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IntroductionIn Malaysia, lean was initiated in 2012 as part of an effort to reduce waiting time at the Ministry of Health (MOH) hospitals. As of now, there are 52 public hospitals that have officially implemented lean. However, little is known whether lean is sustained within the hospitals and the critical success factors (CSFs) affecting sustainability. Therefore, this study protocol aims to fill the gap by (i) identifying the critical success factors [CSFs] for lean sustainability in the MOH, (ii) developing a validated framework to support hospitals in sustaining lean, (iii) the framework will be adapted into a checklist to measure the level of lean sustainability (iv) interviewing hospitals with the lowest and highest level of lean sustainability to further explore the barriers and boosters in sustaining lean.Methods and analysisThis study will employ a mixed-method approach and will be conducted in three phases. The first phase involves a combination of scoping review and interviews with key informants to identify the CSFs known to affect lean sustainability at the MOH hospitals and present them in a validated framework. In the second phase, the framework will be adapted into a checklist to measure the level of lean sustainability in the MOH hospitals. The findings will be used to select the hospital with the lowest and highest level of lean sustainability for an interview in the third phase.DiscussionThe lean sustainability framework will be able to provide more relevant guidance on how to increase the likelihood of lean sustainability and serve as a validated measurement tool for MOH hospitals. In addition, this study will be able to outline the differences in the contributing factors between health organizations that showed a high level of lean sustainability compared to those struggling to sustain.

High body mass index is a known barrier to access to kidney transplantation in patients with end-stage kidney disease. The extent to which weight and weight changes affect access to transplantation among obese candidates differentially by race/ethnicity has received little attention. We included 10 221 obese patients waitlisted for kidney transplantation prior to end-stage kidney disease onset between 1995-2015. We used multinomial logistic regression models to examine the association between race/ethnicity and annualized change in body mass index (defined as stable [-2 to 2 kg/m2/year], loss [>2 kg/m2/year] or gain [>2 kg/m2/year]). We then used Fine-Gray models to examine the association between weight changes and access to living or deceased donor transplantation by race/ethnicity, accounting for the competing risk of death. Overall, 29% of the cohort lost weight and 7% gained weight; 46% received a transplant. Non-Hispanic blacks had a 24% (95% CI 1.12-1.38) higher odds of weight loss and 22% lower odds of weight gain (95% CI 0.64-0.95) compared with non-Hispanic whites. Hispanics did not differ from whites in their odds of weight loss or weight gain. Overall, weight gain was associated with lower access to transplantation (HR 0.88 [95% CI 0.79-0.99]) compared with maintenance of stable weight, but weight loss was not associated with better access to transplantation (HR 0.96 [95% CI 0.90-1.02]), although this relation differed by baseline body mass index and for recipients of living versus deceased donor organs. For example, weight loss was associated with improved access to living donor transplantation (HR 1.24 [95% CI 1.07-1.44]) in whites but not in blacks or Hispanics. In a cohort of obese patients waitlisted before dialysis, blacks were more likely to lose weight and less likely to gain weight compared with whites. Weight loss was only associated with improved access to living donor transplantation among whites. Further studies are needed to understand the reasons for the observed associations.

In an era marked by pervasive digital connectivity, cybersecurity concerns have escalated. The rapid evolution of technology has led to a spectrum of cyber threats, including sophisticated zero-day attacks. This research addresses the challenge of existing intrusion detection systems in identifying zero-day attacks using the CIC-MalMem-2022 dataset and autoencoders for anomaly detection. The trained autoencoder is integrated with XGBoost and Random Forest, resulting in the models XGBoost-AE and Random Forest-AE. The study demonstrates that incorporating an anomaly detector into traditional models significantly enhances performance. The Random Forest-AE model achieved 100% accuracy, precision, recall, F1 score, and Matthews Correlation Coefficient (MCC), outperforming the methods proposed by Balasubramanian et al., Khan, Mezina et al., Smith et al., and Dener et al. When tested on unseen data, the Random Forest-AE model achieved an accuracy of 99.9892%, precision of 100%, recall of 99.9803%, F1 score of 99.9901%, and MCC of 99.8313%. This research highlights the effectiveness of the proposed model in maintaining high accuracy even with previously unseen data. [ABSTRACT FROM AUTHOR]

BackgroundThere are no effective treatments or validated clinical response markers in systemic sclerosis (SSc). We assessed imaging biomarkers and performed gene expression profiling in a single-arm open-label clinical trial of tyrosine kinase inhibitor dasatinib in patients with SSc-associated interstitial lung disease (SSc-ILD).MethodsPrimary objectives were safety and pharmacokinetics. Secondary outcomes included clinical assessments, quantitative high-resolution computed tomography (HRCT) of the chest, serum biomarker assays and skin biopsy-based gene expression subset assignments. Clinical response was defined as decrease of >5 or >20% from baseline in the modified Rodnan Skin Score (MRSS). Pulmonary function was assessed at baseline and day 169.ResultsDasatinib was well-tolerated in 31 patients receiving drug for a median of nine months. No significant changes in clinical assessments or serum biomarkers were seen at six months. By quantitative HRCT, 65% of patients showed no progression of lung fibrosis, and 39% showed no progression of total ILD. Among 12 subjects with available baseline and post-treatment skin biopsies, three were improvers and nine were non-improvers. Improvers mapped to the fibroproliferative or normal-like subsets, while seven out of nine non-improvers were in the inflammatory subset (p = 0.0455). Improvers showed stability in forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), while both measures showed a decline in non-improvers (p = 0.1289 and p = 0.0195, respectively). Inflammatory gene expression subset was associated with higher baseline HRCT score (p = 0.0556). Non-improvers showed significant increase in lung fibrosis (p = 0.0313).ConclusionsIn patients with SSc-ILD dasatinib treatment was associated with acceptable safety profile but no significant clinical efficacy. Patients in the inflammatory gene expression subset showed increase in skin fibrosis, decreasing pulmonary function and worsening lung fibrosis during the study. These findings suggest that target tissue-specific gene expression analyses can help match patients and therapeutic interventions in heterogeneous diseases such as SSc, and quantitative HRCT is useful for assessing clinical outcomes.Trial registrationClinicaltrials.gov NCT00764309.

The laboratory rat is emerging as an attractive preclinical animal model of autism spectrum disorder (ASD), allowing investigators to explore genetic, environmental and pharmacological manipulations in a species exhibiting complex, reciprocal social behavior. The present study was carried out to compare two commonly used strains of laboratory rats, Sprague-Dawley (SD) and Long-Evans (LE), between the ages of postnatal day (PND) 26-56 using high-throughput behavioral phenotyping tools commonly used in mouse models of ASD that we have adapted for use in rats. We detected few differences between young SD and LE strains on standard assays of exploration, sensorimotor gating, anxiety, repetitive behaviors, and learning. Both SD and LE strains also demonstrated sociability in the 3-chamber social approach test as indexed by spending more time in the social chamber with a constrained age/strain/sex matched novel partner than in an identical chamber without a partner. Pronounced differences between the two strains were, however, detected when the rats were allowed to freely interact with a novel partner in the social dyad paradigm. The SD rats in this particular testing paradigm engaged in play more frequently and for longer durations than the LE rats at both juvenile and young adult developmental time points. Results from this study that are particularly relevant for developing preclinical ASD models in rats are threefold: (i) commonly utilized strains exhibit unique patterns of social interactions, including strain-specific play behaviors, (ii) the testing environment may profoundly influence the expression of strain-specific social behavior and (iii) simple, automated measures of sociability may not capture the complexities of rat social interactions.

BackgroundWe conducted a prospective cohort study at Kaiser Permanente Southern California to study the vaccine effectiveness (VE) of mRNA-1273 over time and during the emergence of the Delta variant.MethodsThe cohort for this planned interim analysis consisted of individuals aged ≥18 years receiving 2 doses of mRNA-1273 through June 2021, matched 1:1 to randomly selected unvaccinated individuals by age, sex, and race/ethnicity, with follow-up through September 2021. Outcomes were SARS-CoV-2 infection, and COVID-19 hospitalization and hospital death. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHR) with 95% confidence intervals (CIs) comparing outcomes in the vaccinated and unvaccinated groups. Adjusted VE (%) was calculated as (1-aHR)x100. HRs and VEs were also estimated for SARS-CoV-2 infection by age, sex, race/ethnicity, and during the Delta period (June-September 2021). VE against SARS-CoV-2 infection and COVID-19 hospitalization was estimated at 0-Results927,004 recipients of 2 doses of mRNA-1273 were matched to 927,004 unvaccinated individuals. VE (95% CI) was 82.8% (82.2-83.3%) against SARS-CoV-2 infection, 96.1% (95.5-96.6%) against COVID-19 hospitalization, and 97.2% (94.8-98.4%) against COVID-19 hospital death. VE against SARS-CoV-2 infection was similar by age, sex, and race/ethnicity, and was 86.5% (84.8-88.0%) during the Delta period. VE against SARS-CoV-2 infection decreased from 88.0% at 0-ConclusionsThese interim results provide continued evidence for protection of 2 doses of mRNA-1273 against SARS-CoV-2 infection over 8 months post-vaccination and during the Delta period, and against COVID-19 hospitalization and hospital death.

Infections caused by Fusobacterium species are rare; however serious infections with complications or mortality may occur occasionally. We conducted a retrospective study to investigate the clinical features of patients with Fusobacterium infections and the differences between infections caused by the species F. necrophorum, F. nucleatum, and F. varium. Additionally, we attempted to identify risk factors for Fusobacterium-associated mortality. This study included all patients at a large tertiary care teaching hospital in South Korea with Fusobacterium infections from January 2006 to April 2021. Demographic, clinical, laboratory, and outcome data were analyzed. Multiple logistic regression analysis was performed to assess the risk factors for in-hospital mortality associated with F. nucleatum and F. varium infections. We identified 272 patients with Fusobacterium infections during the study period. The number of Fusobacterium cases has increased recently, with F. varium infections markedly increasing since 2016 and causing a significant proportion of infections. Patients with F. varium infections were older and had a higher proportion of nosocomial infections than the other groups. The F. nucleatum and F. varium groups showed higher in-hospital mortality than the F. necrophorum group. Through logistic regression analysis, APACHE II score and serum albumin level were considered risk factors for in-hospital mortality. APACHE II score was positively correlated with age, red cell distribution width, and serum blood urea nitrogen, and negatively correlated with serum albumin level. Infections caused by Fusobacterium species are increasing. F. varium causes a significant proportion of severe infections.

BackgroundMultiple prevention measures have the possibility of impacting HIV incidence in South Korea, including early diagnosis, early treatment, and pre-exposure prophylaxis (PrEP). We investigated how each of these interventions could impact the local HIV epidemic, especially among men who have sex with men (MSM), who have become the major risk group in South Korea. A mathematical model was used to estimate the effects of each these interventions on the HIV epidemic in South Korea over the next 40 years, as compared to the current situation.MethodsWe constructed a mathematical model of HIV infection among MSM in South Korea, dividing the MSM population into seven groups, and simulated the effects of early antiretroviral therapy (ART), early diagnosis, PrEP, and combination interventions on the incidence and prevalence of HIV infection, as compared to the current situation that would be expected without any new prevention measures.ResultsOverall, the model suggested that the most effective prevention measure would be PrEP. Even though PrEP effectiveness could be lessened by increased unsafe sex behavior, PrEP use was still more beneficial than the current situation. In the model, early diagnosis of HIV infection was also effectively decreased HIV incidence. However, early ART did not show considerable effectiveness. As expected, it would be most effective if all interventions (PrEP, early diagnosis and early treatment) were implemented together.ConclusionsThis model suggests that PrEP and early diagnosis could be a very effective way to reduce HIV incidence in South Korea among MSM.

Background: Evidence regarding differences in survival associated with the site of metastasis in triple-negative breast cancer (TNBC) remains limited. Our aim was to analyze the overall survival (OS), distant relapse free survival (DRFS), and survival since the diagnosis of the relapse (MS), according to the side of metastasis. Methods: This was a retrospective study of TNBC patients with distant metastases at the Instituto Nacional de Enfermedades Neoplasicas (Lima, Peru) from 2000 to 2014. Prognostic factors were determined by multivariate Cox regression analysis. Results: In total, 309 patients were included. Regarding the type of metastasis, visceral metastasis accounted for 41% and the lung was the most frequent first site of metastasis (33.3%). With a median follow-up of 10.2 years, the 5-year DRFS and OS were 10% and 26%, respectively. N staging (N2-N3 vs. N0, HR = 1.49, 95%CI: 1.04–2.14), metastasis in visceral sites (vs. bone; HR = 1.55, 95%CI: 0.94–2.56), the central nervous system (vs. bone; HR = 1.88, 95% CI: 1.10–3.22), and multiple sites (vs. bone; HR = 2.55, 95%CI:1.53–4.25) were prognostic factors of OS whereas multiple metastasis (HR = 2.30, 95% CI: 1.42–3.72) was a predictor of MS. In terms of DRFS, there were no differences according to metastasis type or solid organ. Conclusion: TNBC patients with multiple metastasis and CNS metastasis have an increased risk of death compared to those with bone metastasis in terms of OS and MS. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are important mediators of anti-tumor immunity and are active against several hematologic malignancies, including multiple myeloma (MM). Umbilical cord blood (CB) is a promising source of allogeneic NK cells but large scale ex vivo expansion is required for generation of clinically relevant CB-derived NK (CB-NK) cell doses. Here we describe a novel strategy for expanding NK cells from cryopreserved CB units using artificial antigen presenting feeder cells (aAPC) in a gas permeable culture system. After 14 days, mean fold expansion of CB-NK cells was 1848-fold from fresh and 2389-fold from cryopreserved CB with >95% purity for NK cells (CD56(+)/CD3(-)) and less than 1% CD3(+) cells. Though surface expression of some cytotoxicity receptors was decreased, aAPC-expanded CB-NK cells exhibited a phenotype similar to CB-NK cells expanded with IL-2 alone with respect to various inhibitory receptors, NKG2C and CD94 and maintained strong expression of transcription factors Eomesodermin and T-bet. Furthermore, CB-NK cells formed functional immune synapses with and demonstrated cytotoxicity against various MM targets. Finally, aAPC-expanded CB-NK cells showed significant in vivo activity against MM in a xenogenic mouse model. Our findings introduce a clinically applicable strategy for the generation of highly functional CB-NK cells which can be used to eradicate MM.

Pulmonary surfactant protein D (SP-D) is a host defence lectin of the innate immune system that enhances clearance of pathogens and modulates inflammatory responses. Recently it has been found that systemic SP-D is associated with metabolic disturbances and that SP-D deficient mice are mildly obese. However, the mechanism behind SP-D's role in energy metabolism is not known.Here we report that SP-D deficient mice had significantly higher ad libitum energy intake compared to wild-type mice and unchanged energy expenditure. This resulted in accumulation but also redistribution of fat tissue. Blood pressure was unchanged. The change in energy intake was unrelated to the basal levels of hypothalamic Pro-opiomelanocortin (POMC) and Agouti-related peptide (AgRP) gene expression. Neither short time systemic, nor intracereberoventricular SP-D treatment altered the hypothalamic signalling or body weight accumulation.In ad libitum fed animals, serum leptin, insulin, and glucose were significantly increased in mice deficient in SP-D, and indicative of insulin resistance. However, restricted diets eliminated all metabolic differences except the distribution of body fat. SP-D deficiency was further associated with elevated levels of systemic bacterial lipopolysaccharide.In conclusion, our findings suggest that lack of SP-D mediates modulation of food intake not directly involving hypothalamic regulatory pathways. The resulting accumulation of adipose tissue was associated with insulin resistance. The data suggest SP-D as a regulator of energy intake and body composition and an inhibitor of metabolic endotoxemia. SP-D may play a causal role at the crossroads of inflammation, obesity, and insulin resistance.

Introduction: In Malaysia, lean was initiated in 2012 as part of an effort to reduce waiting time at the Ministry of Health (MOH) hospitals. As of now, there are 52 public hospitals that have officially implemented lean. However, little is known whether lean is sustained within the hospitals and the critical success factors (CSFs) affecting sustainability. Therefore, this study protocol aims to fill the gap by (i) identifying the critical success factors [CSFs] for lean sustainability in the MOH, (ii) developing a validated framework to support hospitals in sustaining lean, (iii) the framework will be adapted into a checklist to measure the level of lean sustainability (iv) interviewing hospitals with the lowest and highest level of lean sustainability to further explore the barriers and boosters in sustaining lean. Methods and analysis: This study will employ a mixed-method approach and will be conducted in three phases. The first phase involves a combination of scoping review and interviews with key informants to identify the CSFs known to affect lean sustainability at the MOH hospitals and present them in a validated framework. In the second phase, the framework will be adapted into a checklist to measure the level of lean sustainability in the MOH hospitals. The findings will be used to select the hospital with the lowest and highest level of lean sustainability for an interview in the third phase. Discussion: The lean sustainability framework will be able to provide more relevant guidance on how to increase the likelihood of lean sustainability and serve as a validated measurement tool for MOH hospitals. In addition, this study will be able to outline the differences in the contributing factors between health organizations that showed a high level of lean sustainability compared to those struggling to sustain. [ABSTRACT FROM AUTHOR]

Construction waste is a serious problem that should be addressed to protect environment and save resources, some of which have a high recovery value. To efficiently recover construction waste, an online classification system is developed using an industrial near-infrared hyperspectral camera. This system uses the industrial camera to capture a region of interest and a hyperspectral camera to obtain the spectral information about objects corresponding to the region of interest. The spectral information is then used to build classification models based on extreme learning machine and resemblance discriminant analysis. To further improve this system, an online particle swarm optimization extreme learning machine is developed. The results indicate that if a near-infrared hyperspectral camera is used in conjunction with an industrial camera, construction waste can be efficiently classified. Therefore, extreme learning machine and resemblance discriminant analysis can be used to classify construction waste. Particle swarm optimization can be used to further enhance the proposed system.

This study aimed to determine serial changes in self-assessed goal achievement (SAGA) and treatment satisfaction after HoLEP, to identify correlations between the two, and to compare them with results assessed by traditional outcome measures. For a total of 170 patients, outcomes were evaluated serially at postoperative 1-, 3-, 6-, and 12-months using IPSS, OABSS, SAGA questionnaires and uroflowmetry. The SAGA questionnaire consisted of five questions including one open-ended question (self-assessed goals and degree of SAGA) and another question regarding treatment satisfaction. The number of self-assessed treatment goals was two or more in 74.1% of the patients. Most common treatment goal was relief from straining/hesitancy, followed by increased daytime frequency, nocturia and feeling of incomplete emptying. Degree of achievement for the first or second goal and treatment satisfaction tended to increase with time throughout the follow-up period. Patients with the greatest treatment satisfaction scores showed greater improvement by traditional outcome parameters including quality of life (QOL) index, total OABSS, maximum flow rate (Qmax), post-void residual urine volume (PVR) and bladder voiding efficiency (BVE) compared to those without treatment satisfaction. After adjusting for other influential variables, the improvements in subjective outcome parameters including total IPSS, QOL index and total OABSS were significantly associated with treatment satisfaction, but improvements in objective outcome parameters including Qmax, PVR and BVE were not. In addition, the degree of SAGA for the first goal or second goal was more predictive in determining treatment satisfaction than the traditional outcome measures. In conclusion, treatment goals of patients with lower urinary tract symptoms (LUTS)/BPH vary from individual to individual. The degree of SAGA and treatment satisfaction for HoLEP tends to increase with time throughout the follow-up period. Compared to the traditional outcome measures, the degree of goal achievement can be more predictive when assessing patient-centered outcomes such as treatment satisfaction.

Although phosphate-solubilizing bacteria (PSBs) are used in agricultural production, comprehensive research on PSB that colonize the rhizosphere of different plants and promote plant growth is lacking. This study was conducted to examine the growth-promoting effects and colonizing capacity of strain YL6, a PSB. YL6 not only increased the biomass of soybean and wheat in pot experiments but also increased the yield and growth of Chinese cabbage under field conditions. The observed growth promotion was related to the capacity of YL6 to dissolve inorganic and organic phosphorus and to produce indole-3-acetic (IAA) and gibberellin (GA). After applying YL6 to soybean, wheat and Chinese cabbage, the rhizosphere soil available phosphorus (available P) content increased by 120.16%, 62.47% and 7.21%, respectively, and the plant total phosphorus content increased by 198.60%, 6.20% and 78.89%, respectively, compared with plants not treated with YL6. To examine plant colonization, YL6 labeled with green fluorescent protein (YL6-GFP) was inoculated into the plant rhizosphere and found to first colonize the root surface and hairs and then to penetrate into the intercellular spaces and vessels. Collectively, these results demonstrate that YL6 promotes the growth of three different crops and colonizes them in a similar manner. The findings therefore provide a solid foundation for probing the mechanisms by which PSB affect plant growth.

[This corrects the article DOI: 10.1371/journal.pone.0168347.].

A multi-objective modeling approach is required in the context of generator maintenance scheduling (GMS) for power generation systems. Most multi-objective modeling approaches in practice are modeled using a periodic system approach that caters for a fixed maintenance window. This approach is not suitable for different types of generating units and cannot extend the generator lifespan. To address this issue, this study proposes a tri-objective GMS model with three conflicting objectives based on the sequential system approach that accounts for operating hours and start-up times. The GMS model's objectives are to minimize the total operation cost, maximize system reliability and minimize violation. The main difference between the proposed tri-objective GMS model and other multi-objective GMS models, is that the proposed model uses a sequential strategy based on operating hours and start-up times. In addition, the proposed model has considered the most important criteria in scheduling the generator maintenance, and this reflects the real-life requirements in electrical power systems. A multi-objective graph model is also developed to generate the maintenance units scheduling and used in developing the proposed Pareto ant colony system (PACS) algorithm. A PACS algorithm is proposed to implement the model and obtain solution for GMS. The performance of the proposed model was evaluated using the IEEE RTS 26, 32, and 36-unit systems dataset. The performance metrics used comprise the GMS model objectives. The experimental results showed that the obtained solution from the proposed tri-objective GMS model was a robust solution by considering the different initial operational hours of the units. [ABSTRACT FROM AUTHOR]

Background and aims: There is a demand for longitudinal studies that use both objective and subjective measures of physical activity to investigate the association of physical activity with the change in carotid intima-media thickness (CIMT). In order to investigate such association, we conducted an 8-year follow-up study that used both objective and subjective measures of physical activity. Methods: This cohort study used subsamples of the ongoing Korean Genome and Epidemiology Study (KoGES). Included participants were between 49 to 79 years of age at baseline. Exclusion criteria included incomplete assessments of pedometer/accelerometer, international physical activity questionnaire (IPAQ), and baseline CIMT. Participants with a history of cardiovascular diseases were further excluded. Linear regression models were used for the main analysis. Age differences were assessed by stratifying the participants into < 60 years and ≥ 60 years. Results: After removing excluded participants, 835 participants were included in the final analysis (age, 59.84 ± 6.53 years; 326 (39.04%) males). 453 participants were < 60 years and 382 participants were ≥ 60 years. The daily total step count was inversely associated with the percent change in overall CIMT over 8-years (β = -0.015, standard error = 0.007, P = 0.034). This association was present among participants in the < 60-year-old group (β = -0.026, standard error = 0.010, P = 0.006), but not among participants in the ≥ 60-year-old group (β = -0.010, standard error = 0.011, P = 0.38). Conclusions: The findings suggest that taking preemptive actions of increasing physical activity may prevent the incidence of atherosclerosis. [ABSTRACT FROM AUTHOR]

This study aimed to assess the safety and effectiveness of the highly cross-linked hyaluronic acid—LBSA0103—in patients with knee osteoarthritis (OA) as per the prescribing information (PI) in South Korea. A total of 3,140 subjects aged ≥19 years were enrolled in this post-marketing surveillance (PMS) study from 2013 to 2019. The subjects received one or two injections of LBSA0103. The median duration of follow-up was 308 days. Adverse events (AEs), adverse drug reactions (ADRs), and serious AEs (SAEs) were monitored. Effectiveness was evaluated based on an index of effectiveness in accordance with the guidelines established by the Ministry of Food and Drug Safety and using a 100-mm visual analog scale (VAS) for weight-bearing pain. Overall, 250 subjects (7.96%) experienced 292 AEs and of these, unexpected AEs occurred in 114 subjects (3.63% [95% CI: 3.00–4.35]). Injection site pain was the most frequent AE reported by 81 subjects (2.58% [95% confidence intervals (CI): 2.05–3.20]). One hundred subjects experienced 108 ADRs (3.18% [95% CI: 2.60, 3.86]) and 15 unexpected ADRs were experienced by 13 subjects (0.41% [95% CI: 0.22–0.71]). Seventeen subjects experienced 22 SAEs (0.54% [95% CI: 0.32–0.87]) during the entire PMS period, and all were considered "unlikely" related to the study drug. Most AEs were mild in terms of severity and resolved during the study period. LBSA0103 was also effective in relieving symptomatic pain in knee OA patients. The condition in more than 80% of the subjects was considered to be improved when assessed by the investigators. LBSA0103 resulted in a significant reduction in the mean VAS score at 12 weeks after the first and second injections (24.79 (± 20.55) mm and 17.63 (±12.31) mm, respectively; p<0.0001). In conclusion, LBSA0103, used for the treatment of knee OA in a real-world setting, was well tolerated, with an acceptable safety profile and consistent therapeutic effect. [ABSTRACT FROM AUTHOR]

To explore the interior of a lesion in a 3D endoluminal view, this study investigates the application of an 'electronic biopsy' (EB) technique to computed tomographic colonography (CTC) for further differentiation and 2D image correlation of endoluminal lesions in the air spaces. A retrospective study of sixty-two various endoluminal lesions from thirty patients (13 males, 17 females; age range, 31 to 90 years) was approved by our institutional review board and evaluated. The endoluminal lesions were segmented using gray-level threshold and reconstructed into isosurfaces using a marching cube algorithm. EB allows users to interactively erode and apply grey-level mapping (GM) to the surface of the region of interest (ROI) in 3D CTC. Radiologists conducted the clinical evaluation, and the resulting data were analyzed. EB significantly improves 3D gray-level presentation for evaluating the surface and inside of endoluminal lesions over that of SR, GM or target GM (TGM) (P < 0.01) with preservation of the 3D spatial effect. Moreover, 3D to 2D image correlation were achieved in any layer of the lesion using EB as did GM/TGM on the surface. The specificity and diagnostic accuracy of EB are significantly greater than those of SR (P < 0.01). These performance can be better further with GM/TGM and reach the best with EB (specificity, 89.3–92.9%; accuracy, 95.2–96.8%). EB can be used in CTC to improve the differentiation of endoluminal lesions. EB increases 3D to 2D image correlations of the lesions on or beneath the lesion surface. [ABSTRACT FROM AUTHOR]

The impact of adjuvant acid suppression via proton pump inhibitors or histamine-2 receptor antagonists after endoscopic variceal ligation remains uncertain. We therefore aimed to evaluate the effect of adjuvant acid suppression on the rebleeding and mortality rates in patients who received endoscopic variceal ligation and vasoconstrictor therapy for bleeding esophageal varices. Data from 1997 to 2011 were extracted from the National Health Insurance Research Database in Taiwan. A total of 1576 cirrhotic patients aged > 18 years with a primary diagnosis of acute esophageal variceal bleeding who received endoscopic variceal ligation therapy were screened. After strict exclusion, 637 patients were recruited. The exclusion criteria included patients with gastric variceal bleeding, failure in the control of bleeding, mortality within 12 hours, and history of hepatocellular carcinoma or gastric cancer. Patients were divided into two groups: the vasoconstrictors group (n = 126) and vasoconstrictors plus acid suppression group (n = 511). We observed that the rebleeding and mortality rates were not significantly different between 2 groups during hospitalization and the 15-year follow-up period after discharge. A Charlson score ≥3 (odds ratio: 2.42, 95% confidence interval: 1.55 ~3.79, P = 0.0001), presence of hepatitis C virus (odds ratio: 1.70, 95% confidence interval: 1.15 ~2.52, P = 0.0085), and cirrhosis (odds ratio: 1.69, 95% confidence interval: 1.08 ~2.66, P = 0.0229) were the independent risk factors of mortality after discharge. In conclusion, the results of the current study suggest that adjuvant acid suppression prescription to patients who received endoscopic variceal ligation and vasoconstrictor therapy for bleeding esophageal varices may not change the rebleeding and mortality outcomes compared to that for those who received endoscopic variceal ligation and vasoconstrictor agents without acid suppression.

OBJECTIVE:To investigate the impact of national implementation of age restriction on fluoroquinolone prescription in children and adolescents. METHODS:Data collected from the database of Health Insurance Review and Assessment Service in South Korea, a national health insurance system to analyze fluoroquinolone prescribing practice in children and adolescents younger than 18 years, between 2007 and 2015. The age restriction was implemented in December 2009. The annual prescription rate of FQ per 100,000 person-years was calculated and an autoregressive model was used to predict the prescription pattern if an intervention had not occurred. RESULTS:A total of 505,859 children received systemic fluoroquinolone during the study period-297,054 ciprofloxacin, and 208,805 levofloxacin. After implementation of the drug utilization review program, the annual prescription rate for ciprofloxacin declined by 97.5% (from 840 to 21 per 100,000 person-years, P < 0.001), and for levofloxacin by 96.4% (from 598 to 11 per 100,000 person-years, P < 0.001). The decline was more dramatic in the outpatient setting than in the inpatient setting for both drugs. CONCLUSION:The dramatic and sustained decline in prescription number and change in prescription pattern after the regulatory action suggests that the implementation under drug utilization review program was successful in controlling excessive and inappropriate use of fluoroquinolones in children, possibly guiding towards more judicious and selective prescription behavior.

Although a few studies have investigated the risks of peptic ulcer bleeding (PUB) in cirrhotic patients, large population-based studies on in-hospital and long-term reports on recurrent PUB in a cohort of cirrhotic patients are lacking. This 12-year nationwide cohort study aimed to investigate the risks of in-hospital and long-term rebleeding and mortality in cirrhotic patients and to identify possible risk factors. Patient data from 1997 to 2008 were extracted from the National Health Insurance Research Database in Taiwan. A total of 15,575 patients who were discharged with a diagnosis of PUB were identified after strict exclusions (n = 2889). Among them, patients with cirrhosis (n = 737) and those with chronic hepatitis (n = 1044) were compared to propensity-score matched normal controls at a ratio of 1:1. Accumulated in-hospital and long-term follow-up PUB-free survival rates were analyzed in patients with cirrhosis, patients with chronic hepatitis, and matched controls. Cox proportional hazards regression was used to identify each independent risk factor. Compared with matched controls, patients with cirrhosis exhibited a 2.62-fold (95% CI: 1.74-3.92) higher risk of developing in-hospital rebleeding, but the risk of long-term rebleeding was comparable between cirrhotic patients and matched controls (hazard ratio: 1.29, 95% CI: 0.8-2.09). On the other hand, no significant difference was observed in in-hospital and long-term rebleeding between chronic hepatitis patients and matched controls. We compared the survival rates of cirrhotic and chronic hepatitis patients to that of matched controls. After propensity score matching, both cirrhotic and chronic hepatitis patients showed significantly lower survival than the matched controls (P < 0.0001 and 0.033, respectively) during the 12-year follow-up period. However, in-hospital and long-term rebleeding rates were not significantly different between chronic hepatitis patients and matched controls (P = 0.251 and 0.474, respectively). In conclusion, liver cirrhosis increased health care expenses in patients with PUB and these patients exhibited higher recurrent bleeding rate than non-cirrhotic patients during hospitalization. Cirrhosis and chronic hepatitis are independently associated with an increased long-term mortality when compared with patients without liver disease.

Symptomatic basilar artery stenosis (BAS) is associated with high risk of ischemic stroke recurrence. We aimed to investigate whether statin therapy might prevent the progression of symptomatic BAS and stroke recurrence.We retrospectively analyzed the data of patients with acute ischemia with symptomatic BAS, which was assessed using magnetic resonance angiogram (MRA) imaging on admission day, and 1 year later (or the day of the clinical event). The clinical endpoints were recurrent ischemic stroke and its composites, transient ischemic attack, coronary disease, and vascular death.Of the 153 patients with symptomatic BAS, 114 (74.5%) were treated with a statin after experiencing a stroke. Statin therapy significantly prevented the progression of symptomatic BAS (7.0% vs 28.2%) and induced regression (22.8% vs 15.4%) compared to non-statin users (p = 0.002). There were 31 ischemic stroke incidences and 38 composite vascular events. Statin users showed significantly lower stroke recurrence (14.9% vs 35.9%, p = 0.05) and composite vascular events (17.5% vs 46.2%; odds ratio [OR], 0.29; 95% confidence interval [CI], 0.13-0.64) than those not using statins did. Recurrent stroke in the basilar territory and composite vascular events were more common in patients with progression of BAS than they were in other patients (OR, 5.16; 95% CI, 1.63-16.25 vs OR, 4.2; 95% CI, 1.56-11.34).Our study suggests that statin therapy may prevent the progression of symptomatic BAS and decrease the risk of subsequent ischemic stroke. Large randomized trials are needed to confirm this result.

The prognostic value of repeat transurethral resection of bladder tumor (TURBT) in patients with diagnosed high-risk, non-muscle-invasive bladder cancer (NMIBC) was investigated. We retrospectively reviewed the medical records of patients treated from October 2004 to December 2013 at Seoul National University who underwent repeated TURBT within 2-6 weeks after an initial resection. The study enrolled patients who had been diagnosed with NMIBC at both the initial and repeat TURBT; patients with muscle-invasive tumors on repeat TURBT were excluded. We used stepwise multivariate Cox regression models stratified by study to assess the independent effects of the predictive factors and estimated hazard ratios (HRs) from the Cox models. We investigated a total of 198 patients who were diagnosed with high-risk NMIBC. In logistic regression analyses, number of bladder tumors (2-7: OR, 2.319; 8≤: OR, 3.353; p

Ambient air pollution poses a significant risk for a group of common and often debilitating respiratory diseases, but its direct impact on cause-specific respiratory diseases using emergency room visit (ERV) as an indicator remains to be fully explored. In this study, we conducted a time-series study of ambient PM2.5, NO2, SO2 and their association with ERV for asthma, COPD and pneumonia in a four-year time span. Relative risks for ERV as per log increase in the level of ambient pollutants with time lags of up to 10 days were calculated, using a generalized additive model of Poisson regression. Daily 24-h average concentrations of PM2.5 and pollutant gases were obtained from a local Gutting air quality monitoring station. Results showed that the ERVs for pneumonia and asthma were associated with the level of PM2.5. The effects of PM2.5 on the risk of ERV for asthma were found to be significant at lag days 1 and 2 with increasing risk of 4.34% [RR: 1.091; CI: 1.020-1.166 (95%)] and 3.58% [RR: 1.074; CI: 1.007-1.146 (95%)], respectively. The ERV for pneumonia was associated with the level of PM2.5 at lag days 5, 6 and 7, with increasing risk of 1.92% [RR: 1.039; CI: 1.009-1.070 (95%)], 2.03% [RR: 1.041; CI: 1.009-1.075 (95%)], and 1.82% [RR: 1.037; CI: 1.001-1.075 (95%)], respectively. Further, PM2.5, but not NO2 and SO2, posed a significant risk of ERV for asthma during spring at lag days 0, 1 and 2 (17.12%, RR: 1.408, CI: 1.075-1.238; 15.30%, RR: 1.358 CI: 1.158-1.166; 11.94%, RR: 1.165, CI: 1.004-1.121), which was particularly evident for those who were younger than 75 years of age. In contrast, only PM2.5 was a significant risk of ERV for COPD, which was primarily for those who were younger than 75 years of age during summer season at lag days 3, 4 and 5. (26.66%, RR: 1.704, CI: 1.104-2.632; 26.99%; RR: 1.716, CI: 1.151-2.557; 24.09%; RR: 1.619, CI: 1.111-2.360). Collectively, these results suggested significant seasonal variation and differential time lag effects of PM2.5 on ERV for asthma, COPD and pneumonia.

Death by suicide is a major public health problem. People living with human immunodeficiency virus (PLHIV) have higher risk of suicidal behavior than the general population. The aim of this review is to summarize suicidal behavior, associated risk factors, and risk populations among PLHIV. Research studies in six databases from January 1, 1988, to July 8, 2021, were searched using keywords that included "HIV," "suicide," and "risk factors." The study design, suicide measurement techniques, risk factors, and study findings were extracted. A total of 193 studies were included. We found that the Americas, Europe, and Asia have the highest rates of suicidal behavior. Suicide risk factors include demographic factors, mental illness, and physiological, psychological, and social support. Depression is the most common risk factor for PLHIV, with suicidal ideation and attempt risk. Drug overdosage is the main cause of suicide death. In conclusion, the current study found that PLHIV had experienced a high level of suicidal status. This review provides an overview of suicidal behavior and its risk factors in PLHIV with the goal of better managing these factors and thus preventing death due to suicide. [ABSTRACT FROM AUTHOR]

Identifications of novel genetic signals conferring susceptibility to human complex diseases is pivotal to the disease diagnosis, prevention, and treatment. Genetic association study is a powerful tool to discover candidate genetic signals that contribute to diseases, through statistical tests for correlation between the disease status and genetic variations in study samples. In such studies with a case-control design, a standard practice is to perform the Cochran-Armitage (CA) trend test under an additive genetic model, which suffers from power loss when the model assumption is wrong. The Jonckheere-Terpstra (JT) trend test is an alternative method to evaluate association in a nonparametric way. This study compares the power of the JT trend test and the CA trend test in various scenarios, including different sample sizes (200–2000), minor allele frequencies (0.05–0.4), and underlying modes of inheritance (dominant genetic model to recessive genetic model). By simulation and real data analysis, it is shown that in general the JT trend test has higher, similar, and lower power than the CA trend test when the underlying mode of inheritance is dominant, additive, and recessive, respectively; when the sample size is small and the minor allele frequency is low, the JT trend test outperforms the CA trend test across the spectrum of genetic models. In sum, the JT trend test is a valuable alternative to the CA trend test under certain circumstances with higher statistical power, which could lead to better detection of genetic signals to human diseases and finer dissection of their genetic architecture. [ABSTRACT FROM AUTHOR]

Objectives: There is no consensus on the management plan for incidental prostate cancer (IPCa) after holmium laser enucleation of the prostate (HoLEP). This study aims to investigate the natural course of this disease and suggest appropriate treatment in real clinical practice. Methods: The medical records of a prospective cohort of patients with LUTS/BPH who underwent HoLEP between July 2008 and December 2020 at Seoul National University Hospital were retrospectively reviewed. Patients who underwent HoLEP for palliative purpose of prostate cancer control were excluded. The natural history of IPCa was assessed by the clinician in a descriptive manner for each treatment option. Results: Among 2630 patients, 141 (5.4%) were diagnosed with IPCa after HoLEP. Pathologic T stage and magnetic resonance imaging results were highly associated with the physician's primary treatment decision-making for IPCa. Active surveillance (AS) was performed in 80% of patients, of whom 90% underwent follow-up without intervention, while the remaining 10% underwent deferred active treatment with a median follow-up of 46.3 months due to International Society of Urological Pathology grade group upgrading or increasing core involvement percentage. Meanwhile, 20% of patients underwent immediate active treatment. With a median follow-up period of 88.3 months after treatment, only one of 25 patients had biochemical recurrence. Conclusions: The incidence of IPCa after HoLEP was 5.4%, and among these, approximately 20% proceeded with immediate definitive therapy and an additional 6% ultimately received definitive therapy within a median of 4 years of AS but showed excellent oncological outcomes. [ABSTRACT FROM AUTHOR]

Given the shortage of cost-of-illness studies in dementia outside of the Western population, the current study estimated the annual cost of dementia in Taiwan and assessed whether different categories of care costs vary by severity using multiple disease-severity measures.This study included 231 dementia patient-caregiver dyads in a dementia clinic at a national university hospital in southern Taiwan. Three disease measures including cognitive, functional, and behavioral disturbances were obtained from patients based on medical history. A societal perspective was used to estimate the total costs of dementia according to three cost sub-categories. The association between dementia severity and cost of care was examined through bivariate and multivariate analyses.Total costs of care for moderate dementia patient were 1.4 times the costs for mild dementia and doubled from mild to severe dementia among our community-dwelling dementia sample. Multivariate analysis indicated that functional declines had a greater impact on all cost outcomes as compared to behavioral disturbance, which showed no impact on any costs. Informal care costs accounted for the greatest share in total cost of care for both mild (42%) and severe (43%) dementia patients.Since the total costs of dementia increased with severity, providing care to delay disease progression, with a focus on maintaining patient physical function, may reduce the overall cost of dementia. The greater contribution of informal care to total costs as opposed to social care also suggests a need for more publicly-funded long-term care services to assist family caregivers of dementia patients in Taiwan.

Obstructive sleep apnea syndrome (OSA) has been recognized as a common health problem, and increasing obesity rates have led to further remarkable increases in the prevalence of OSA, along with more prominent cardiovascular morbidities. Though previous studies have reported an independent relationship between elevated high sensitivity C-reactive protein (hsCRP) levels and OSA, the issue remains controversial owing to inadequate consideration of obesity and various confounding factors. So far, few population based studies of association between OSA and hsCRP levels have been published. Therefore, the purpose of the present study was to investigate whether OSA is associated with increased hsCRP levels independent of obesity in a large population-based study. A total of 1,835 subjects (968 men and 867 women) were selected from a larger cohort of the ongoing Korean Genome and Epidemiology Study (KoGES). Overnight polysomnography was performed on each participant. All participants underwent anthropometric measurements and biochemical analyses, including analysis of lipid profiles and hsCRP levels. Based on anthropometric data, body mass index (BMI) and waist hip ratio (WHR) were calculated and fat mass (FM) were measured by means of multi-frequency bioelectrical impedance analysis (BIA). Mild OSA and moderate to severe OSA were defined by an AHI >5 and ≥15, respectively. The population was sub-divided into 3 groups based on the tertile cut-points for the distribution of hsCRP levels. The percentage of participants in the highest tertile of hsCRP increased dose-dependently according to the severity of OSA. After adjustment for potential confounders and obesity-related variables (BMI, WHR, and body fat) in a multiple logistic model, participants with moderate to severe OSA had 1.73-, 2.01-, and 1.61-fold greater risks of being in the highest tertile of hsCRP levels than participants with non-OSA, respectively. Interaction between obesity (BMI ≥25kg/m2) and the presence of moderate-to-severe OSA was significant on the middle tertile levels of hsCRP (OR = 2.4), but not on the highest tertile, compared to the lowest tertile. OSA is independently associated with elevated hsCRP levels and may reflect an increased risk for cardiovascular morbidity. However, we found that OSA and obesity interactively contribute to individuals with general levels of hsCRP (

Chronic myeloid leukemia (CML) is a myeloproliferative disease. Imatinib (IM), the first line treatment for CML, is excessively expensive and induces various side effects in CML patients. Therefore, it is essential to investigate a new strategy for improving CML therapy. Our immunoblot data revealed that RanGTPase activating protein 1 (RanGAP1) protein levels increased by approximately 30-fold in K562 cells compared with those in normal cells. RanGAP1 is one of the important components of RanGTPase system, which regulates the export of nuclear protein. However, whether RanGAP1 level variation influences BCR-ABL nuclear export is still unknown. In this report, using shRNA to downregulate RanGAP1 expression level augmented K562 cell apoptosis by approximately 40% after treatment with 250 nM IM. Immunofluorescence assay also indicated that three-fold of nuclear BCR-ABL was detected. These data suggest that BCR-ABL nuclear entrapment induced by RanGAP1 downregulation can be used to improve IM efficacy. Moreover, our qRT-PCR data indicated a trend of inverse correlation between the RanGAP1 and microRNA (miR)-1301 levels in CML patients. MiR-1301, targeting the RanGAP1 3' untranslated region, decreased by approximately 100-fold in K562 cells compared with that in normal cells. RanGAP1 downregulation by miR-1301 transfection impairs BCR-ABL nuclear export to increase approximately 60% of cell death after treatment of 250 nM IM. This result was almost the same as treatment with 1000 nM IM alone. Furthermore, immunofluorescence assay demonstrated that Tyr-99 of nuclear P73 was phosphorylated accompanied with nuclear entrapment of BCR-ABL after transfection with RanGAP1 shRNA or miR-1301 in IM-treated K562 cells. Altogether, we demonstrated that RanGAP1 downregulation can mediate BCR-ABL nuclear entrapment to activate P73-dependent apoptosis pathway which is a novel strategy for improving current IM treatment for CML.

PURPOSE:There have been conflicting reports regarding the association of perioperative blood transfusion (PBT) with oncologic outcomes including recurrence rates and survival outcomes in prostate cancer. We aimed to evaluate whether perioperative blood transfusion (PBT) affects biochemical recurrence-free survival (BRFS), cancer-specific survival (CSS), and overall survival (OS) following radical prostatectomy (RP) for patients with prostate cancer. MATERIALS AND METHODS:A total of 2,713 patients who underwent RP for clinically localized prostate cancer between 1993 and 2014 were retrospectively analyzed. We performed a comparative analysis based on receipt of transfusion (PBT group vs. no-PBT group) and transfusion type (autologous PBT vs. allogeneic PBT). Univariate and multivariate Cox-proportional hazard regression analysis were performed to evaluate variables associated with BRFS, CSS, and OS. The Kaplan-Meier method was used to calculate survival estimates for BRFS, CSS, and OS, and log-rank test was used to conduct comparisons between the groups. RESULTS:The number of patients who received PBT was 440 (16.5%). Among these patients, 350 (79.5%) received allogeneic transfusion and the other 90 (20.5%) received autologous transfusion. In a multivariate analysis, allogeneic PBT was found to be statistically significant predictors of BRFS, CSS, and OS; conversely, autologous PBT was not. The Kaplan-Meier survival analysis showed significantly decreased 5-year BRFS (79.2% vs. 70.1%, log-rank, p = 0.001), CSS (98.5% vs. 96.7%, log-rank, p = 0.012), and OS (95.5% vs. 90.6%, log-rank, p < 0.001) in the allogeneic PBT group compared to the no-allogeneic PBT group. In the autologous PBT group, however, none of these were statistically significant compared to the no-autologous PBT group. CONCLUSIONS:We found that allogeneic PBT was significantly associated with decreased BRFS, CSS, and OS. This provides further support for the immunomodulation hypothesis for allogeneic PBT.

Chronic kidney disease (CKD) is a major complication of metabolic disorders such as diabetes mellitus, obesity, and hypertension. Comorbidity of these diseases is the factor exacerbating CKD progression. Statins are commonly used in patients with metabolic disorders to decrease the risk of cardiovascular complications. Sarpogrelate, a selective antagonist of 5-hydroxytryptamine (5-HT) 2A receptor, inhibits platelet aggregation and is used to improve peripheral circulation in diabetic patients. Here, we investigated the effects of sarpogrelate and rosuvastatin on CKD in mice that were subjected to a high fat diet (HFD) for 22 weeks and a single low dose of streptozotocin (STZ, 40 mg/kg). When mice were administrated sarpogrelate (50 mg/kg, p.o.) for 13 weeks, albuminuria and urinary cystatin C excretion were normalized and histopathological changes such as glomerular mesangial expansion, tubular damage, and accumulations in lipid droplets and collagen were significantly improved. Sarpogrelate treatment repressed the HFD/STZ-induced CD31 and vascular endothelial growth factor receptor-2 expressions, indicating the attenuation of glomerular endothelial proliferation. Additionally, sarpogrelate inhibited interstitial fibrosis by suppressing the increases in transforming growth factor-β1 (TGF-β1) and plasminogen activator inhibitor-1 (PAI-1). All of these functional and histological improvements were also seen in rosuvastatin (20 mg/kg) group and, notably, the combinatorial treatment with sarpogrelate and rosuvastatin showed additive beneficial effects on histopathological changes by HFD/STZ. Moreover, sarpogrelate reduced circulating levels of PAI-1 that were elevated in the HFD/STZ group. As supportive in vitro evidence, sarpogrelate incubation blocked TGF-β1/5-HT-inducible PAI-1 expression in murine glomerular mesangial cells. Taken together, sarpogrelate and rosuvastatin may be advantageous to control the progression of CKD in patients with comorbid metabolic disorders, and particularly, the use of sarpogrelate as adjunctive therapy with statins may provide additional benefits on CKD.

Continuous imaging of live tissues provides clear temporal sequence of biological events. The Drosophila imaginal discs have been popular experimental subjects for the study of a wide variety of biological phenomena, but long term culture that allows normal development has not been satisfactory. Here we report a culture method that can sustain normal development for 18 hours and allows live imaging. The method is validated in multiple discs and for cell proliferation, differentiation and migration. However, it does not support disc growth and cannot support cell proliferation for more than 7 to 12 hr. We monitored the cellular behavior of retinal basal glia in the developing eye disc and found that distinct glia type has distinct properties of proliferation and migration. The live imaging provided direct proof that wrapping glia differentiated from existing glia after migrating to the anterior front, and unexpectedly found that they undergo endoreplication before wrapping axons, and their nuclei migrate up and down along the axons. UV-induced specific labeling of a single carpet glia also showed that the two carpet glia membrane do not overlap and suggests a tiling or repulsion mechanism between the two cells. These findings demonstrated the usefulness of an ex vivo culture method and live imaging.

To assess the neuroprotective effects of flibanserin (formerly BIMT-17), a dual 5-HT1A agonist and 5-HT2A antagonist, in a light-induced retinopathy model.Albino BALB/c mice were injected intraperitoneally with either vehicle or increasing doses of flibanserin ranging from 0.75 to 15 mg/kg flibanserin. To assess 5-HT1A-mediated effects, BALB/c mice were injected with 10 mg/kg WAY 100635, a 5-HT1A antagonist, prior to 6 mg/kg flibanserin and 5-HT1A knockout mice were injected with 6 mg/kg flibanserin. Injections were administered once immediately prior to light exposure or over the course of five days. Light exposure lasted for one hour at an intensity of 10,000 lux. Retinal structure was assessed using spectral domain optical coherence tomography and retinal function was assessed using electroretinography. To investigate the mechanisms of flibanserin-mediated neuroprotection, gene expression, measured by RT-qPCR, was assessed following five days of daily 15 mg/kg flibanserin injections.A five-day treatment regimen of 3 to 15 mg/kg of flibanserin significantly preserved outer retinal structure and function in a dose-dependent manner. Additionally, a single-day treatment regimen of 6 to 15 mg/kg of flibanserin still provided significant protection. The action of flibanserin was hindered by the 5-HT1A antagonist, WAY 100635, and was not effective in 5-HT1A knockout mice. Creb, c-Jun, c-Fos, Bcl-2, Cast1, Nqo1, Sod1, and Cat were significantly increased in flibanserin-injected mice versus vehicle-injected mice.Intraperitoneal delivery of flibanserin in a light-induced retinopathy mouse model provides retinal neuroprotection. Mechanistic data suggests that this effect is mediated through 5-HT1A receptors and that flibanserin augments the expression of genes capable of reducing mitochondrial dysfunction and oxidative stress. Since flibanserin is already FDA-approved for other indications, the potential to repurpose this drug for treating retinal degenerations merits further investigation.

The roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in obesity-associated insulin resistance have been explored in both animal and human studies. However, our current understanding of obesity-associated insulin resistance relies on studies of artificial metabolic extremes. The purpose of this study was to explore the roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in human patients with modest obesity and early metabolic dysfunction. We obtained omental adipose tissue and fasting blood samples from 51 females undergoing gynecologic surgery. We investigated serum concentrations of proinflammatory cytokines and adipokines as well as the mRNA expression of proinflammatory and macrophage phenotype markers in visceral adipose tissue using ELISA and quantitative RT-PCR. We measured adipose tissue inflammation and macrophage infiltration using immunohistochemical analysis. Serum levels of adiponectin and leptin were significantly correlated with HOMA-IR and body mass index. The levels of expression of MCP-1 and TNF-α in visceral adipose tissue were also higher in the obese group (body mass index ≥ 25). The expression of mRNA MCP-1 in visceral adipose tissue was positively correlated with body mass index (r = 0.428, p = 0.037) but not with HOMA-IR, whereas TNF-α in visceral adipose tissue was correlated with HOMA-IR (r = 0.462, p = 0.035) but not with body mass index. There was no obvious change in macrophage phenotype or macrophage infiltration in patients with modest obesity or early metabolic dysfunction. Expression of mRNA CD163/CD68 was significantly related to mitochondrial-associated genes and serum inflammatory cytokine levels of resistin and leptin. These results suggest that changes in the production of inflammatory biomolecules precede increased immune cell infiltration and induction of a macrophage phenotype switch in visceral adipose tissue. Furthermore, serum resistin and leptin have specific roles in the regulation of adipose tissue macrophages in patients with modest obesity or early metabolic dysfunction.

A hypothetical protein TON_0340 of a Thermococcus species is a protein conserved in a variety of organisms including human. Herein, we present four different crystal structures of TON_0340, leading to the identification of an active-site cavity harboring a metal-binding site composed of six invariant aspartate and glutamate residues that coordinate one to three metal ions. Biochemical and mutational analyses involving many phosphorous compounds show that TON_0340 is a Mn2+-dependent phosphatase. Mg2+ binds to TON_0340 less tightly and activates the phosphatase activity less efficiently than Mn2+. Whereas Ca2+ and Zn2+ are able to bind to the protein, they are unable to activate its enzymatic activity. Since the active-site cavity is small and largely composed of nearly invariant stretches of 11 or 13 amino acids, the physiological substrates of TON_0340 and its homologues are likely to be a small and the same molecule. The Mn2+-bound TON_0340 structure provides a canonical model for the ubiquitously present TON_0340 homologues and lays a strong foundation for the elucidation of their substrate and biological function.

Enzyme replacement therapy with intravenous idursulfase (recombinant iduronate-2-sulfatase) is approved for the treatment of Hunter syndrome. Intravenous administration does not, however, treat the neurological manifestations, due to its low central nervous system bioavailability. Using intrathecal-lumbar administration, iduronate-2-sulfatase is delivered directly to the central nervous system. This study investigates the central nervous system biodistribution of intrathecal-lumbar administered iduronate-2-sulfatase in cynomolgus monkeys. Twelve monkeys were administered iduronate-2-sulfatase in one 30 mg intrathecal-lumbar injection. Brain, spinal cord, liver, and kidneys were collected for iduronate-2-sulfatase concentration (measured by an enzyme linked immunosorbent assay) and enzyme activity measurement (via a method utilizing 4-methylumbelliferyl-α-iduronate-2-sulfate) at 1, 2, 5, 12, 24, and 48 hours following administration. The tissue enzyme linked immunosorbent assay confirmed iduronate-2-sulfatase uptake to the brain, spinal cord, kidneys, and liver in a time-dependent manner. In spinal cord and brain, iduronate-2-sulfatase appeared as early as 1 hour following administration, and peak concentrations were observed at ~2 and ~5 hours. Iduronate-2-sulfatase appeared in liver and kidneys 1 hour post intrathecal-lumbar dose with peak concentrations between 5 and 24 hours. Liver iduronate-2-sulfatase concentration was approximately 10-fold higher than kidney. The iduronate-2-sulfatase localization and enzyme activity in the central nervous system, following intrathecal administration, demonstrates that intrathecal-lumbar treatment with iduronate-2-sulfatase may be considered for further investigation as a treatment for Hunter syndrome patients with neurocognitive impairment.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that primarily affects women during their reproductive years. The interaction between SLE and pregnancy remains debated. The objective of this study was to analyze the fetal and maternal outcomes of Chinese women with SLE. A total of 109 pregnancies in 83 SLE patients from June 2004 to June 2014 at a tertiary university hospital were reviewed retrospectively. Patients' characteristics, clinical and laboratory data during pregnancy were obtained from electronic medical records. After exclusion of elective abortions, the live birth rate was 61.5%. Significantly, APS (antiphospholipid syndrome), disease activity, hypertension, hypocomplementemia, thrombocytopenia, and anemia during pregnancy were more commonly observed in fetal loss pregnancies than in live birth pregnancies. Compared to the 64 women with a history of SLE, 19 women with new-onset lupus during pregnancy had worse pregnancy outcome. Furthermore, the 64 patients with a history of SLE were divided into lupus nephritis group and SLE group (non-renal involvement). We found that the lupus nephritis group had worse maternal outcome than the SLE group. We conclude that new-onset lupus during pregnancy predicts both adverse maternal and fetal outcomes, while a history of lupus nephritis predicts adverse maternal outcomes. It is essential to provide SLE women with progestational counseling and regular multispecialty care during pregnancy.

Quaking (QKI), which belongs to the STAR family of KH domain-containing RNA-binding proteins, functions in pre-mRNA splicing, microRNA regulation, and formation of circular RNA. QKI plays critical roles in myelinogenesis in the central and peripheral nervous systems and has been implicated neuron-glia fate decision in the brain; however, neither the expression nor function of QKI in the neural retina is known. Here we report the expression of QKI RNA-binding protein in the developing and mature mouse retina. QKI was strongly expressed by Müller glial cells in both the developing and adult retina. Intriguingly, during development, QKI was expressed in early differentiating neurons, such as the horizontal and amacrine cells, and subsequently in later differentiating bipolar cells, but not in photoreceptors. Neuronal expression was uniformly weak in the adult. Among QKI isoforms (5, 6, and 7), QKI-5 was the predominantly expressed isoform in the adult retina. To study the function of QKI in the mouse retina, we examined quakingviable(qkv) mice, which have a dysmyelination phenotype that results from deficiency of QKI expression and reduced numbers of mature oligodendrocytes. In homozygous qkv mutant mice (qkv/qkv), the optic nerve expression levels of QKI-6 and 7, but not QKI-5 were reduced. In the retina of the mutant homozygote, QKI-5 levels were unchanged, and QKI-6 and 7 levels, already low, were also unaffected. We conclude that QKI is expressed in developing and adult Müller glia. QKI is additionally expressed in progenitors and in differentiating neurons during retinal development, but expression weakened or diminished during maturation. Among QKI isoforms, we found that QKI-5 predominated in the adult mouse retina. Since Müller glial cells are thought to share properties with retinal progenitor cells, our data suggest that QKI may contribute to maintaining retinal progenitors prior to differentiation into neurons. On the other hand, the expression of QKI in different retinal neurons may suggest a role in neuronal cell type specific fate determination and maturation. The data raises the possibility that QKI may function in retinal cell fate determination and maturation in both glia and neurons.

Due to the ever-growing popularity mobile devices of various kinds have received worldwide, the demands on large-scale wireless network infrastructure development and enhancement have been rapidly swelling in recent years. A mobile device holder can get online at a wireless network access point, which covers a limited area. When the client leaves the access point, there will be a temporary disconnection until he/she enters the coverage of another access point. Even when the coverages of two neighboring access points overlap, there is still work to do to make the wireless connection smoothly continue. The action of one wireless network access point passing a client to another access point is referred to as the handover. During handover, for security concerns, the client and the new access point should perform mutual authentication before any Internet access service is practically gained/provided. If the handover protocol is inefficient, in some cases discontinued Internet service will happen. In 2013, Li et al. proposed a fast handover authentication mechanism for wireless mesh network (WMN) based on tickets. Unfortunately, Li et al.'s work came with some weaknesses. For one thing, some sensitive information such as the time and date of expiration is sent in plaintext, which increases security risks. For another, Li et al.'s protocol includes the use of high-quality tamper-proof devices (TPDs), and this unreasonably high equipment requirement limits its applicability. In this paper, we shall propose a new efficient handover authentication mechanism. The new mechanism offers a higher level of security on a more scalable ground with the client's privacy better preserved. The results of our performance analysis suggest that our new mechanism is superior to some similar mechanisms in terms of authentication delay.