Real-time characterization of risks of death associated with the Middle East respiratory syndrome (MERS) in the Republic of Korea, 2015.

BACKGROUND: An outbreak of the Middle East respiratory syndrome (MERS), comprising 185 cases linked to healthcare facilities, occurred in the Republic of Korea from May to July 2015. Owing to the nosocomial nature of the outbreak, it is particularly important to gain a better understanding of the epidemiological determinants characterizing the risk of MERS death in order to predict the heterogeneous risk of death in medical settings. METHODS: We have devised a novel statistical model that identifies the risk of MERS death during the outbreak in real time. While accounting for the time delay from illness onset to death, risk factors for death were identified using a linear predictor tied to a logit model. We employ this approach to (1) quantify the risks of death and (2) characterize the temporal evolution of the case fatality ratio (CFR) as case ascertainment greatly improved during the course of the outbreak. RESULTS: Senior persons aged 60 years or over were found to be 9.3 times (95% confidence interval (CI), 5.3-16.9) more likely to die compared to younger MERS cases. Patients under treatment were at a 7.8-fold (95% CI, 4.0-16.7) significantly higher risk of death compared to other MERS cases. The CFR among patients aged 60 years or older under treatment was estimated at 48.2% (95% CI, 35.2-61.3) as of July 31, 2015, while the CFR among other cases was estimated to lie below 15%. From June 6, 2015, onwards, the CFR declined 0.3-fold (95% CI, 0.1-1.1) compared to the earlier epidemic period, which may perhaps reflect enhanced case ascertainment following major contact tracing efforts. CONCLUSIONS: The risk of MERS death was significantly associated with older age as well as treatment for underlying diseases after explicitly adjusting for the delay between illness onset and death. Because MERS outbreaks are greatly amplified in the healthcare setting, enhanced infection control practices in medical facilities should strive to shield risk groups from MERS exposure.

Modeling COVID-19 vaccine booster-elicited antibody response and impact of infection history.

The 3-dose COVID-19 vaccine (booster vaccination) has been offered worldwide. As booster vaccinations continue, it is important to understand the antibody dynamics elicited by booster vaccination in order to evaluate and develop vaccination needs and strategies. Here, we investigated longitudinal data by monitoring IgG antibodies against the receptor binding domain (RBD) in health care workers. We extended our previously developed mathematical model to booster vaccines and successfully fitted antibody titers over time in the absence and presence of past SARS-CoV-2 infection. Quantitative analysis using our mathematical model indicated that anti-RBD IgG titers increase to a comparable extent after booster vaccination, regardless of the presence or absence of infection, but infection history extends the duration of antibody response by 1.28 times. Such a mathematical modeling approach can be used to inform future vaccination strategies on the basis of an individual's immune history. Our simple quantitative approach can be extended to any kind of vaccination and therefore can form a basis for policy decisions regarding the distribution of booster vaccines to strengthen immunity in future pandemics.

Microsurgical Resection of Tuberculum Sellae Meningioma through Pterional Approach with Extradural Optic Canal Unroofing.

Tuberculum sellae meningiomas pose significant challenges because they are surrounded by crucial neurovascular structures, such as the optic and oculomotor nerves, pituitary stalk, internal carotid artery and its branches, and the anterior cerebral arteries. Even if small, such meningiomas frequently extend to the optic canal that is considered a poor prognostic factor for vision. In this video clip, we illustrate the case of a 60-year-old female who had an approximately 3-cm tuberculum sellae meningioma with optic canal involvement. She underwent surgical resection of the tumor through a pterional approach. After extradural optic canal unroofing, detaching, devascularizing, and debulking the tumor, careful dissection of the meningioma from the surrounding tissues was performed. Next, the tumor extensions into both of the optic canals were removed. Finally, coagulation and resection of the tumor origin on the dura of the tuberculum sellae following Simpson's grade-I resection were performed. Histopathology revealed that the tumor was a World Health Organization (WHO) grade-I meningioma. The patient had an uneventful postoperative course and her visual acuity was preserved, with no visual field defect on postoperative visual examination. In this video, the basic surgical techniques in performing extradural optic canal unroofing, preserving the arachnoid plane, and stay in collect layer, which is the essential technique for dissecting meningiomas and for preserving neurovascular structures, are demonstrated. The link to the video can be found at: https://youtu.be/vD54Iji0C4Q .

Chronic Subdural Hematoma after Craniotomy with Preoperative Embolization of Middle Meningeal Artery: A Case Report.

Endovascular embolization of the middle meningeal artery (MMA) has been reported as an effective method for treating chronic subdural hematoma (CSDH); however, its preventive effect on CSDH following craniotomy is unknown. We present a case in which MMA embolization was ineffective in preventing CSDH following craniotomy. A 56-year-old man who complained of diplopia was diagnosed with sphenoid ridge meningioma with a 3-cm diameter. MMA embolization prior to the operation and total surgical removal of the tumor were performed. Two months postoperatively, the patient complained of headache and hemiparesis of the left side. CSDH with a 15-mm thickness and a midline shift was observed. MMA embolization before inflammation may not play a role in preventing CSDH development because MMA embolization is considered effective in CSDH because it is associated with the blood supply of neovessels that are newly formed due to inflammation. Therefore, MMA embolization might not be effective in preventing the occurrence of CSDH following craniotomy.

Preoperative Prediction of Intracranial Meningioma Grade Using Conventional CT and MRI.

Objective Preoperative diagnosis of tumor grade can assist in treatment-related decision-making for patients with intracranial meningioma. This study aimed to distinguish between high-grade and low-grade meningiomas using conventional CT and MRI. Methodology We retrospectively analyzed 173 consecutive patients with intracranial meningioma (149 low-grade and 24 high-grade tumors) who were treated surgically at the National Hospital Organization Kyushu Medical Center from 2008 to 2020. Clinical and radiological features, including tumor doubling time (Td) and relative growth rate (RGR), were compared between low-grade and high-grade meningiomas. Results Multivariate logistic regression analysis showed that symptomatic tumor (p=0.001), non-skull base location (p=0.006), irregular tumor shape (p=0.043), tumor heterogeneity (p=0.025), and peritumoral brain edema (p=0.003) were independent predictors of high-grade meningioma. In 53 patients who underwent surgery because of tumor progression, progression to symptoms (p=0.027), intratumoral heterogeneity (p<0.001), peritumoral brain edema (p=0.001), larger tumor volume (p=0.005), shorter Td (p<0.001), and higher RGR (P<0.001) were significantly associated with high-grade meningioma. Receiver operating characteristics (ROC) curve analysis showed that the optimal Td and annual RGR cut-off values to distinguish high-grade from low-grade meningioma were 460.5 days and 73.2%, respectively (100% sensitivity and 78.6% specificity). Conclusion Based on our findings, conventional CT and MRI are useful methods to predict meningioma grades before surgery. High-grade lesions are associated with non-skull base location, irregular tumor shape, intratumoral heterogeneity, and peritumoral brain edema. High-grade meningioma should be suspected in tumors that exhibit Td <460.5 days or annual RGR >73.2% or those that develop intratumoral heterogeneity or surrounding brain edema on surveillance imaging.

Discrepancy in the Ki67 labeling index of brain and orbital metastatic lesions from gastrointestinal neuroendocrine tumors: A case report.

Proliferative activity examined by Ki67 labeling index (LI) plays pivotal role for managing gastrointestinal neuroendocrine tumor (GI-NET). Few reports indicated the intra-patient heterogeneity of Ki67-LI among metastatic tumor sites. We report a case of brain and orbital metastases from GI-NET that showed discrepancy of the Ki67-LI. A 71 year-old woman who was diagnosed as GI-NET with liver and bone metastases and performed medical therapy, had headache, right exophthalmos, and pain of right eye and was referred to our department. Magnetic resonance image revealed that tumors in the left occipital region and right orbit. We diagnosed as metastatic brain and orbital tumors from GI-NET. Surgical removal of both symptomatic lesions was performed and the diagnosis was pathologically confirmed. Immunohistochemical studies revealed the discrepancy of the Ki67-LI of the lesions (brain tumor: 8% versus orbital tumor: 22%). Sampling of multiple metastatic sites may prevent underestimate tumor proliferative activity.

Metabolic remodeling of pyrimidine synthesis pathway and serine synthesis pathway in human glioblastoma.

Glioblastoma is the most common brain tumor with dismal outcomes in adults. Metabolic remodeling is now widely acknowledged as a hallmark of cancer cells, but glioblastoma-specific metabolic pathways remain unclear. Here we show, using a large-scale targeted proteomics platform and integrated molecular pathway-level analysis tool, that the de novo pyrimidine synthesis pathway and serine synthesis pathway (SSP) are the major enriched pathways in vivo for patients with glioblastoma. Among the enzymes associated with nucleotide synthesis, RRM1 and NME1 are significantly upregulated in glioblastoma. In the SSP, SHMT2 and PSPH are upregulated but the upstream enzyme PSAT1 is downregulated in glioblastoma. Kaplan-Meier curves of overall survival for the GSE16011 and The Cancer Genome Atlas datasets revealed that high SSP activity correlated with poor outcome. Enzymes relating to the pyrimidine synthesis pathway and SSP might offer therapeutic targets for new glioblastoma treatments.

Five-Year Changes in Cognitive Function and Their Predictor in Adult Moyamoya Disease.

OBJECTIVE: The long-term outcomes of cognitive function in moyamoya disease remain unknown. We aimed to assess 5-year changes in cognitive function in adult moyamoya disease patients and to evaluate the value of the magnetic resonance angiography (MRA) steno-occlusive score to predict cognitive changes. METHODS: Participants comprised 20 consecutive patients whose cognitive functions had been evaluated using the Frontal Assessment Battery (FAB) and Neurobehavioral Cognitive Status Examination (Cognistat) at baseline and reassessed 5 years later. RESULTS: The total FAB score and total Cognistat score were lower after 5 years in 9 patients each. The Wilcoxon signed-rank test showed that subscores for conceptualization and comprehension increased, while subscores for mental flexibility, programming, and inhibitory control significantly decreased after 5 years. The right MRA total score and right posterior cerebral artery score were negatively associated with 5-year changes in the total FAB score and total Cognistat score. The right posterior cerebral artery score was significantly associated with changes in subscores for mental flexibility, programming, sensitivity to interference, and construction. CONCLUSIONS: Specific cognitive domains can decline over time in patients with adult moyamoya disease. MRA findings might be useful for predicting future declines in cognitive function.

Ankle-Brachial Index and Cardio-Ankle Vascular Index as Predictors of Cognitive Decline Over Time After Carotid Endarterectomy.

OBJECTIVE: Patients with carotid stenosis risk cognitive impairment even after carotid endarterectomy (CEA) because of the long-term presence of vascular risk factors. Early prediction of cognitive decline is useful because early appropriate training for impaired cognitive domains can improve their functions. Ankle-brachial index (ABI) and cardio-ankle vascular index (CAVI) are frequently used as general indicators of systemic atherosclerosis and are associated with cognitive function in the general population. This study aimed to evaluate the utility of those vascular biomarkers for predicting cognitive decline in patients after CEA. METHODS: Patients who had undergone both CEA at our institute and cognitive evaluations between March 2016 and January 2022 were invited to participate in this study. Associations between ABI or CAVI three years before baseline and cognitive function at baseline were assessed retrospectively in 94 patients, and associations between ABI or CAVI at baseline and three-year changes in cognitive functions were assessed prospectively in 24 patients. Cognitive functions were assessed using the Frontal Assessment Battery (FAB) and Neurobehavioral Cognitive Status Examination (Cognistat). RESULTS: Low ABI three years before baseline was associated with poor performances on Cognistat and FAB at baseline. ABI, as a continuous measure, three years before baseline, showed positive linear associations with total Cognistat score and subscores for naming, construction, and judgment at baseline. The Wilcoxon signed-rank test showed that the total Cognistat score, total FAB score, and subscores for attention and inhibitory control declined after three years. CAVI at baseline was negatively associated with three-year changes in total Cognistat score and subscores for naming, construction, and memory. CONCLUSION: Cognitive function can decline over time in patients with carotid stenosis even after CEA. ABI and CAVI might be useful to predict cognitive function and its decline among patients who have undergone CEA.

Efficacy of endoscopic treatment for chronic subdural hematoma surgery.

Endoscopic treatment is a potential therapeutic addition to chronic subdural hematoma (CSDH) surgery. However, the effect of endoscopic treatment remains controversial. Herein, we examined the optimal indication for endoscopic treatment in CSDH surgery. We retrospectively analyzed 380 consecutive patients with CSDH who underwent single burr-hole craniostomy. We defined postoperative rebleeding as radiological re-accumulation or increased computed tomography value of the hematoma. Reoperation was performed following further hematoma accumulation and/or neurological deterioration. Complicated CSDH was radiologically defined as a hematoma with a clot and/or fibrous septum. There were no differences in baseline characteristics or postoperative mortality and morbidity between the endoscope (97 patients) and control (283 patients) groups. The incidence of postoperative rebleeding (9.3% vs 25.1%, respectively; P = 0.001) and reoperation (0% vs 9.2%, respectively; P = 0.004) were significantly lower in the endoscope group versus controls. Multivariate analysis showed that males (odds ratio 2.14, 95% confidence interval 1.19-3.81; P = 0.012) and endoscopy (odds ratio 0.29, 95% confidence interval 0.13-0.59; P = 0.001) were independently associated with postoperative rebleeding. When CSDHs were divided into two types based on hematoma component, 175 patients exhibited complicated CSDH. There was a significant reduction in postoperative rebleeding (6.5% vs 23.0%, respectively; P = 0.010) and reoperation (0% vs 9.7%, respectively; P = 0.027) in complicated CSDH patients. Endoscopic treatment in CSDH surgery does not increase the risk of surgical complications. Complicated CSDH with a clot and/or septum may be an optimal indication for endoscopic treatment in CSDH surgery to reduce postoperative recurrence.

Neuroimaging Recommendations in Outpatients With Dementia: Three Cases of Frontal Meningioma Demonstrating Reversible Dementia.

Benign brain tumors largely affect the brain and can lead to reversible dementia, which can be resolved following the treatment of the primary etiology. Herein, we report three cases of relatively large frontal meningiomas in patients who presented with cognitive impairment as initial symptoms. The three participants demonstrated notable dementia alongside frontal meningioma. Following resection, all patients showed dramatic cognitive function improvement, and they successfully returned to society. Our cases illustrate the benefit of active surveillance with neuroimaging in selected patients, especially those who present with acute or subacute dementia.

Carotid ultrasonography predicts collateral development following combined direct and indirect revascularization surgery in adult ischemic Moyamoya disease.

OBJECTIVE: The relationship between carotid ultrasonographic parameters and postoperative collateral development in adult ischemic moyamoya disease (MMD) patients who received combined direct and indirect revascularization surgery remains unclear. Herein, we investigated the postoperative changes in carotid ultrasonographic parameters in patients with adult ischemic MMD. METHODS: We studied 28 adult ischemic MMD patients (31 hemispheres) who underwent combined revascularization surgery. Patients underwent preoperative and postoperative (within 14 days and 3, 12, and 24 months after surgery) magnetic resonance imaging and carotid ultrasonography. We defined the hemisphere in which all signal intensities of the superficial temporal, middle meningeal, and deep temporal arteries were increased compared with that before surgery on magnetic resonance angiography as well-developed collateral establishment. RESULTS: Patients with good collateral establishment on MRA at 2-year after surgery had a lower external carotid artery (ECA) pulsatility index (PI) (P = 0.0413) and ECA/internal carotid artery (ICA) pulsatility index (PI) ratio (P = 0.0427) at 3-month post-operation. At 3-month post-operation, a cut-off ECA PI of 1.416 (sensitivity 40.0 %, specificity 92.3 %, area under the curve 0.7282, likelihood ratio 5.20, P = 0.0404) and ECA/ICA PI ratio of 0.8768 (sensitivity 50.0 %, specificity 92.31 %, area under the curve 0.7308, likelihood ratio 6.50, P = 0.0415) provided reliable values for good prediction of collateral development at 2 years after revascularization. CONCLUSION: ECA/ICA PI ratio and ECA PI at 3-month after surgery can be one of the indicators for predicting future well-developed neovascularization on MRA and better outcome in patients with adult ischemic MMD who received combined direct and indirect revascularization surgery.

Discrepancy in the Ki67 labeling index of brain and orbital metastatic lesions from gastrointestinal neuroendocrine tumors: A case report.

Proliferative activity examined by Ki67 labeling index (LI) plays pivotal role for managing gastrointestinal neuroendocrine tumor (GI-NET). Few reports indicated the intra-patient heterogeneity of Ki67-LI among metastatic tumor sites. We report a case of brain and orbital metastases from GI-NET that showed discrepancy of the Ki67-LI. A 71 year-old woman who was diagnosed as GI-NET with liver and bone metastases and performed medical therapy, had headache, right exophthalmos, and pain of right eye and was referred to our department. Magnetic resonance image revealed that tumors in the left occipital region and right orbit. We diagnosed as metastatic brain and orbital tumors from GI-NET. Surgical removal of both symptomatic lesions was performed and the diagnosis was pathologically confirmed. Immunohistochemical studies revealed the discrepancy of the Ki67-LI of the lesions (brain tumor: 8% versus orbital tumor: 22%). Sampling of multiple metastatic sites may prevent underestimate tumor proliferative activity.

Impact of antithrombotic therapy on surgical treatment in patients with chronic subdural hematoma.

OBJECTIVE: The effects of antithrombotic therapy on chronic subdural hematoma (CSDH) are controversial. Herein, we investigated the association of antithrombotic therapy with surgical complications and outcomes in patients with CSDH. METHODS: We retrospectively analyzed 323 consecutive patients with CSDH who underwent single burr-hole craniostomy. RESULTS: One hundred and eight patients (33%) underwent preoperative antithrombotic therapy. Hemorrhagic and thromboembolic complications were detected in 6 and 8 patients, respectively, which peaked at 3 and 4.5 days after CSDH surgery, respectively. CSDH recurrence was detected in 62 cases, and reoperation was required in 16 cases. Discontinuance of antiplatelet therapy for >2 weeks was significantly associated with thromboembolic complications (43%; p = 0.005). Postoperative use of multiple antithrombotic agents was significantly associated with CSDH recurrence (40%; p = 0.03). Further, earlier recurrence within 2 weeks was significantly associated with the following reoperation (62%; p = 0.006). CONCLUSIONS: To reduce morbidity and minimize the risk of CSDH reoperation, the optimal timing for resumption of antithrombotic agents is approximately 3 days after CSDH surgery. Postoperative use of multiple antithrombotic agents can increase CSDH recurrence, while earlier recurrence may be a predictor for the following reoperation.

Estimating risks of importation and local transmission of Zika virus infection.

Background. An international spread of Zika virus (ZIKV) infection has attracted global attention. ZIKV is conveyed by a mosquito vector, Aedes species, which also acts as the vector species of dengue and chikungunya viruses. Methods. Arrival time of ZIKV importation (i.e., the time at which the first imported case was diagnosed) in each imported country was collected from publicly available data sources. Employing a survival analysis model in which the hazard is an inverse function of the effective distance as informed by the airline transportation network data, and using dengue and chikungunya virus transmission data, risks of importation and local transmission were estimated. Results. A total of 78 countries with imported case(s) have been identified, with the arrival time ranging from 1 to 44 weeks since the first ZIKV was identified in Brazil, 2015. Whereas the risk of importation was well explained by the airline transportation network data, the risk of local transmission appeared to be best captured by additionally accounting for the presence of dengue and chikungunya viruses. Discussion. The risk of importation may be high given continued global travel of mildly infected travelers but, considering that the public health concerns over ZIKV infection stems from microcephaly, it is more important to focus on the risk of local and widespread transmission that could involve pregnant women. The predicted risk of local transmission was frequently seen in tropical and subtropical countries with dengue or chikungunya epidemic experience.

A theoretical estimate of the risk of microcephaly during pregnancy with Zika virus infection.

OBJECTIVES: There has been a growing concern over Zika virus (ZIKV) infection, particularly since a probable link between ZIKV infection during pregnancy and microcephaly in the baby was identified. The present study aimed to estimate a theoretical risk of microcephaly during pregnancy with ZIKV infection in Northeastern Brazil in 2015. METHODS: Temporal distributions of microcephaly, reported dengue-like illness and dengue seropositive in Brazil were extracted from secondary data sources. Using an integral equation model and a backcalculation technique, we estimated the risk of microcephaly during pregnancy with Zika virus infection. RESULTS: If the fraction of Zika virus infections among a total of seronegative dengue-like illness cases is 30%, the risk of microcephaly following infection during the first trimester was estimated at 46.7% (95% CI: 9.1, 84.2), comparable to the risk of congenital rubella syndrome. However, the risk of microcephaly was shown to vary widely from 14.0% to 100%. The mean gestational age at delivery with microcephaly was estimated at 37.5 weeks (95% CI: 36.9, 39.3). CONCLUSIONS: The time interval between peaks of reported dengue-like illness and microcephaly was consistent with cause-outcome relationship. Our modeling framework predicts that the incidence of microcephaly is expected to steadily decline in early 2016, Brazil.

Identifying determinants of heterogeneous transmission dynamics of the Middle East respiratory syndrome (MERS) outbreak in the Republic of Korea, 2015: a retrospective epidemiological analysis.

OBJECTIVES: To investigate the heterogeneous transmission patterns of Middle East respiratory syndrome (MERS) in the Republic of Korea, with a particular focus on epidemiological characteristics of superspreaders. DESIGN: Retrospective epidemiological analysis. SETTING: Multiple healthcare facilities of secondary and tertiary care centres in an urban setting. PARTICIPANTS: A total of 185 laboratory-confirmed cases with partially known dates of illness onset and most likely sources of infection. PRIMARY AND SECONDARY OUTCOME MEASURES: Superspreaders were identified using the transmission tree. The reproduction number, that is, the average number of secondary cases produced by a single primary case, was estimated as a function of time and according to different types of hosts. RESULTS: A total of five superspreaders were identified. The reproduction number throughout the course of the outbreak was estimated at 1.0 due to reconstruction of the transmission tree, while the variance of secondary cases generated by a primary case was 52.1. All of the superspreaders involved in this outbreak appeared to have generated a substantial number of contacts in multiple healthcare facilities (association: p<0.01), generating on average 4.0 (0.0-8.6) and 28.6 (0.0-63.9) secondary cases among patients who visited multiple healthcare facilities and others. The time-dependent reproduction numbers declined substantially below the value of 1 on and after 13 June 2015. CONCLUSIONS: Superspreaders who visited multiple facilities drove the epidemic by generating a disproportionate number of secondary cases. Our findings underscore the need to limit the contacts in healthcare settings. Contact tracing efforts could assist early laboratory testing and diagnosis of suspected cases.

Investigating the immunizing effect of the rubella epidemic in Japan, 2012-14.

OBJECTIVES: A rubella epidemic occurred in Japan from 2012-14, involving more than 15,000 cases. The present study aimed to estimate the immunizing effect of the epidemic, analyzing seroepidemiological data that were collected over time and age. METHODS: Annual nationwide cross-sectional surveys were conducted from July to September, collecting serum from at least 5,400 individuals. The proportions seropositive were estimated before (2012), during (2013) and after (2014) the epidemic. RESULTS: While the cases were mainly seen among men aged from 30-49 years, no significant increase was observed in the proportion seropositive in the corresponding age group. Even after the epidemic, age-standardized proportion seropositive of the total population remained 79.3% (95% confidence interval (CI): 75.2, 83.4) and that among males was as small as 76.7% (95% CI: 73.8, 79.6). CONCLUSIONS: Susceptible pockets remain in Japan, exposing the country to risk of additional rubella epidemics.

Estimating the risk of Middle East respiratory syndrome (MERS) death during the course of the outbreak in the Republic of Korea, 2015.

OBJECTIVES: A large cluster of the Middle East respiratory syndrome (MERS) linked to healthcare setting occurred from May to July 2015 in the Republic of Korea. The present study aimed to estimate the case fatality ratio (CFR) by appropriately taking into account the time delay from illness onset to death. We then compare our estimate against previously published values of the CFR for MERS, i.e., 20% and 40%. METHODS: Dates of illness onset and death of the MERS outbreak in the Republic of Korea were extracted from secondary data sources. Using the known distribution of time from illness onset to death and an integral equation model, we estimated the delay-adjusted risk of MERS death for the South Korean cluster. RESULTS: Our most up-to-date estimate of CFR for the MERS outbreak in South Korea was estimated at 20.0% (95% confidence intervals (CI): 14.6, 26.2). During the course of the outbreak, estimate of the CFR in real time appeared to have decreased and become significantly lower than 40%. CONCLUSIONS: The risk of MERS death in Korea was consistent with published CFR. The estimate decreased with time perhaps due to time-dependent increase in case ascertainment. Crude ratio of cumulative deaths to cases underestimates the actual risk of MERS death because of time delay from illness onset to death.