Therapeutic Efficacy and Radiobiological Effects of Boric-Acid-Mediated BNCT in an Osteosarcoma-Bearing SD Rat Model.

BACKGROUND: Osteosarcoma (OS) is the most common primary malignancy of the bone and is notoriously resistant to radiation therapy. High-dose cytotoxic chemotherapy and surgical resection have improved the survival rate and prognosis of patients with OS. Nonetheless, treatment challenges remain when the tumor cannot be removed by surgery. Boron neutron capture therapy (BNCT) provides high linear energy transfer (LET) radiation, and its internal targeted characteristics make BNCT a novel therapy for removing OS and reducing radiation damage to adjacent healthy tissues. METHODS: In this study, a UMR-106-grafted OS rat model was developed, and boric acid (BA) was used as the boron drug for BNCT. The pharmacokinetics of BA, following intravenous injection, were evaluated to determine the optimal time window for neutron irradiation. OS-bearing rats were irradiated by an epithermal neutron beam at Tsing Hua Open-Pool Reactor (THOR). The therapeutic efficacy of and tissue response after BNCT were evaluated by radiographic and histopathological observations. RESULTS: OS-bearing rats were irradiated by neutrons in the first hour following the intravenous injection of BA. The prescription-absorbed doses in the tumor regions were 5.8 and 11.0 Gy. BNCT reduced the body weight of the tumor-bearing rats, but they recovered after a few days. The BA-mediated BNCT effectively controlled the orthotopic OS tumor, reduced osteolysis, and induced bone healing. Autoradiography and histological analysis confirmed that the BA retention region is consistent with the calcification region in OS tissue. CONCLUSION: BA is specifically retained in OS, and the BA-mediated BNCT can significantly reduce the tumor burden and osteolysis in OS-bearing rats.

An application for classifying perceptions on my health bank in Taiwan using convolutional neural networks and web-based computerized adaptive testing: A development and usability study.

BACKGROUND: The classification of a respondent's opinions online into positive and negative classes using a minimal number of questions is gradually changing and helps turn techniques into practices. A survey incorporating convolutional neural networks (CNNs) into web-based computerized adaptive testing (CAT) was used to collect perceptions on My Health Bank (MHB) from users in Taiwan. This study designed an online module to accurately and efficiently turn a respondent's perceptions into positive and negative classes using CNNs and web-based CAT. METHODS: In all, 640 patients, family members, and caregivers with ages ranging from 20 to 70 years who were registered MHB users were invited to complete a 3-domain, 26-item, 5-category questionnaire asking about their perceptions on MHB (PMHB26) in 2019. The CNN algorithm and k-means clustering were used for dividing respondents into 2 classes of unsatisfied and satisfied classes and building a PMHB26 predictive model to estimate parameters. Exploratory factor analysis, the Rasch model, and descriptive statistics were used to examine the demographic characteristics and PMHB26 factors that were suitable for use in CNNs and Rasch multidimensional CAT (MCAT). An application was then designed to classify MHB perceptions. RESULTS: We found that 3 construct factors were extracted from PMHB26. The reliability of PMHB26 for each subscale beyond 0.94 was evident based on internal consistency and stability in the data. We further found the following: the accuracy of PMHB26 with CNN yields a higher accuracy rate (0.98) with an area under the curve of 0.98 (95% confidence interval, 0.97-0.99) based on the 391 returned questionnaires; and for the efficiency, approximately one-third of the items were not necessary to answer in reducing the respondents' burdens using Rasch MCAT. CONCLUSIONS: The PMHB26 CNN model, combined with the Rasch online MCAT, is recommended for improving the accuracy and efficiency of classifying patients' perceptions of MHB utility. An application developed for helping respondents self-assess the MHB cocreation of value can be applied to other surveys in the future.

An App for Identifying Children at Risk for Developmental Problems Using Multidimensional Computerized Adaptive Testing: Development and Usability Study.

BACKGROUND: The use of multidomain developmental screening tools is a viable strategy for pediatric professionals to identify children at risk for developmental problems. However, a specialized multidimensional computer adaptive testing (MCAT) tool has not been developed to date. OBJECTIVE: We developed an app using MCAT, combined with Multidimensional Screening in Child Development (MuSiC) for toddlers, to help patients and their family members or clinicians identify developmental problems at an earlier stage. METHODS: We retrieved 75 item parameters from the MuSiC literature item bank for 1- to 3-year-old children, and simulated 1000 person measures from a normal standard distribution to compare the efficiency and precision of MCAT and nonadaptive testing (NAT) in five domains (ie, cognitive skills, language skills, gross motor skills, fine motor skills, and socioadaptive skills). The number of items saved and the cutoff points for the tool were determined and compared. We then developed an app for a Web-based assessment. RESULTS: MCAT yielded significantly more precise measurements and was significantly more efficient than NAT, with 46.67% (=(75-40)/75) saving in item length when measurement differences less than 5% were allowed. Person-measure correlation coefficients were highly consistent among the five domains. Significantly fewer items were answered on MCAT than on NAT without compromising the precision of MCAT. CONCLUSIONS: Developing an app as a tool for parents that can be implemented with their own computers, tablets, or mobile phones for the online screening and prediction of developmental delays in toddlers is useful and not difficult.

Choropleth map legend design for visualizing the most influential areas in article citation disparities: A bibliometric study.

BACKGROUND: Disparities in health outcomes across countries/areas are a central concern in public health and epidemiology. However, few authors have discussed legends that can be complemental to choropleth maps (CMs) and merely linked differences in outcomes to other factors like density in areas. Thus, whether health outcome rates on CMs showing the geographical distribution can be applied to publication citations in bibliometric analyses requires further study. The legends for visualizing the most influential areas in article citation disparities should have sophisticated designs. This paper illustrates the use of cumulative frequency (CF) map legends along with Lorenz curves and Gini coefficients (GC) to characterize the disparity of article citations in areas on CMs, based on the quantile classification method for classes. METHODS: By searching the PubMed database (pubmed.com), we used the keyword "Medicine" [journal] and downloaded 7042 articles published from 1945 to 2016. A total number of 41,628 articles were cited in Pubmed Central (PMC). The publication outputs based on the author's x-index were applied to plot CM about research contributions. The approach uses two methods (i.e., quantiles and equal total values for each class) with CF legends, in order to highlight the difference in x-indices across geographical areas on CMs. GC was applied to observe the x-index disparities in areas. Microsoft Excel Visual Basic for Application (VBA) was used for creating the CMs. RESULTS: Results showed that the most productive and cited countries in Medicine (Baltimore) were China and the US. The most-cited states and cities were Maryland (the US) and Beijing (China). Taiwan (x-index = 24.38) ranked behind Maryland (25.97), but ahead of Beijing (16.9). China earned lower disparity (0.42) than the US (0.49) and the rest of the world (0.53) when the GCs were applied. CONCLUSION: CF legends, particularly using the quantile classification for classes, can be useful to complement CMs. They also contain more information than those in standard CM legends that are commonly used with other classification methods. The steps of creating CM legends are described and introduced. Bibliometric analysts on CM can be replicated in the future.

PrtA immunization fails to protect against pulmonary and invasive infection by Streptococcus pneumoniae.

BACKGROUND: Streptococcus pneumoniae is a respiratory pathogen causing severe lung infection that may lead to complications such as bacteremia. Current polysaccharide vaccines have limited serotype coverage and therefore cannot provide maximal and long-term protection. Global efforts are being made to develop a conserved protein vaccine candidate. PrtA, a pneumococcal surface protein, was identified by screening a pneumococcal genomic expression library using convalescent patient serum. The prtA gene is prevalent and conserved among S. pneumoniae strains. Its protective efficacy, however, has not been described. Mucosal immunization could sensitize both local and systemic immunity, which would be an ideal scenario for preventing S. pneumoniae infection. METHODS: We immunized BALB/c mice intranasally with a combination of a PrtA fragment (amino acids 144-1041) and Th17 potentiated adjuvant, curdlan. We then measured the T-cell and antibody responses. The protective efficacy conferred to the immunized mice was further evaluated using a murine model of acute pneumococcal pneumonia and pneumococcal bacteremia. RESULTS: There was a profound antigen-specific IL-17A and IFN-γ response in PrtA-immunized mice compared with that of adjuvant control group. Even though PrtA-specific IgG and IgA titer in sera was elevated in immunized mice, only a moderate IgA response was observed in the bronchoalveolar lavage fluid. The PrtA-immunized antisera facilitated the activated murine macrophage, RAW264.7, to opsonophagocytose S. pneumoniae D39 strain; however, PrtA-specific immunoglobulins bound to pneumococcal surfaces with a limited potency. Finally, PrtA-induced immune reactions failed to protect mice against S. pneumoniae-induced acute pneumonia and bacterial propagation through the blood. CONCLUSIONS: Immunization with recombinant PrtA combined with curdlan produced antigen-specific antibodies and elicited IL-17A response. However, it failed to protect the mice against S. pneumoniae-induced infection.

Primary effusion lymphoma in Taiwan shows two distinctive clinicopathological subtypes with rare human immunodeficiency virus association.

AIMS: To investigate the clinicopathological and molecular features of primary effusion lymphoma (PEL) in Taiwan and the association with human immunodeficiency virus (HIV), human herpesvirus 8 (HHV8) and Epstein-Barr virus (EBV). METHODS AND RESULTS: We investigated retrospectively 26 cases with a median age of 76.5. Only one (4%) patient was infected with HIV. Cytologically, all lymphoma cells revealed typical immunoblastic to plasmablastic morphology. Immunohistochemically, HHV8 was positive in eight (32%) tumours and negative in 17 (68%) cases. All 23 tested cases examined were of the non-germinal-centre B cell phenotype. MYC proto-oncogene (MYC) and Epstein-Barr encoding mRNA (EBER) were positive in 43% (nine of 21) and 17% (four of 23) cases, respectively. Immunoglobulin heavy chain (IGH), B cell lymphoma (BCL)2, BCL6 and MYC were rearranged in 71%, 11%, 12% and 18% cases, respectively. By univariate analysis, the overall survival (OS) was associated statistically with MYC expression (P = 0.012) and BCL2 rearrangement (P = 0.035), but not with the others. By multivariate analysis, no factor was statistically significant. Compared to the HHV8-negative cases, the HHV8-positive cases were mainly of the plasmablastic immunophenotype expressing CD30 and CD138, and with a less frequent expression of pan-B cell markers. CONCLUSIONS: Apart from the phenotypical difference, our HHV8-positive neoplasms were not distinct from the HHV8-negative group. Literature review of 256 cases, including our cases, revealed that HHV8-positive cases were associated more frequently with HIV and EBV infection, with rare MYC rearrangement, and a poorer prognosis than HHV8-negative cases. We propose to name the HHV8-positive cases as 'classical' or 'type I PEL' and the HHV8-negative cases as 'type II PEL', stressing the similarities and the distinctive features between these two groups.

Bidirectional association between ESRD dialysis and diabetes: National cohort study.

BACKGROUND: Diabetes is associated with development of end-stage renal disease (ESRD) dialysis, but it is not clear whether ESRD dialysis is a risk factor for new-onset diabetes (NODM). METHODS: Using the Taiwan National Health Insurance Research Database, we designed two cohort studies to determine the association between dialysis and diabetes. Analysis 1 estimated the hazard ratios (HR) of ESRD dialysis in 20,585 patients with type 2 diabetes (T2DM) and 82,340 gender- and age- matched controls without diabetes. Analysis 2 estimated the HRs of NODM in 18,489 ESRD patients undergoing dialysis and 73,956 gender- and age- matched controls without ESRD dialysis. The follow-up period was from 2000 to date of endpoint, the date of death, or December 31, 2008. Cox proportional models were used to estimate the relative hazards. RESULTS: In analysis 1, the incidence of ESRD dialysis was higher in the T2DM cohort than in the non-diabetes cohort (6.78 vs. 0.61 per 1,000 person-years; HR: 7.97; 95%CI: 7.05-8.00). In analysis 2, the incidence of NODM was higher in the ESRD dialysis cohort than in the without-ESRD dialysis cohort (22.84 vs. 13.99 per 1,000 person-years; HR: 1.40; 95% CI: 1.34-1.47). CONCLUSIONS: ESRD dialysis and diabetes were bidirectionally associated. The relationship between T2DM and incident ESRD dialysis was much stronger than between ESRD dialysis and NODM. Further studies are needed to determine the mechanism of ESRD dialysis-related NODM.

Epstein-Barr virus transcription activator Rta upregulates decoy receptor 3 expression by binding to its promoter.

Decoy receptor 3 (DcR3) is a soluble decoy receptor belonging to the tumor necrosis factor receptor superfamily that is overexpressed in various malignant tumor types. DcR3 has been implicated in tumor cell survival by inhibiting apoptosis and by interfering with immune surveillance. A previous study showed that DcR3 expression is associated with Epstein-Barr virus (EBV)-positive lymphomas but rarely with non-EBV-positive B-cell lymphomas, suggesting that the presence of EBV may affect DcR3 expression. Here, we demonstrated enhanced DcR3 expression upon EBV reactivation in P3HR1 cells and in EBV-infected 293 cells. This enhancement, however, could not be detected in 293 cells infected with EBV with BRLF1 deleted. We found that EBV transactivator, Rta, could upregulate DcR3 expression by direct binding to an Rta-responsive element (RRE) located in the DcR3 promoter region and that this RRE is important for Rta-mediated DcR3 expression. Overexpressing CREB-binding protein (CBP) further enhanced Rta-dependent DcR3 expression, suggesting Rta-dependent DcR3 transcription activity is mediated by CBP. Previously, Rta was shown to enhance phosphatidylinositol-3 kinase (PI3-K) activity. However, Rta-transduced PI 3-K activity plays a minor role in DcR3 expression. This is the first report to demonstrate that Rta upregulates a cellular gene by direct binding to an RRE.

Enterotoxin B is the predominant toxin involved in staphylococcal scarlet fever in Taiwan.

This study retrospectively reviewed all pediatric cases of staphylococcal scarlet fever (SSF) that occurred during a 10-year period in a 1400-bed tertiary medical center in northern Taiwan. All 20 cases of SSF occurred in previously healthy individuals. Skin and soft-tissue infections predominated among children from whom Staphylococcus aureus was isolated. Polymerase chain reaction testing was used to detect known staphylococcal toxin genes, and of the isolates studied, most (18 [90%] of 20) contained only the staphylococcal enterotoxin B. One of the other strains was positive for staphylococcal enterotoxin A only, and the last strain was positive for both staphylococcal enterotoxin G and staphylococcal enterotoxin I. Pulsed-field gel electrophoresis identified a small cluster of isolates (6 [30%] of 20) that were genetically related, but these strains came from epidemiologically unrelated patients during a 3-year period.