAH. Readmission may indicate clinical deterioration, and patients who are at a high risk for DCI should be monitored to prevent readmission.

Humans may serve as a reservoir host of Staphylococcus aureus, resulting in transmission to animals. Previously, we used RNA polymerase beta subunit gene (rpoB)-based genotyping and classified S. aureus strains into rpoB sequence types (RSTs). According to our previous work, the predominant genotypes of S. aureus in humans and cows differ in Korea, but some predominant genotypes (RST4–1 and RST2–1) in humans have been isolated from bovine mastitis. Therefore, it needs to be determined whether some strains of the predominant human genotypes have adapted to or caused occasional infections in cows. We determined the whole genome sequences of 2 bovine mastitis-origin strains, PMB179 (RST4–1) and PMB196 (RST2–1), and performed comparative genomics with the corresponding RST4–1 and RST2–1 S. aureus strains in the NCBI database. We identified 257 and 180 pseudogenes among 131 RST4–1 and 54 RST2–1 strains, respectively, for the comparison of pseudogene profiles. RST4–1 strains shared more common pseudogenes than RST2–1 strains, and some epidemiologically related strains shared common pseudogenes. However, most of the pseudogenes were strain-specific, and diverse pseudogene profiles were apparent in both the RST4–1 and RST2–1 strains. Furthermore, analysis of the mobile genetic elements, virulence genes, and antibiotic resistance genes revealed no molecular markers to differentiate PMB179 and PMB196 from human strains. Interestingly, the collective comparison of RST4–1 or RST2–1 strains revealed cumulative acquisition steps of genomic islands and antibiotic resistance genes. In conclusion, our data support PMB179 and PMB196 causing occasional infections that result in bovine mastitis.

The treatment of complicated anterior cerebral artery aneurysms remains challenging. Here, the authors describe a case of ruptured complicated A3 aneurysm, which was treated with trapping and in-situ bypass. A 47-year-old man presented to the emergency department with severe headache and vomiting. Computed tomography illustrated acute intracerebral hemorrhage in the right frontal lobe. Digital subtraction angiography (DSA) confirmed a ruptured fusiform A3 aneurysm with lobulation and a daughter sac. Trapping of the ruptured fusiform A3 aneurysm and distal end-toside A4 anastomosis was performed. DSA on postoperative day 7 showed mild vasospasm to the afferent artery. However, 2 months later, DSA demonstrated that the antegrade flow through the anastomosis site had recovered. Thus, surgeons should be aware of the possibility of postsurgical vasospasm of anastomosed arteries, especially in cases of ruptured aneurysms.

Traumatic brain injury (TBI) is the leading cause of death and disability in children. Survivors of severe TBI are more susceptible to functional deficits, resulting in disability, poor quality of life, cognitive decline, and mental health problems. Despite this, little is known about the pathophysiology of TBI in children and how to manage it most effectively. Internationally, efforts are being made to expand knowledge of pathophysiology and develop practical clinical treatment recommendations to improve outcomes. Here we discuss recently updated evidence and management of severe pediatric TBI.

Cerebral herniation due to brain edema is the major cause of neurological worsening in patients suffering large hemispheric strokes. In this study, we investigated whether quantitative pupillary response could help identify the neurological worsening due to brain swelling in patients with large hemispheric strokes. Quantitative pupillary assessment using an automated pupillometer (NPi-100) was performed between April 2017 and August 2019 for patients suffering large hemispheric strokes. Consecutive pupillary responses were measured every 2 or 4 h as a part of routine clinical care. We compared the mean neurological pupil index (NPi) values, NPi value at the time of neurological deterioration, and percentage change in NPi from the immediate previous value between patients with and without neurological worsening. In this study, 2442 quantitative pupillary assessments were performed (n = 30; mean age, 67.9 years; males, 60.0%). Among the included patients, 10 (33.3%) experienced neurological worsening. Patients with neurological worsening had a significantly lower mean value of NPi and a sudden decrease in the NPi value as compared to those without neurological worsening during the whole monitoring period (3.88 ± 0.65 vs. 4.45 ± 0.46, P

Aims: A hospital outbreak of Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPN) linked with an index case of community-acquired infection occurred in an urban tertiary ...

Background To determine the effects of implementing a rapid response system (RRS) on code rates and in-hospital mortality in medical wards. Methods This retrospective study included adult patients admitted to medical wards at Seoul National University Hospital between July 12, 2016 and March 12, 2018; the sample comprised 4,224 patients admitted 10 months before RRS implementation and 4,168 patients admitted 10 months following RRS implementation. Our RRS only worked during the daytime (7 AM to 7 PM) on weekdays. We compared code rates and in-hospital mortality rates between the preintervention and postintervention groups. Results There were 62.3 RRS activations per 1,000 admissions. The most common reasons for RRS activation were tachypnea or hypopnea (44%), hypoxia (31%), and tachycardia or bradycardia (21%). Code rates from medical wards during RRS operating times significantly decreased from 3.55 to 0.96 per 1,000 admissions (adjusted odds ratio [aOR], 0.29; 95% confidence interval [CI], 0.10 to 0.87; P=0.028) after RRS implementation. However, code rates from medical wards during RRS nonoperating times did not differ between the preintervention and postintervention groups (2.60 vs. 3.12 per 1,000 admissions; aOR, 1.23; 95% CI, 0.55 to 2.76; P=0.614). In-hospital mortality significantly decreased from 56.3 to 42.7 per 1,000 admissions after RRS implementation (aOR, 0.79; 95% CI, 0.64 to 0.97; P=0.024). Conclusions Implementation of an RRS was associated with significant reductions in code rates during RRS operating times and in-hospital mortality in medical wards.

Encephaloduroarteriosynangiosis (EDAS) is a commonly used indirect revascularization operation method to treat pediatric patients with Moyamoya disease (MMD). Arachnoid dissection frequently has been performed during the EDAS operation to promote better revascularization. However, no studies have yet proven its surgical benefits. In this study, we investigated the impact of arachnoid preservation on the surgical outcome and postoperative complication by comparing pediatric patients with MMD who had the arachnoid membrane preserved during EDAS operation with those who had it dissected.This was a retrospective cohort study based on a single surgeon's experience at a single institution. A total of 206 pediatric patients with MMD who underwent EDAS operation at Seoul National University Children's Hospital were recruited for the study. We compared the surgical outcome and the postoperation complication rate of these 2 groups. Furthermore, risk factors for postoperative complication were analyzed.The overall clinical outcome (P = 0.342) and the extent of revascularization of middle cerebral artery territories (P = 0.736) were not different between the arachnoid dissection group and the arachnoid preservation group. However, the postoperative infarction/hemorrhage rate was significantly greater in the arachnoid dissection group (P = 0.005). Arachnoid dissection (P = 0.011) and young age (3 years old, P = 0.012) were significantly associated with increased risk of postoperative complications.Arachnoid preservation may help to reduce postoperative complications without decreasing the surgical outcome of EDAS. Furthermore, factors such as the patient's age should be taken into account when treating pediatric patients with MMD.

OBJECTIVE Complete exclusion of multiple unruptured intracranial aneurysms (UIAs) in one session of intervention may be ideal. However, such situations are not always feasible in terms of treatment modalities and outcomes. The authors aimed to analyze their experience with 1-stage clipping of multiple UIAs. METHODS Medical records between March 2013 and December 2018 were retrospectively reviewed, and 111 1-stage keyhole approaches in 110 patients with 261 multiple UIAs were ultimately included in this study. Clinical and radiological outcomes were analyzed, as well as postoperative complications up to 1 month after the surgery and their risk factors. RESULTS Keyhole approaches included unilateral supraorbital in 87 operations (78.4%), bilateral supraorbital in 12 (10.8%), and others in 12. The mean operative duration was 169.6 minutes (range 80–490 minutes). The highest numbers of aneurysms clipped at once were 2 (73.9%) and 3 (18.9%). Complete exclusion and residual neck of the clipped aneurysms were achieved in 89.3% and 7.3%, respectively. There was no significant difference between pre- and postoperative 1-month neurological states (p = 0.14). The permanent morbidity rate was 1.8% (n = 2), and there were no deaths. Postoperative transient neurological deterioration (TND) with no radiological and electrophysiological abnormalities occurred in 8 operations (7.2%). Hypertension was the only significant risk factor for postoperative TND (adjusted odds ratio 17.03, 95% confidence interval 1.99–2232.24, p = 0.01). CONCLUSIONS One-stage clipping of multiple UIAs via keyhole approaches showed satisfactory treatment outcomes with a low permanent morbidity. Patients with chronic hypertension had a high risk of postoperative TND.

Fowl typhoid is caused by Salmonella enterica serovar Gallinarum biovar Gallinarum (SG), and live attenuated, rough vaccine strains have been used. Both humoral and cellular immune responses are involved in protection, but the humoral responses to different forms of SG antigens are unclear. In this study, we compared humoral responses to a killed oil-emulsion (OE) smooth vaccine (SG002) and its rough mutant vaccine (SR2-N6) strains using proteomics techniques. We identified two immunogenic outer membrane proteins (OmpA and OmpX), and the selected linear epitopes were successfully applied in peptide-ELISA. Our peptide- and total OMP-ELISAs were used to compare the temporal humoral responses to various SG antigens: OE SG002 and SR2-N6; live, killed [PBS-suspension (PS) and OE)] and mixed (live and PS) formulations of another rough vaccine strain (SG 9R); and orally challenge with a field strain. Serum antibodies to the linear epitopes of OmpA and OmpX lasted only for the first 2 weeks, but serum antibodies against OMPs increased over time. The rough strain (SR2-N6) and mixed SG 9R induced higher serum antibody titers than the smooth strain (SG002) and single SG 9R (OE, live and PS SG 9R), respectively. Infection with the field strain delayed the serum antibody response by ~2 weeks. Mucosal immunity was not induced by any formulation, except for infection with the field strain after SG 9R vaccination. Thus, our results may be useful to understand humoral immunity against various SG antigens and to improve vaccine programs and serological diagnosis in the field.

Marked protein catabolism is common in critically ill patients. We hypothesized that optimal protein supplementation using nitrogen balance might be associated with better outcomes in the neurointensive care unit (NICU) patients. A total of 175 patients admitted to the NICU between July 2017 and December 2018 were included. Nitrogen balance was measured after NICU admission and measurements were repeated in 77 patients. The outcomes were compared according to initial nitrogen balance results and improvement of nitrogen balance on follow-up measurements. A total of 140 (80.0%) patients had a negative nitrogen balance on initial assessments. The negative balance group had more events of in-hospital mortality and poor functional outcome at three months. In follow-up measurement patients, 39 (50.6%) showed an improvement in nitrogen balance. The improvement group had fewer events of in-hospital mortality (p = 0.047) and poor functional outcomes (p = 0.046). Moreover, improvement of nitrogen balance was associated with a lower risk of poor functional outcomes (Odds ratio, 0.247, 95% confidence interval, 0.066&ndash, 0.925, p = 0.038). This study demonstrated that a significant proportion of patients in the NICU were under protein hypercatabolism. Moreover, an improvement in protein balance was related to improved outcomes in neurocritically ill patients. Further studies are needed to confirm the relationship between protein balance and outcomes.

Background Treatment options for a ruptured anterior communicating artery (ACoA) pseudoaneurysm are limited. In most cases trapping of the ACoA is the best treatment option. Occasionally, bypass surgery is warranted to ensure blood flow to the contralateral anterior cerebral artery (ACA) in cases with one dominant A1. We report a case of an ACoA pseudoaneurysm presenting with delayed subarachnoid hemorrhage following surgical clipping of an unruptured ACoA aneurysm, with a review of the literature. Case description A 74-year-old female had undergone surgical clipping of a 1.2-cm-sized unruptured ACoA aneurysm through the left supraorbital keyhole approach. During the operation, there had been a small tear between the aneurysm neck and the right proximal A2, and the tear point was controlled by clipping of the tear site. One month later, she was admitted again because of subarachnoid hemorrhage. Cerebral angiography showed a probable pseudoaneurysm from the previous tear site. The patient had a dominant left A1 with a right A1 aplasia. The pseudoaneurysm was treated with side-to-side bypass between the distal ACAs and subsequent trapping of the ACoA harboring a pseudoaneurysm. Both the distal ACAs were preserved; however, post-hemorrhagic neurological sequelae remained. Conclusions Side-to-side bypass between distal ACAs and surgical trapping of the ACoA for the ruptured ACoA pseudoaneurysm was a good rescue option to prevent rebleeding and preserve blood supply to the contralateral ACA territory.

BACKGROUND Antiplatelet premedication is widely accepted for interventional treatment of cerebral aneurysms to prevent thromboembolism. However, antiplatelet resistance sometimes limits the effectiveness of premedication. OBJECTIVE To compare 2 groups administered low-dose prasugrel (PSG group) or clopidogrel-based tailored antiplatelet (CPG group) in terms of platelet function and procedure-related complications. METHODS A total of 411 patients with 505 unruptured aneurysms who underwent endovascular treatment within the past 17 mo were retrospectively enrolled in this study. The PSG (225 patients with 277 aneurysms) and CPG groups (186 patients with 228 aneurysms) were administered the respective medication prior to endovascular treatment. We measure the response to the antiplatelet medication with a laboratory test. Episodes of periprocedural bleeding and thromboembolism were compared between the 2 groups. RESULTS There were significant differences between the 2 groups in terms of the mean P2Y12 reaction unit values (125.7 in the PSG group vs 251.0 in the CPG group; P

Objective Susceptibility artifacts from metal clips in magnetic resonance (MR) imaging present an obstacle to evaluating the status of clipped aneurysms, parent arteries, and adjacent brain parenchyma. We aimed to develop MR-compatible aneurysm clips. Methods Considering the mechanical and biologic properties, as well as MR compatibility of candidate materials, a prototype clip with a zirconia body and a polyurethane head spring (zirconia clip [ZC], straight, 9-mm long) was developed. The closing forces, opening width of blades, and in vitro and in vivo artifact volumes in 3 tesla MR imaging were compared among the prototype and commercial metal clips such as a Yasargil clip (YC, curved type, 8.3-mm long) and a Sugita clip (SC, straight type, 10-mm long). An in vivo animal study was performed with a canine venous pouch aneurysm model. Results The closing forces (N) at 1 mm and 8 mm from the blade tip were 2.09 and 3.77 in YC, 1.85 and 3.04 in SC, and 2.05 and 4.60 in ZC. The maximum opening widths (mm) was 6.8, 9.0, and 3.0 in YC, SC, and ZC, respectively. The in vitro artifact volumes of YC, SC, and ZC in time-of-flight MR imaging were 26.9, 29.7, and 1.9 times larger than the respective real volumes. The in vivo artifact volumes of YC, SC, and ZC were respectively 21.4, 29.4, and 2.6 times larger than real ones. Conclusions ZC showed the smallest susceptibility artifacts and satisfactory closing forces. However, the narrow opening width of the blades was a weak point.

Objective Cerebral varices (CVs) without an arteriovenous shunt, so called nonfistulous CVs, are very rare, and their etiology and natural course are not well understood. The aim of this study is to evaluate the clinical outcomes of nonfistulous CVs by the analysis of 39 cases. Methods From 2000 to 2015, 22 patients with 39 nonfistulous CVs (≥5 mm) were found by searching the medical and radiologic records of our institute. Clinical data and radiological data including numbers, sizes and locations of CVs and associated anomalies were retrospectively collected and analyzed. Previously reported cases in literature were reviewed as well. Results The mean age of the patients was 21 years (range, 0-78 years). On average, 1.8±1.2 CVs were found per patient. CVs were categorized as either fusiform or saccular depending on their shapes. Two patients had saccular type CVs, seventeen patients had fusiform types, and three patients had both fusiform and saccular CVs. Eight patients had associated compromise of the vein of Galen and the straight sinus. Four of those patients had sinus pericranii, as well. Five patients had CVs that were distal draining veins of large developmental venous anomalies. One patient had associated migration anomaly, and two patients had Sturge- Weber syndrome. Six patients with an isolated cerebral varix were observed. Of the 39 CVs in 22 patients, 20 lesions in 14 patients were followed up in outpatient clinics with imaging studies. The average follow-up duration was 6.6 years. During this period, no neurological events occurred, and all the lesions were managed conservatively. Conclusion Nonfistulous CVs seemed to be asymptomatic in most cases and remained clinically silent. Hence, we suggest conservative management.

The aim of this study was to investigate the specific thyroid condition and thyroid autoantibodies in adult moyamoya disease (MMD) according to clinical presentation (ischemia vs. hemorrhage stroke). In addition, a meta-analysis was performed to reveal the association between adult MMD and elevated thyroid function, or autoantibodies. Prospectively collected data on 169 consecutive patients with MMD at a single institution were analyzed. Community-based controls matched for age and sex were selected for comparison. Penalized multinomial logistic regression analysis was used for factors affecting stroke. For meta-analysis, heterogeneity was evaluated by using the I2 test. If I2 < 50%, a fixed effect model was used. Fifty-four cases (32.0%) presented with ischemic stroke and 37 cases (21.9%) with hemorrhage stroke. Hyperthyroidism had a marginally increased risk of MMD with ischemic stroke with reference value of MMD without stroke [odds ratio (OR), 2.53; P = 0.055]. Anti-thyroperoxidase antibody (TPOAb) increased the risk of MMD presenting with ischemic stroke significantly (OR, 2.99; P = 0.020). A meta-analysis revealed that adult MMD was significantly associated with elevated autoantibodies (OR, 7.663; P = 0.002) and hyperthyroidism (OR, 10.936; P < 0.001). Elevated TPOAb and hyperthyroidism may play important roles in adult MMD with ischemic stroke. Studies focusing on targeted hyperthyroidism and thyroid autoantibodies are necessary in treating adult MMD patients in the future.

Elastin encoded by elastin gene (ELN) is a crucial extracellular matrix protein responsible for arterial resilience. The objective of this study was to identify single nucleotide polymorphisms (SNPs) of ELN gene susceptible to intracranial aneurysm (IA) in Korean population. Two SNPs of ELN gene, rs2071307 (Gly422Ser) and rs2856728 (intron), were genotyped in 90 patients with IA and 90 age and frequency matched controls. Fisher’s exact test was conducted to evaluate allelic association with IA. Of the two SNPs in ELN gene, T allele of rs2856728 (intron) showed statistically significant association with increased development of IA (odds ratio [OR]: 2.34, 95% confidence interval [CI]: 1.44–3.81, P = 7.6 × 10−4). However, G allele of rs2071307 (Gly422Ser) had no significant association with the development of IA (OR: 1.27, 95% CI: 1.44–3.81, P = 0.607). Interestingly, the odds of having rs2856728 variant was approximately 2-fold higher in males than that in females (OR: 3.46 vs. 1.88, P < 0.05). However, none of SNPs showed difference between single and multiple IA in this study. This preliminary study implies that the rs2856728 variant in ELN gene polymorphisms might play crucial roles in the development and pathogenesis of IA in Korean population.

Background and Purpose— In pediatric moyamoya disease, there are few reports on the efficacy of surgical intervention for stroke prevention. We evaluated the long-term outcomes of indirect bypass surgery on a relatively large number of children with moyamoya disease in a single center. Methods— From August 1988 to December 2012, 772 children underwent indirect bypass surgery. This study included 629 patients who were followed up for >5 years, excluding patients with moyamoya syndrome. The mean clinical follow-up duration was 12 years (range, 5–29 years). Cross-sectional analysis was performed based on either Karnofsky Performance Scale or Lansky Play Performance Scale to evaluate overall clinical outcomes and factors associated with unfavorable outcomes. To analyze the longitudinal effect of surgery, the annual risk of symptomatic infarction or hemorrhage on the operated hemisphere after indirect bypass 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 in 95% of the patients. The annual risks of symptomatic infarction and hemorrhage on the operated hemispheres were 0.08% and 0.04%, respectively. Furthermore, the 10-year event-free survival rates for symptomatic infarction and hemorrhage were 99.2% and 99.8%. Conclusions— Indirect bypass surgery could provide satisfactory long-term improvement in overall clinical outcome and prevention of recurrent stroke in children with moyamoya disease.

The live attenuated vaccine strain, SG9R, has been used against fowl typhoid worldwide, but it can revert to the pathogenic smooth strain owing to single nucleotide changes such as nonsense mutations in the rfaJ gene. As SG9R possesses an intact Salmonella plasmid with virulence genes, it exhibits dormant pathogenicity and can cause fowl typhoid in young chicks and stressed or immunocompromised brown egg-laying hens. To tackle these issues, we knocked out the rfaJ gene of SG9R (named Safe-9R) to eliminate the reversion risk and generated detoxified strains of Safe-9R by knocking out lpxL, lpxM, pagP, and phoP/phoQ genes to attenuate the virulence. Among the knockout strains, live ΔlpxL- (Dtx-9RL) and ΔlpxM-9R (Dtx-9RM) strains induced remarkably less expression of inflammatory cytokines in chicken macrophage cells, and oil emulsion (OE) Dtx-9RL did not cause body weight loss in chicks. Live Dtx-9RM exhibited efficacy against field strain challenge in one week without any bacterial re-isolation, while the un-detoxified strains showed the development of severe liver lesions and re-isolation of challenged strains. Thus, SG9R was optimally detoxified by knockout of lpxL and lpxM, and Dtx-9RL and Dtx-9RM might be applicable as OE and live vaccines, respectively, to prevent fowl typhoid irrespective of the age of chickens.