Association of scrub typhus with incidence of dementia: a nationwide population-based cohort study in Korea.

BACKGROUND: Scrub typhus is a mite-borne infectious rickettsial disease that can occur in rural and urban areas, with an especially high prevalence in older populations. This disease causes systemic vasculitis that can invade the central nervous system. Considering these characteristics, here we examined whether scrub typhus was associated with the occurrence of dementia, using large population-based cohort data. METHOD: This population-based cohort study enrolled patients aged 60-89 years using data from the Health Insurance Review and Assessment database of South Korea between 2009 and 2018. We defined scrub typhus and dementia using International Classification of Diseases, Tenth Edition diagnostic codes. The control group was stratified according to age and sex at a ratio of 1:5 to the case group in the study population. The index date was set after 90 days beyond the date of the scrub typhus diagnosis, while the observation period was from the time of the index appointment to December 31, 2020. The primary outcome was newly diagnosed dementia. The secondary outcome was dementia classification, such as Alzheimer's disease, vascular dementia, and other. All analyses were conducted by matching age, gender, and comorbidity. RESULTS: During the observation period, 10,460 of 71,047 (14.7%) people who had a history of scrub typhus versus 42,965 of 355,235 (12.1%) people in the control group, that is, with no history of scrub typhus, were diagnosed with dementia (adjusted hazard ratio, 1.12; 95% confidence interval, 1.10-1.15, p < 0.001). The Kaplan-Meier curves for time to cumulative incidence of dementia showed that the dementia incidence in both groups increased over time, while individuals with a past history of scrub typhus had a higher incidence of dementia than the control group. Second, the risk of Alzheimer's disease was significantly higher among patients with a history of scrub typhus (adjusted hazard ratio, 1.15; 95% confidence interval 1.13-1.18, p < 0.001). CONCLUSION: In conclusion, a history of scrub typhus infection in old age is significantly associated with an increase in dementia, especially Alzheimer's disease. Our results suggest that prevention and appropriate treatment of scrub typhus should be emphasized as a dementia prevention measure.

Uranium Concentrations in Private Wells of Potable Groundwater, Korea.

Uranium (U) is one of the typical naturally occurring radioactive elements enriched in groundwater through geological mechanisms, thereby bringing about adverse effects on human health. For this reason, some countries and the World Health Organization (WHO) regulate U with drinking water standards and monitor its status in groundwater. In Korea, there have been continuous investigations to monitor and manage U in groundwater, but they have targeted only public groundwater wells. However, the features of private wells differ from public ones, particularly in regard to the well's depth and diameter, affecting the U distribution in private wells. This study was initiated to investigate U concentrations in private groundwater wells for potable use, and the significant factors controlling them were also elucidated through statistical methods. The results obtained from the analyses of 7036 groundwater samples from private wells showed that the highest, average, and median values of U concentrations were 1450, 0.4, and 4.0 µg/L, respectively, and 2.1% of the wells had U concentrations exceeding the Korean and WHO standard (30 µg/L). In addition, the U concentrations were highest in areas of the Jurassic granite, followed by Quaternary alluvium and Precambrian metamorphic rocks. A more detailed investigation of the relationship between U concentration and geology revealed that the Jurassic porphyritic granite, mainly composed of Daebo granite, showed the highest U contents, which indicated that U might originate from uraninite (UO2) and coffinite (USiO4). Consequently, significant caution should be exercised when using the groundwater in these geological areas for potable use. The results of this study might be applied to establish relevant management plans to protect human health from the detrimental effect of U in groundwater.

Immunogenicity after outbreak response immunization activities among young healthcare workers with secondary vaccine failure during the measles epidemic in Korea, 2019.

BACKGROUND: Despite high vaccination coverage, measles outbreaks have been reported in measles elimination countries, especially among healthcare workers in their 20 and 30 s. This study was designed to identify measles-susceptible individuals and to evaluate whether primary or secondary vaccine failure occurred during measles outbreak response immunization (ORI) activities. METHODS: The study population was divided into three groups as follows: natural immunity group (Group 1), vaccine-induced immunity group (Group 2), and vaccine failure group (Group 3). We evaluated the immunogenicity of measles among healthcare workers using three methods-enzyme-linked immunoassays, plaque reduction neutralization tests, and avidity assays. The results were assessed at baseline, 4 weeks after, and 6 months after the completion of measles-mumps-rubella (MMR) vaccination. RESULTS: In total, 120 subjects were enrolled, with 40 subjects in each group. The median age of Group 3 was 29 years, which was significantly lower than that of the other groups. The baseline negative measles virus (MeV) IgG in Group 3 increased to a median value of 165 AU/mL at 4 weeks after ORI and was lower than that in Groups 1 and 2. The median neutralizing antibody titer was highest in Group 1, and this was significantly different from that in Group 2 or Group 3 at 4 weeks (944 vs. 405 vs. 482 mIU/mL, P = 0.001) and 6 months (826 vs. 401 vs. 470, P = 0.011) after ORI. The rates of high MeV avidity IgG were highest in Group 2, and these were significantly different from those in Groups 1 or 3 at 4 weeks (77.5 vs. 90% vs. 88.6%, P = 0.03) and 6 months (81 vs. 94.8 vs. 82.1%, P = 0.01) after ORI. CONCLUSIONS: Considering the MeV-neutralizing antibodies and IgG avidity after MMR vaccination in measles-susceptible group, vaccine failure is inferred as secondary vaccine failure, and further data regarding the maintenance of immunogenicity are needed based on long-term data. The MeV-neutralizing antibody levels were highest in the natural immunity group, and the primary vaccine-induced immunity group showed the highest rates of high MeV IgG avidity.

Revitalization of Total Petroleum Hydrocarbon Contaminated Soil Remediated by Landfarming.

Soil health deteriorates through the contamination and remediation processes, resulting in the limitation of the reuse and recycling of the remediated soils. Therefore, soil health should be recovered for the intended purposes of reuse and recycling. This study aimed to evaluate the applicability and effectiveness of several amendments to revitalize total petroleum hydrocarbon contaminated soils remediated by the landfarming process. Ten inorganic, organic, and biological amendments were investigated for their dosage and duration, and nine physicochemical, four fertility, and seven microbial (soil enzyme activity) factors were compared before and after the treatment of amendments. Finally, the extent of recovery was quantitatively estimated, and the significance of results was confirmed with statistical methods, such as simple regression and correlation analyses assisted by principal component analysis. The landfarming process is considered a somewhat environmentally friendly remediation technology to minimize the adverse effect on soil quality, but four soil properties-such as water holding capacity (WHC), exchangeable potassium (Ex. K), nitrate-nitrogen (NO3-N), available phosphorus (Av. P), and urease-were confirmed to deteriorate through the landfarming process. The WHC was better improved by organic agents, such as peat moss, biochar, and compost. Zeolite was evaluated as the most effective material for improving Ex. K content. The vermicompost showed the highest efficacy in recovering the NO3-N content of the remediated soil. Chlorella, vermicompost, and compost were investigated for their ability to enhance urease activity effectively. Although each additive showed different effectiveness according to different soil properties, their effect on overall soil properties should be considered for cost-effectiveness and practical implementation. Their overall effect was evaluated using statistical methods, and the results showed that compost, chlorella, and vermicompost were the most relevant amendments for rehabilitating the overall health of the remediated soil for the reuse and/or recycling of agricultural purposes. This study highlighted how to practically improve the health of remediated soils for the reuse and recycling of agricultural purposes.

Feasibility of ultraviolet light-emitting diode irradiation robot for terminal decontamination of coronavirus disease 2019 (COVID-19) patient rooms.

OBJECTIVE: To investigate the feasibility of using an ultraviolet light-emitting diode (UV LED) robot for the terminal decontamination of coronavirus disease 2019 (COVID-19) patient rooms. METHODS: We assessed the presence of viral RNA in samples from environmental surfaces before and after UV LED irradiation in COVID-19 patient rooms after patient discharge. RESULTS: We analyzed 216 environmental samples from 17 rooms: 2 from airborne infection isolation rooms (AIIRs) in the intensive care unit (ICU) and 15 from isolation rooms in the community treatment center (CTC). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in 40 (18.5%) of 216 samples after patient discharge: 12 (33.3%) of 36 samples from AIIRs in the ICU, and 28 (15.6%) of 180 samples from isolation rooms in the CTC. In 1 AIIR, all samples were PCR negative after UV LED irradiation. In the CTC rooms, 14 (8.6%) of the 163 samples were PCR positive after UV LED irradiation. However, viable virus was not recovered from the culture of any of the PCR-positive samples. CONCLUSIONS: Although no viable virus was recovered, SARS-CoV-2 RNA was detected on various environmental surfaces. The use of a UV LED disinfection robot was effective in spacious areas such as an ICU, but its effects varied in small spaces like CTC rooms. These findings suggest that the UV LED robot may need enough space to disinfect rooms without recontamination by machine wheels or insufficient disinfection by shadowing.

Extraintestinal Manifestation of Yersinia pseudotuberculosis Bacteremia as Acute Hepatitis: Case Report and Review of the Literature.

Yersinia pseudotuberculosis is a causative agent of foodborne zoonosis that usually causes self-limiting pseudoappendicitis. Y. pseudotuberculosis infection also causes systemic spread or extraintestinal manifestations in patients with predisposing conditions. Here, we present a case of acute hepatitis with Y. pseudotuberculosis bacteremia in a 30-year-old man. He was previously healthy without significant medical history other than obesity and current smoking. At the time of admission, he presented with high fever accompanied by chills, jaundice, abdominal pain, and watery diarrhea. Laboratory studies revealed leukocytosis and elevated liver function parameters. A stool culture showed no causative pathogens. Empiric antibiotic therapy with ceftriaxone and metronidazole was administered. Y. pseudotuberculosis was later isolated from the initial blood culture performed on the day of admission using MALDI-TOF mass spectrometry. Antibiotic treatment was continued based on the susceptibility testing results from MALDI-TOF MS and VITEk®2, as well as clinical and laboratory improvements. The patient was discharged on the tenth day of admission and remained healthy with no recurrence during the 12-month follow-up. Here, we review the literature on the systemic infection caused by Y. pseudotuberculosis, including extraintestinal manifestations. This case highlights that Y. pseudotuberculosis may be considered a differential causative organism in patients with acute colitis and hepatitis.

SARS-CoV-2-specific T cell memory is sustained in COVID-19 convalescent patients for 10 months with successful development of stem cell-like memory T cells.

Memory T cells contribute to rapid viral clearance during re-infection, but the longevity and differentiation of SARS-CoV-2-specific memory T cells remain unclear. Here we conduct ex vivo assays to evaluate SARS-CoV-2-specific CD4+ and CD8+ T cell responses in COVID-19 convalescent patients up to 317 days post-symptom onset (DPSO), and find that memory T cell responses are maintained during the study period regardless of the severity of COVID-19. In particular, we observe sustained polyfunctionality and proliferation capacity of SARS-CoV-2-specific T cells. Among SARS-CoV-2-specific CD4+ and CD8+ T cells detected by activation-induced markers, the proportion of stem cell-like memory T (TSCM) cells is increased, peaking at approximately 120 DPSO. Development of TSCM cells is confirmed by SARS-CoV-2-specific MHC-I multimer staining. Considering the self-renewal capacity and multipotency of TSCM cells, our data suggest that SARS-CoV-2-specific T cells are long-lasting after recovery from COVID-19, thus support the feasibility of effective vaccination programs as a measure for COVID-19 control.

Does enhanced environmental cleaning reduce carbapenem-resistant Acinetobacter baumannii colonization in the intensive care unit?

OBJECTIVE: To evaluate the impact of enhanced environmental cleaning (two times per day) compared with conventional cleaning on the acquisition of carbapenem-resistant Acinetobacter baumannii (CRAB) in a highly endemic intensive care unit (ICU). METHODS: The intervention consisted of alternating environmental cleaning and conventional cleaning every 3 months during the study period from July 2018 to June 2019. CRAB acquisition was assessed using incidence and prevalence rates, and colonization pressure. RESULTS: The incidence rates of CRAB with and without enhanced cleaning were 16.3 and 13.9 cases per 1000 population, respectively; and the prevalence rates were 66.9 and 61.7 cases per 1000 population, respectively. Colonization pressure was 53.3% with enhanced cleaning and 51.3% without enhanced cleaning. No association was found between enhanced environmental cleaning and the incidence (P=0.156), prevalence (P=0.888) and colonization pressure (P=0.825) of CRAB acquisition. The ventilator utilization ratio increased the colonization pressure of CRAB acquisition (P=0.010, ß coefficient=0.37). The proportion of new nurses with <3 years of clinical practice experience was positively correlated with the incidence and prevalence of CRAB acquisition. CONCLUSION: Enhanced environmental cleaning alone failed to reduce CRAB acquisition in a highly endemic ICU. The ventilator utilization ratio may be of more importance than environmental cleaning. Inexperienced nurses may need to be monitored regarding infection control activities in addition to hand hygiene adherence.

COVID-19 infection with asymptomatic or mild disease severity in young patients: Clinical course and association between prevalence of pneumonia and viral load.

Few studies have focused on clinical courses or viral loads in young asymptomatic or mild patients with COVID-19 infection. We sought to better understand the clinical course and association between viral load and prevalence of pneumonia in young COVID-19 patients with asymptomatic or mild disease severity. In this retrospective study, 106 COVID-19 young patients with asymptomatic or mild disease severity were analyzed for clinical characteristics, clinical course, prevalence of radiologically proven pneumonia and viral load. The cut-off value of viral load for presence of pneumonia was also investigated. The mean age was 28.0±9.3 years. Eleven patients (10.4%) experienced viral remission within one week of diagnosis, but one (0.9%) transferred to the hospital due to aggravation of pneumonia. Patients with pneumonia had significantly higher viral load than those without, and the cut-off value of the Ct value for presence of pneumonia were 31.38. The patients with pneumonia had significantly slower recovery times than those without. Diarrhea was significantly more common in patients with pneumonia than patients without pneumonia. In conclusion, most young asymptomatic and mildly symptomatic patients showed stable clinical course. There were significant differences in viral load and recovery times between patients with and without pneumonia.

PD-1-Expressing SARS-CoV-2-Specific CD8+ T Cells Are Not Exhausted, but Functional in Patients with COVID-19.

Memory T cell responses have been demonstrated in COVID-19 convalescents, but ex vivo phenotypes of SARS-CoV-2-specific T cells have been unclear. We detected SARS-CoV-2-specific CD8+ T cells by MHC class I multimer staining and examined their phenotypes and functions in acute and convalescent COVID-19. Multimer+ cells exhibited early differentiated effector-memory phenotypes in the early convalescent phase. The frequency of stem-like memory cells was increased among multimer+ cells in the late convalescent phase. Cytokine secretion assays combined with MHC class I multimer staining revealed that the proportion of interferon-γ (IFN-γ)-producing cells was significantly lower among SARS-CoV-2-specific CD8+ T cells than those specific to influenza A virus. Importantly, the proportion of IFN-γ-producing cells was higher in PD-1+ cells than PD-1- cells among multimer+ cells, indicating that PD-1-expressing, SARS-CoV-2-specific CD8+ T cells are not exhausted, but functional. Our current findings provide information for understanding of SARS-CoV-2-specific CD8+ T cells elicited by infection or vaccination.

Trend of Olfactory and Gustatory Dysfunction in COVID-19 Patients in a Quarantine Facility.

BACKGROUND: Olfactory and gustatory dysfunction has been reported as characteristic symptoms of coronavirus disease 2019 (COVID-19). This study evaluated olfactory and gustatory dysfunction in mild COVID-19 patients using validated assessment methods. METHODS: A prospective surveillance study was conducted for mild COVID-19 patients who were isolated at the Gyeonggi International Living and Treatment Support Center (LTSC), Korea. Olfactory function was assessed using the Korean version of the Questionnaire of Olfactory Disorders (QOD) and Cross-Cultural Smell Identification Test (CC-SIT). Gustatory function was assessed using an 11-point Likert scale and 6-n-propylthiouracil, phenylthiocarbamide, and control strips. All patients underwent nasal and oral cavity endoscopic examination. RESULTS: Of the 62 patients at the LTSC, 15 patients (24.2%) complained of olfactory or gustatory dysfunction on admission. Four of 10 patients who underwent functional evaluation did not have general symptoms and 2 were asymptomatic. The mean short version of QOD-negative statements and QOD-visual analogue scale scores were 13 ± 6 and 4.7 ± 3.6, respectively. The mean CC-SIT score was 8 ± 2. No patients showed anatomical abnormalities associated with olfactory dysfunction on endoscopic examination. The mean Likert scale score for function was 8 ± 2, and there were no abnormal lesions in the oral cavity of any patient. CONCLUSIONS: The prevalence of olfactory and gustatory dysfunction was 24.2% in mild COVID-19 patients. All patients had hyposmia due to sensorineural olfactory dysfunction, which was confirmed using validated olfactory and gustatory evaluation methods and endoscopic examination. Olfactory and gustatory dysfunction may be characteristic indicators of mild COVID-19.

Antimicrobial Therapy and Antimicrobial Stewardship in Sepsis.

Since sepsis was first defined, sepsis management has remained challenging. To improve mortality rates for sepsis and septic shock, an accurate diagnosis and prompt administration of appropriate antibiotics are essential. The goals of antimicrobial stewardship are to achieve optimal clinical outcomes and to ensure cost-effectiveness and minimal unintended consequences, such as toxic effects and development of resistant pathogens. A combination of inadequate diagnostic criteria for sepsis and time pressure to provide broad-spectrum antimicrobial therapy remains an obstacle for antimicrobial stewardship. Efforts such as selection of appropriate empirical antibiotics and de-escalation or determination of whether or not to stop antibiotics may help to improve a patient's clinical prognosis as well as the successful implementation of antimicrobial stewardship.

Combustible Gas Classification Modeling using Support Vector Machine and Pairing Plot Scheme.

Combustible gases, such as CH4 and CO, directly or indirectly affect the human body. Thus, leakage detection of combustible gases is essential for various industrial sites and daily life. Many types of gas sensors are used to identify these combustible gases, but since gas sensors generally have low selectivity among gases, coupling issues often arise which adversely affect gas detection accuracy. To solve this problem, we built a decoupling algorithm with different gas sensors using a machine learning algorithm. Commercially available semiconductor sensors were employed to detect CH4 and CO, and then support vector machine (SVM) applied as a supervised learning algorithm for gas classification. We also introduced a pairing plot scheme to more effectively classify gas type. The proposed model classified CH4 and CO gases 100% correctly at all levels above the minimum concentration the gas sensors could detect. Consequently, SVM with pairing plot is a memory efficient and promising method for more accurate gas classification.

Correction to: Characteristics of residual lymph nodes after six months of antituberculous therapy in HIV-negative individuals with cervical tuberculous lymphadenitis.

After publication of the original article [1], we were notified that an author's name has been incorrectly spelled. Soon You Kwon's correct full name is Soon Young Kwon.

Gossypol Suppresses Growth of Temozolomide-Resistant Glioblastoma Tumor Spheres.

Temozolomide is the current first-line treatment for glioblastoma patients but, because many patients are resistant to it, there is an urgent need to develop antitumor agents to treat temozolomide-resistant glioblastoma. Gossypol, a natural polyphenolic compound, has been studied as a monotherapy or combination therapy for the treatment of glioblastoma. The combination of gossypol and temozolomide has been shown to inhibit glioblastoma, but it is not clear yet whether gossypol alone can suppress temozolomide-resistant glioblastoma. We find that gossypol suppresses the growth of temozolomide-resistant glioblastoma cells in both tumor sphere and adherent culture conditions, with tumor spheres showing the greatest sensitivity. Molecular docking and binding energy calculations show that gossypol has a similar affinity to the Bcl2 (B-cell lymphoma 2) family of proteins and several dehydrogenases. Gossypol reduces mitochondrial membrane potential and cellular ATP levels before cell death, which suggests that gossypol inhibits several dehydrogenases in the cell's metabolic pathway. Treatment with a Bcl2 inhibitor does not fully explain the effect of gossypol on glioblastoma. Overall, this study demonstrates that gossypol can suppress temozolomide-resistant glioblastoma and will be helpful for the refinement of gossypol treatments by elucidating some of the molecular mechanisms of gossypol in glioblastoma.

Characteristics of residual lymph nodes after six months of antituberculous therapy in HIV-negative individuals with cervical tuberculous lymphadenitis.

BACKGROUND: The therapeutic response of cervical tuberculous lymphadenitis (CTBL) may be delayed or paradoxical, with the frequent development of residual lymph nodes (LNs) during and after antituberculous treatment. We investigated the incidence of residual LNs and the clinical, radiological, microbiological, and pathologic responses of patients with CTBL after 6 months of antituberculous therapy. METHODS: The medical records of HIV-negative adult patients with CTBL diagnosed between July 2009 and December 2017 were analyzed. After 6 months of first-line antituberculous treatment, computed tomography (CT) scans were conducted to evaluate for residual LNs. Fine-needle aspiration biopsy (FNAB) was carried out if a patient presented with residual LNs > 10 mm in diameter with central necrosis, peripheral rim enhancement, or perinodal inflammation on CT scan. RESULTS: Residual LNs were detected in 35 of 157 patients who underwent follow-up CT scans and were more commonly observed in younger patients who completed the treatment (mean years ± standard deviation [SD]: 33 ± 13 vs. 44 ± 16, p < 0.001). The recurrence rate was approximately 5%, which was not significantly different in both groups. Among the 15 patients who underwent FNAB, 3 (30%) presented with granuloma, and 2 of 15 and 10 of 14 patients had positive AFB and TB PCR results, respectively. The TB culture results of 15 patients were negative. CONCLUSIONS: Residual LNs may still be observed after 6 months of antituberculous treatment. Although the radiologic and pathologic findings after treatment are still indicative of TB, not all residual LNs indicate recurrence or treatment failure. A six-month therapy may be sufficient for cervical tuberculous lymphadenitis.

A novel method for real-time monitoring of soil ecological toxicity - Detection of earthworm motion using a vibration sensor.

The aim of this study was to develop a new method, using a vibration sensor, to address the drawbacks of preexisting methods for monitoring soil ecological toxicity. A novel method was designed by inspiration from seismometers, which record signals originating from the ground motion caused by earthquake events. Similarly, the newly developed method using a vibration sensor detects the signals generated by earthworm activity, which reflects the soil ecological toxicity. To establish the new method, a stepwise approach was adopted: (1) the effects of operational conditions on the overall performance of the system were evaluated, and (2) the feasibility of the method was tested by an application study. A number of crucial factors influencing the overall performance of the method were evaluated. These were categorized based on three features: soil, tested organism, and instrumentation. The soil properties evaluated included soil type (artificial and natural), moisture content, and bulk density. In terms of the organism, the effect of the number of earthworms was investigated. Finally, with regard to instrumentation, appropriate soil chamber specifications and monitoring duration were identified. The most effective conditions for each factor were determined based on a comparative evaluation of changes in the activity levels and body weights of the earthworms. After the first step of the study, an application study was carried out to demonstrate the feasibility of the proposed method. Zinc (Zn)-contaminated soils were tested under the most efficient operational conditions identified in the preceding study. The results of the study confirm that the method is applicable to natural soils, and the best performance was achieved under soil conditions of 50-60% maximum water holding capacity and 0.95 g/cm3 bulk density. Furthermore, the optimal number of earthworms was found to be five, which corresponds 19.84 g soil per earthworm. With respect to the instrumental conditions, the most efficient specification was a cylindrical soil chamber with a diameter of 94 mm and height of 54 mm. Additionally, the most relevant monitoring duration was found to be 7 days. The results indicate that the method can shorten the testing period, reduce the soil amount and earthworm number required, and facilitate the real-time monitoring of mortality. Based on the results of the application study, we validated the proposed vibration sensor-based method for characterizing earthworm behavior in terms of its feasibility for monitoring the ecological toxicity of soil. The results indicate that dermal contact and feeding activity of earthworms decreased significantly with increasing Zn concentrations in the soil. The EC50 value of Zn calculated based on the earthworm behavior was 340.97 mg/kg. Based on the results, it is concluded that the proposed method cannot only overcome the shortcomings of traditional test methods using earthworms, but also enable real-time ecotoxicity in soil environments.

Aerosol transmission of severe fever with thrombocytopenia syndrome virus during resuscitation.

We investigated potential nosocomial aerosol transmission of severe fever with thrombocytopenia syndrome virus (SFTSV) with droplet precautions. During aerosol generating procedures, SFTSV was be transmitted from person to person through aerosols. Thus, airborne precautions should be added to standard precautions to avoid direct contact and droplet transmission.

Farnesyl diphosphate synthase is important for the maintenance of glioblastoma stemness.

Glioblastoma is a highly malignant tumor that easily acquires resistance to treatment. The stem-cell-like character (stemness) has been thought to be closely associated with the treatment resistance of glioblastoma cells. In this study, we determined that farnesyl diphosphate synthase (FDPS), a key enzyme in isoprenoid biosynthesis, plays an important role in maintaining glioblastoma stemness. A comparison of the mRNA expression in patient-derived glioblastoma sphere cells, which maintain stemness, and their differentiated counterparts, which lose stemness, via RNA sequencing showed that most of the altered genes were networked in the cholesterol biosynthesis pathway. We screened Federal Drug Administration (FDA)-approved drugs targeting specific enzymes in the cholesterol biosynthesis pathway for their ability to inhibit glioblastoma sphere formation. Inhibitors of FDPS, such as alendronate and zoledronate, significantly reduced the formation of glioblastoma spheres, and alendronate was effective at a lower molar concentration than zoledronate. Knockdown of FDPS using short hairpin RNA also completely inhibited the formation of secondary spheres. FDPS mRNA in patients with glioblastoma was associated with malignancy in three independent microarray data sets. RNA sequencing showed that alendronate treatment reduced the embryonic stem cell signature and activated development- and necrosis-related pathways in glioblastoma spheres. These results suggest that FDPS is important for the maintenance of glioblastoma stemness and that alendronate, a drug widely used to treat osteoporosis, can be repositioned to treat glioblastoma.

Temporary Haptic Externalization and Four-point Fixation of Intraocular Lens in Scleral Fixation to Enhance Stability.

PURPOSE: To report the results of a new technique for intraocular lens scleral fixation of temporary haptic externalization and four-point fixation for enhanced stability. METHODS: Two 10-0 polypropylene strands were fixed at two points 2 mm apart on each haptic of a conventional three-piece intraocular lens, using our previously reported method of temporary haptic externalization after injector implantation. Postoperative refractive outcome and stability were evaluated. RESULTS: Although the intraocular lens was fixed at a total of four points, no intraoperative difficulties were observed during the process. Patients showed successful fixation of the intraocular lens postoperatively. The fixed intraocular lens showed good centering and minimal tilting. When compared to the two-point fixation technique, postoperative astigmatism was significantly smaller in the four-point fixation group (1.80 ± 0.84 vs. 1.00 ± 0.0.50, p = 0.033). Lens-induced astigmatism calculated from subtraction of corneal astigmatism from total astigmatism was also significantly smaller in the four-point fixation group (2.23 ± 0.98 vs.1.17 ± 0.0.70, p = 0.043). No postoperative complications were identified during a mean follow-up period of 14.8 months (range, 10 to 19 months). CONCLUSIONS: By fixing the intraocular lens at two points on each side of the haptics, this method minimizes the tilting of the intraocular lens and thus decreases postoperative lens-induced astigmatism. Also, the possibility of intraocular lens dislocation in the long term might be decreased by this two-point fixation technique.