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Oral formulations of insulin are typically designed to improve its intestinal absorption and increase its blood bioavailability. Here we show that polymerized ursodeoxycholic acid, selected from a panel of bile-acid polymers and formulated into nanoparticles for the oral delivery of insulin, restored blood-glucose levels in mice and pigs with established type 1 diabetes. The nanoparticles functioned as a protective insulin carrier and as a high-avidity bile-acid-receptor agonist, increased the intestinal absorption of insulin, polarized intestinal macrophages towards the M2 phenotype, and preferentially accumulated in the pancreas of the mice, binding to the islet-cell bile-acid membrane receptor TGR5 with high avidity and activating the secretion of glucagon-like peptide and of endogenous insulin. In the mice, the nanoparticles also reversed inflammation, restored metabolic functions and extended animal survival. When encapsulating rapamycin, they delayed the onset of diabetes in mice with chemically induced pancreatic inflammation. The metabolic and immunomodulatory functions of ingestible bile-acid-polymer nanocarriers may offer translational opportunities for the prevention and treatment of type 1 diabetes.

Background The present study focused on the inflammatory disease progress after periodontal defect induction and aimed to specifically determine periodontal tissue responses following dental plaque accumulation by ligatures on a site with/without standardized periodontal defect induction. Methods After 1 month from extraction of the adjacent teeth, semi-circumferential defects were surgically created in the unilateral second and fourth premolars (test group), whereas no defects were being induced at the contralateral sites (control group). One week later, silk was used to ligate the tooth cervix at both sites to encourage the accumulation of dental plaque. Four weeks later, the tissue samples were collected for histological/histomorphometric and microarray analysis. Microbiological analysis was performed before defect induction and at ligatures, and after 4 weeks of dental plaque accumulation. Results Remarkable inflammation was clinically and histologically observed in both groups after plaque accumulation, and the intrabony type of periodontal defect exaggerated inflammatory cell infiltration into the connective tissue layer. Expression of genes related to inflammation such as IL-1 was highly up-regulated in test sites. However, these inflammatory infiltrations did not invade to a boundary of periodontal ligament and connective tissue attachment in both groups, and histomorphometric results corresponds to these observational results. Bacterial findings also showed no significant differences in detected microbiome compositions between control and test groups at three-time points. Conclusion Intrabony defect might exaggerate the plaque-induced inflammation in the aspect of inflammatory cell infiltration and the related gene expression, but both dental plaque and the pre-existing periodontal defect negligibly disrupt periodontal attachment and the underlying alveolar bone.

Anti-leucine-rich glioma-inactivated 1 (LGI-1) encephalitis is clinically characterized by subacute cognitive decline and frequent seizures including fasciobrachial dystonic seizures. A 67-year-old man visited the emergency department due to the recurrent episodes of seizures of 4 days duration. At the time of the visit, he showed hyponatremia at Na 121 mg/dL. His symptoms were relieved by 3% sodium chloride and water restriction. Here we report a case of anti-LGI-1 encephalitis with worsening symptoms associated with hyponatremia.

Purpose The aim of this study was to compare the characteristic expression patterns of advanced periodontitis in 2 cohort data sets analyzed using different microarray platforms, and to identify differentially expressed genes (DEGs) through a meta-analysis of both data sets. Methods Twenty-two patients for cohort 1 and 40 patients for cohort 2 were recruited with the same inclusion criteria. The 2 cohort groups were analyzed using different platforms: Illumina and Agilent. A meta-analysis was performed to increase reliability by removing statistical differences between platforms. An integrative meta-analysis based on an empirical Bayesian methodology (ComBat) was conducted. DEGs for the integrated data sets were identified using the limma package to adjust for age, sex, and platform and compared with the results for cohorts 1 and 2. Clustering and pathway analyses were also performed. Results This study detected 557 and 246 DEGs in cohorts 1 and 2, respectively, with 146 and 42 significantly enriched gene ontology (GO) terms. Overlapping between cohorts 1 and 2 was present in 59 DEGs and 18 GO terms. However, only 6 genes from the top 30 enriched DEGs overlapped, and there were no overlapping GO terms in the top 30 enriched pathways. The integrative meta-analysis detected 34 DEGs, of which 10 overlapped in all the integrated data sets of cohorts 1 and 2. Conclusions The characteristic expression pattern differed between periodontitis and the healthy periodontium, but the consistency between the data sets from different cohorts and metadata was too low to suggest specific biomarkers for identifying periodontitis., Graphical Abstract

Oculomotor nerve palsy is underrecognized clinical manifestation of extracranial internal carotid artery (ICA) dissection. Herein we report a case of complete oculomotor nerve palsy following endovascular revascularization, which developed in a patient with acute stroke due to extracranial ICA dissecting occlusion. We also discuss about the development mechanism of oculomotor nerve palsy, considering the vascular anatomy and the possibility of periprocedural complications during endovascular treatment.

Highlights • Data are lacking on dengue in Africa. • This surveillance covered the beginning of a dengue outbreak in April-May 2017. • 61% of 482 patients with non-malarial fever in Mombasa were dengue-positive. • Dengue cases presented with rash, retro-orbital pain, myalgia, arthralgia, etc. • Dengue cases were mostly mild with only two cases requiring observation, and no DHF., Objectives Information on dengue in Africa is limited. To estimate the proportion of dengue-positive cases among febrile patients and describe clinical indicators of dengue, we conducted passive health facility-based fever surveillance in Mombasa, Kenya. Methods Non-malarial febrile patients between one and 55 years were enrolled at three health facilities between March 2016 and May 2017. Acute and convalescent blood samples were collected with an interval of 10–21 days. Acute samples were tested with dengue RDT and a selected subset with RT-PCR, and acute/convalescent samples with IgM/IgG ELISA. Results Among 482 enrollees, 295 (61.2%) were dengue-positive based on laboratory results. The surveillance covered the beginning of a dengue outbreak in April-May 2017, during which 73.9% of enrollees were dengue-positive. By contrast, during the non-outbreak period, 54.6% were dengue-positive. Dengue case status was positively associated with rash, fatigue, headache, retro-orbital pain, nausea/vomiting, nose bleeding, gum bleeding, loss of appetite, myalgia, and arthralgia. Dengue-positive cases in our study had mostly mild disease, with only two requiring observation, and no DHF. Conclusions The clinical response was generally mild relative to what was observed in SE Asia and the Americas. Given the high level of DENV transmission in Mombasa, more data would be needed to further understand the disease burden and improve case detection for surveillance/monitoring of outbreaks.

Background To evaluate gingival inflammation from fixed-dose combinations of vitamin C, vitamin E, lysozyme and carbazochrome (CELC) in the treatment of chronic periodontitis following scaling and root planing. Methods One hundred patients were randomly assigned to receive CELC (test) or placebo (control) for the first 4 weeks at a 1:1 ratio, and both groups received CELC for the remaining 4 weeks. Primary outcome was the mean change in the gingival index (GI) after 4 weeks. Secondary outcomes included mean change in GI after 8 weeks and plaque index, probing depth, clinical attachment level, and VAS at 4 weeks and 8 weeks. Results Ninety-three patients completed the study. The GI in the test group significantly decreased after 4 weeks (p

Aim: To compare the supra-alveolar gingival dimension (GD) and the clinical pocket probing depth (PD) by combining data from an intraoral scanner (IOS) and cone-beam computed tomography (CBCT), and identify the clinical features affecting the clinical PD.Materials and Methods: 1,071 sites from 11 patients were selected for whom CBCT, IOS images, and periodontal charts were recorded at the same visit. CBCT and IOS data were superimposed. GD was measured on cross-sectional images of the probed sites. The level of agreement and correlation between GD and PD were assessed for the entire population and also within groups (treated vs untreated, bleeding on probing [BOP] vs no BOP, and PDs of 0–3 mm vs 4–5 mm vs ≥6 mm).Results: The difference between GD and PD was 0.82±0.69 mm (mean±standard deviation), and they were positively correlated (r=0.790, pConclusion: The pocket PD is prone to overestimation. The digital representation of the supra-alveolar GD is similar to the PD.

Background Invasive non-typhoidal Salmonella (iNTS) is a growing health-concern in many parts of sub-Saharan Africa. iNTS is associated with fatal diseases such as HIV and malaria. Despite high case fatality rates, the disease has not been given much attention. The limited number of population-based surveillance studies hampers accurate estimation of global disease burden. Given the lack of available evidence on the disease, it is critical to identify high risk areas for future surveillance and to improve our understanding of iNTS endemicity. Methods Considering that population-based surveillance data were sparse, a composite index called the iNTS risk factor (iNRF) index was constructed based on risk factors that commonly exist across countries. Four risk factors associated with the prevalence of iNTS were considered: malaria, HIV, malnutrition, and safe water. The iNRF index was first generated based on the four risk factors which were collected within a 50 km radius of existing surveillance sites. Pearson product-moment correlation was used to test statistical associations between the iNRF index and the prevalence of iNTS observed in the surveillance sites. The index was then further estimated at the subnational boundary level across selected countries and used to identify high risk areas for iNTS. Results While the iNRF index in some countries was generally low (i.e. Rwanda) or high (i.e. Cote d’Ivoire), the risk-level of iNTS was variable not only by country but also within a country. At the provincial-level, the highest risk area was identified in Maniema, the Democratic Republic of Congo, whereas Dakar in Senegal was at the lowest risk. Conclusions The iNRF index can be a useful tool to understand the geographically varying risk-level of iNTS. Given that conducting a population-based surveillance study requires extensive human and financial resources, identifying high risk areas for iNTS prior to a study implementation can facilitate an appropriate site-selection process in the future.

Magnetic resonance is a key imaging tool for the detection of prostate cancer; however, better tools focusing on cancer specificity are required to distinguish benign from cancerous regions. We found higher expression of claudin-3 (CLDN-3) and -4 (CLDN-4) in higher grade than lower-grade human prostate cancer biopsies (n = 174), leading to the design of functionalized nanoparticles (NPs) with a non-toxic truncated version of the natural ligand Clostridium perfringens enterotoxin (C-CPE) that has a strong binding affinity to Cldn-3 and Cldn-4 receptors. We developed a first-of-its-type, C-CPE-NP-based MRI detection tool in a prostate tumor-bearing mouse model. NPs with an average diameter of 152.9 ± 15.7 nm (RS1) had a 2-fold enhancement of tumor specificity compared to larger (421.2 ± 33.8 nm) NPs (RS4). There was a 1.8-fold (P 0.01) and 1.6-fold (P 0.01) upregulation of the tumor-to-liver signal intensities of C-RS1 and C-RS4 (functionalized NPs) compared to controls, respectively. Also, tumor specificity was 3.1-fold higher (P 0.001) when comparing C-RS1 to C-RS4. This detection tool improved tumor localization of contrast-enhanced MRI, supporting potential clinical applicability.

Because of limited data on dengue virus in Burkina Faso, we conducted 4 consecutive age-stratified longitudinal serologic surveys, ≈6 months apart, among persons 1-55 years of age, during June 2015-March 2017, which included a 2016 outbreak. The seroconversion rate before the serosurvey enrollment was estimated by binomial regression, taking age as the duration of exposure, and assuming constant force of infection (FOI) over age and calendar time. We calculated FOI between consecutive surveys and rate ratios for potentially associated characteristics based on seroconversion using the duration of intervals. Among 2,897 persons at enrollment, 66.3% were IgG-positive, and estimated annual FOI was 5.95%. Of 1,269 enrollees participating in all 4 serosurveys, 438 were IgG-negative at enrollment. The annualized FOI ranged from 10% to 20% (during the 2016 outbreak). Overall, we observed high FOI for dengue. These results could support decision-making about control and preventive measures for dengue

Diagnoses based on oral fluid biomarkers have been introduced to overcome limitations of periodontal probe-based diagnoses. Diagnostic ability of certain biomarkers for periodontitis have been identified and widely studied, however, such studies targeting gingivitis is scarce. The aims of this study were to determine and compare the efficacies and accuracies of eight biomarkers in diagnosing gingivitis with the aid of receiver operating characteristic (ROC) curves. The probing depth (PD), clinical attachment loss (CAL), bleeding on probing (BOP), gingival index (GI), and plaque index (PI) were examined in 100 participants. Gingival crevicular fluid was collected using paper points, and whole-saliva samples were collected using cotton roll. Samples were analyzed using enzyme-linked immunosorbent assay kits for the different biomarkers. The levels of matrix metalloproteinase (MMP)-8, MMP-9, lactoferrin, cystatin C, myeloperoxidase (MPO), platelet-activating factor, cathepsin B, and pyridinoline cross-linked carboxyterminal telopeptide of type I collagen were analyzed. MPO and MMP-8 levels in saliva were strongly correlated with gingivitis, with Pearson&rsquo, s correlation coefficients of 0.399 and 0.217, respectively. The area under the curve (AUC) was largest for MMP-8, at 0.814, followed by values of 0.793 and 0.777 for MPO and MMP-9, respectively. The clinical parameters of GI and PI showed strong correlations and large AUC values, whereas PD and CAL did not. MMP-8 and MPO were found to be effective for diagnosing gingivitis. Further investigations based on the results of this study may identify clinically useful biomarkers for the accurate and early detection of gingivitis.

Background Asians were known to have a relatively lower incidence of venous thromboembolism (VTE), and there is insufficient evidence to suggest a specific D-dimer threshold level for screening VTE in patients with acute stroke. Methods We prospectively enrolled patients with acute ischemic stroke admitted to Jeju National University Hospital. The inclusion criteria were: 1) aged ≥18 years, 2) admission within seven days of symptom onset, and 3) an initial National Institute of Health Stroke Scale (NIHSS) score >1 for the affected lower limb. Ultrasound scans of the lower limbs and plasma D-dimer assays were performed on days 7-14 and 15-28 after stroke onset. Results Of 285 patients admitted during the study period, 52 patients met inclusion criteria (mean age 74.5, male 40.4%, median initial NIHSS score 12, and unable to walk unassisted at discharge 76.9%). During 7-14 days, 23 of 52 patients (44.2%) had a D-dimer level above 1.57 mg/L, and 9.6% had a level above 5.50 mg/L. Proximal deep vein thrombosis (DVT) was detected in 3 patients (5.8%, 95% confidence Interval 1.2-16.0%) on ultrasound examination. All DVTs were found in elderly female patients with severe leg weakness. No patient was diagnosed with pulmonary embolism during the study period. Conclusion The incidence of VTE seems to be very low among Korean patients with acute ischemic stroke. Advanced age, female sex, and severe leg weakness were important risk factors for developing DVT in this study.

Oncothermia, a special form of hyperthermia for oncological purposes, has been widely shown to be an effective mode of cancer therapy. However, its adoption among standard therapeutic practices has been limited by constraints in delivering sufficient thermal energy to tumor targets. To overcome these unique challenges in delivery presented by oncothermic therapeutics, we engineered a novel universal platform for hyperthermia cancer therapy utilizing versatile biocompatible materials. Herein, we show that Gold particle-in-particle (PIP), in which gold nanoparticles are physically confined within PLGA-PEG nanoparticles, significantly enhances thermal energy production by red-shifting the gold nanoparticle's absorption spectra via a mechanism in which we call nanoconfinement-induced therapeutic enhancement (NITE). NITE mediated Gold PIPs significantly suppress breast, skin, and multidrug resistant tumors and result in a multifold increase of heat shock protein expressed by cancer cells

The aims of the present study were (i) to determine the short-term effects of putty-type porcine bone substitute material (PB) with recombinant bone morphogenetic protein-2 (rhBMP-2) for alveolar ridge preservation (ARP) and (ii) evaluate the early healing of labial overaugmentation. Two groups were randomly assigned to the extraction sockets in mandibular incisors of eight dogs: labial overaugmentation with (i) PB (control) or (ii) rhBMP-2-loaded PB (BMP). Microcomputed tomography (micro-CT), and histologic and histomorphometric analyses were performed after 4 weeks. Micro-CT revealed that some of the overaugmented PB was dispersed in both groups. The new bone volume was significantly larger in the BMP group than in the control group (18.4 ± 3.3 vs. 15.5 ± 3.0 mm3, mean ± SD, P

Backgrounds Clinical benefits in bone grafting of intact extraction socket have been widely known, but limited evidence is available for the procedure in damaged extraction sockets due to periodontal disease. Purpose This study aimed to determine the dimensional alteration of alveolar ridge following bone grafting of damaged extraction sockets, and compare the outcomes of using deproteinized bovine (DBBM) versus porcine bone mineral (DPBM) in the damaged sockets. Materials and Methods One hundred patients (n = 50 for each group) with periodontitis‐induced damaged extraction socket were included in this randomized, single‐blind trial. After removal of tooth and granulation tissue, sites were grafted with either DBBM (DBBM group) or DPBM (DPBM group), and covered with collagen membrane. Linear/volumetric analyses of hard and soft‐tissue dimensions were performed on reconstructed/superimposed computed tomography and scanned cast images, taken immediately and 4 months after surgery. Results The two groups showed comparable hard tissue augmentation with minimal reductions in the grafted volume, as well as in vertical (1.22 ± 2.16 and 1.45 ± 1.92 mm for DPBM and DBBM group, respectively) and horizontal (1.43 ± 3.40 and 1.83 ± 2.85 mm on the central section, respectively) dimensions at 4 months after surgery. However, several cases showed large variations in maintenance of the grafted volume. None of the measured parameters in hard and soft tissue dimensions differed significantly between DBBM and DPBM sites. Conclusions DBBM and DPBM can comparably augment damaged extraction sockets with minimal postoperative reduction of the grafted volume. However, the large variations in the results should be further evaluated for application in routine dental clinics.

Background: Group A Streptococcus (Strep A) causes a broad spectrum of disease manifestations, ranging from benign symptoms including throat or skin infections, to fatal illness such as rheumatic heart disease, or chronic renal failure. Currently, there is no vaccine available against Strep A infections. Despite the high burden of Strep A-associated infections worldwide, little attention has been paid to the research of these diseases, including standardized surveillance programs, resulting in a lack of economic evaluations for prevention efforts. This study aims at identifying existing cost-effectiveness analyses (CEA) on any Strep A infections. Methods: A systematic literature review was conducted by searching the PubMed electronic database. Results: Of a total of 321, 44 articles met the criteria for inclusion. Overall, CEA studies on Strep A remain limited in number. In particular, a number of available CEA studies on Strep A are disproportionately lower in low-income countries than in high-income countries. Decision-analytic models were the most popular choice for CEA on Strep A. A majority of the models considered pharyngitis and acute rheumatic fever, but it was rare to observe a model which covered a wide range of disease manifestations. Conclusions: Future research is needed to address missing clinical outcomes, imbalance on study locations by income group, and the transmission dynamic of selected diseases.

A Typhoid Conjugate Vaccine (TCV) is expected to acquire WHO prequalification soon, which will pave the way for its use in many low- and middle-income countries where typhoid fever is endemic. Thus it is critical to forecast future vaccine demand to ensure supply meets demand, and to facilitate vaccine policy and introduction planning. We forecasted introduction dates for countries based on specific criteria and estimated vaccine demand by year for defined vaccination strategies in 2 scenarios: rapid vaccine introduction and slow vaccine introduction. In the rapid introduction scenario, we forecasted 17 countries and India introducing TCV in the first 5 y of the vaccine's availability while in the slow introduction scenario we forecasted 4 countries and India introducing TCV in the same time period. If the vaccine is targeting infants in high-risk populations as a routine single dose, the vaccine demand peaks around 40 million doses per year under the rapid introduction scenario. Similarly, if the vaccine is targeting infants in the general population as a routine single dose, the vaccine demand increases to 160 million doses per year under the rapid introduction scenario. The demand forecast projected here is an upper bound estimate of vaccine demand, where actual demand depends on various factors such as country priorities, actual vaccine introduction, vaccination strategies, Gavi financing, costs, and overall product profile. Considering the potential role of TCV in typhoid control globally; manufacturers, policymakers, donors and financing bodies should work together to ensure vaccine access through sufficient production capacity, early WHO prequalification of the vaccine, continued Gavi financing and supportive policy.

Background Dengue is a major public health problem in the tropics and sub-tropics, but the disease is less known to non-dengue-endemic countries including in Northeast Asia. However, an unexpected dengue outbreak occurred in 2014 in Japan. Given that autochthonous (domestic) dengue cases had not been reported for the past 70 years in Japan, this outbreak was highly unusual and suggests that several environmental factors might have changed in a way that favors vector mosquitoes in the Northeast Asian region. Methods A Climate Risk Factor (CRF) index, as validated in previous work, was constructed using climate and non-climate factors. This CRF index was compared to the number of reported dengue cases in Tokyo, Japan where the outbreak was observed in 2014. In order to identify high-risk areas, the CRF index was further estimated at the 5 km by 5 km resolution and mapped for Japan and South Korea. Results The high-risk areas determined by the CRF index corresponded well to the provinces where a high number of autochthonous cases were reported during the outbreak in Japan. At the provincial-level, high-risk areas for dengue fever were the Eastern part of Tokyo and Kanakawa, the South-Eastern part of Saitama, and the North-Western part of Chiba. While a relatively small number of high-risk areas were identified in South Korea compared with Japan, the high-risk areas in South Korea include popular tourist destinations where international visitors have been increasing. Conclusion The recent dengue outbreak in Japan may signal that the two adjacent non-dengue-endemic countries are also exposed to the risk of temporal and sporadic behavior of dengue fever. It is critical to understand potential high-risk areas for future outbreaks and to set up appropriate prevention activities at the governmental-level.

Background Dengue is a major public health problem in Thailand, but data are often focused on certain dengue-endemic areas. Methods: To better understand dengue epidemiology and clinical characteristics in Thailand, a fever surveillance study was conducted among patients aged 1–55 years, who presented with non-localized febrile illness at Bang Phae Community Hospital in Ratchaburi province, Thailand from October 2011 to September 2016. Results Among 951 febrile episodes, 130 were dengue-confirmed. Individuals aged 10–14 years were mostly affected, followed by those 15–19 years-of-age, with about 15% of dengue-confirmed cases from adults 25 years and older. There were annual peaks of dengue occurrence between June-November. Most prevalent serotype in circulation was DENV-2 in 2012, DENV-3 in 2014, and DENV-4 & -3 in 2015. Among dengue cases, 65% were accurately detected using the dengue NS1 RDT. Detection rate was similar between secondary and primary dengue cases where 66% of secondary vs. 60% of primary dengue cases had positive results on the NS1 RDT. Among dengue cases, 66% were clinically diagnosed with suspected dengue or DHF, prior to lab confirmation. Dengue was positively associated with rash, headache, hematemesis and alterations to consciousness, when compared to non-dengue. Dengue patients were 10.6 times more likely to be hospitalized, compared to non-dengue cases. Among dengue cases, 95 were secondary and 35 were primary infections. There were 8 suspected DHF cases and all were identified to be secondary dengue. Secondary dengue cases were 3.5 times more likely to be hospitalized compared to primary dengue cases. Although the majority of our dengue-positive patients were secondary dengue cases, with few patients showing manifestations of DHF, our dengue cases were mostly mild disease. Even among children < 10 years-of-age, 61% had secondary infection and the rate of secondary infection increased with age. Conclusion While the majority of dengue-confirmed cases were children, almost three-quarters of dengue-confirmed cases in this study were secondary dengue. Our study results consistent with previous data from the country confirm the hyperendemic transmission of DENV in Thailand, even in the non-epidemic years. With various interventions becoming available for dengue prevention and control, including dengue vaccines, decision-making on future implementation strategies should be based on such burden of disease data., Author summary Dengue is a well-known public health problem in Thailand. To identify epidemiologic and clinical patterns of dengue in Thailand, we studied 951 febrile patients with fever, aged 1–55 years, who attended Bang Phae district hospital in Ratchaburi province, Thailand. Patients were tested with a rapid test for dengue, and further tests were carried out on paired blood samples taken 10–21 days apart. Overall, 14% of the febrile episodes identified between October 2011 and September 2016 were dengue-confirmed. Teenagers were mostly affected with only few adults. Dengue peaks occurred between June-November, but there was no large epidemic during the study period. DENV type 2 was the main serotype in circulation in 2012, DENV type 3 in 2014, and DENV types 4 and 3 in 2015. Dengue cases were 11 times more likely to be hospitalized than non-dengue cases. Dengue patients were more likely to present with rash, headache, hematemesis and alterations to consciousness, compared to non-dengue. Two thirds of the dengue cases were clinically diagnosed with suspected dengue or DHF, even without lab confirmation. Secondary dengue cases were about three times more common than primary cases. Even among children < 10 years-of-age, 61% of the patients were of secondary infection. Among dengue cases, 65% were accurately detected using the dengue RDT. This was not different between secondary and primary dengue cases. All 8 patients clinically diagnosed with DHF were secondary dengue cases. Although most of our dengue-positive patients were secondary dengue cases, we only observed few patients showing DHF. Thus, we concluded that our dengue cases were mostly of mild dengue illness. Our study results support the previous data confirming the high burden of dengue in Thailand and such information would help to make decisions on future implementation of various tools for dengue prevention and control.

Background In Africa, information on dengue is limited to outbreak reports and focused on some countries with continuing transmission in West and East Africa. To estimate the proportion of dengue-positive cases among febrile patients and identify clinical indicators of dengue cases, we conducted passive facility-based fever surveillance in a catchment area population of 70,000 residents of Lambaréné and its surroundings in Gabon. Methods Non-malarial febrile patients with current fever or history of fever (≤7 days) between 1 and 55 years of age, were enrolled at Albert Schweitzer Hospital (ASH). Acute (visit 1, day of enrollment) and convalescent blood samples were collected between 10 and 21 days after enrollment. Acute/convalescent samples were tested with IgM/IgG ELISA, and a selected subset of acute samples with RT-PCR. Results Among 682 non-malarial febrile patients enrolled, 119 (17.4%) were identified as dengue-positive (94 dengue-confirmed and 25 dengue-probable cases). Of these dengue-positive cases, 14 were confirmed with PCR, and based on serotyping, two infections were identified to be DENV-2 and two were DENV-3. The majority of our enrolled patients were, Author summary In Africa, information on dengue is limited to outbreak reports focused on some countries in West and East Africa. To estimate the proportion of dengue-positive cases among febrile patients and identify clinical indicators of dengue cases, we conducted passive health facility-based fever surveillance in a catchment area population of 70,000 residents of Lambaréné and its surroundings, Gabon. Among the patients with negative malaria RDT results, those with current fever or history of fever (≤7 days) between 1 and 55 years of age were enrolled at Albert Schweitzer Hospital (ASH). Two samples were collected with an interval of 10 to 21 days after enrollment. Samples underwent different testing for dengue confirmation. Among 682 febrile patients enrolled, 17.4% were identified as dengue-positive. Of these dengue-positive cases, we found DENV-2 and DENV-3 serotypes. Close to 80% of our dengue-positive cases were < 15 years old. Retro-orbital pain and abdominal pain were more commonly found among dengue-positive cases, compared to non-dengue cases. Lambaréné is not considered dengue-endemic. However, one in six non-malarial febrile episodes was found to be dengue-positive in the study period. Clinicians should consider dengue more frequently among non-malarial febrile patients. Given the lack of data on dengue in Gabon, more data should be generated to understand the burden and patterns of dengue for improved case detection.

Subluxation of the extensor tendon results from a disruption to the sagittal band at the metacarpophalangeal joint. When conservative treatment fails to correct the subluxation, surgical treatment may be necessary. Surgical techniques for chronic cases vary in graft source and graft pathway. We present a surgical technique to recentralize and stabilize the extensor tendon using a residual ruptured sagittal band. This technique is simple and effective without donor site morbidity and seems to provide potential biomechanical advantages by restoring nearly normal anatomy.

The beneficial effects of a strength exercise program and a combined exercise program of strength training plus walking were examined in overweight with chronic back pain patients. The participants were randomly placed in the strength exercise group (SEG, n=15), combined exercise group (CEG, n=15), and control group (CG, n=6). All subjects performed exercise twice per week, 50 min per session with a professional instructors for 12 weeks. In order to evaluate exercise intervention effects, lumbar function was measured by back strength and flexibility. Roland-Morris disability questionnaire (RMDQ) and visual analogue scale (VAS) were used to evaluate pain level. Fat and muscle mass were measured to compare body composition changes. All measurements were performed before and after 12 weeks of exercise program. Lumbar function: Back strength was significantly different over time, and significant time×group differences were found between SEG and CG and, CEG and CG. Pain disorder degree: VAS showed a significant group difference, and significant time×group differences were shown between SEG and CG, and CEG and CG. Also, RMDG showed a significant difference between CEG and CG. Body composition: Fat mass was significantly different over time×group between SEG and CG. In conclusion, participating in strength and walking exercises were beneficial to improve lumbar function. Also, the combined exercise program was more effective for reducing pain levels than the strength exercise. Finally, fat mass was reduced in this study and this may play a possible role in the improvement of lumbar function and reduction in low back pain.

Purpose: Mortality in ovarian cancer occurs in the setting of recurrent disease. Recurrent disease is known to arise from residual disease, which persists after the conclusion of standard of care, consequently rebuilding the tumor. Adipose tissue provides cancer cells with a unique microenvironment that can enhance survival by upregulating antiapoptosis genes or by decreasing drug bioavailability. Indeed, adipose-rich organs such as the omentum are not only preferential sites for metastasis but also main sites of residual disease in ovarian cancer. We hypothesized that targeting adipose-rich tissues could limit residual disease and prevent recurrence. Thus, the objective of this study was to develop effective drug delivery platforms that can specifically target residual disease in adipose-rich tissues. Methods: The delivery system is a nanoparticle platform composed of polymerized ursodeoxycholic acid (PUDCA) synthesized by esterification of UDCA monomer. Paclitaxel (PTX) or deep-infrared FL dye (DIR) was encapsulated to a final concentration of 24 ug or 5 mg per mg PUDCA, respectively. In vitro dose response studies were performed using mCherry+ human OCSC1-F2 ovarian cancer cells for 72 h. DMSO-resuspended PTX (DMSO-PTX) was used as control. In vivo studies were performed in athymic nude mice bearing i.p. tumors from mCherry+ OCSC1-F2 cells. For biodistribution studies, DIR-PUDCA was administered as one-time i.p. injection of 1.3 mg of DIR-PUDCA followed by ex vivo measurement of FL intensity after 14 days. DMSO-resuspended DIR (DMSO-DIR) was used as control. For efficacy studies, the groups were: (1) vehicle control; (2) taxol (PTX in Cremaphor; 12mg/kg) + DMSO-PTX (31.2 ug PTX); and (3) taxol + PUDCA-PTX. Treatment was administered i.p. twice a week for a total of 4 doses. Tumor burden and residual disease were determined by quantification of mCherry ROI FL area. Results: PUDCA-PTX demonstrated significantly improved efficacy both in vitro and in vivo. PUDCA-PTX demonstrated a six-fold reduction in in vitro GI50 compared to DMSO-PTX (23.04 nM PUDCA-PTX vs. 137.2 nM DMSO-PTX). Biodistribution studies showed delivery of DIR specifically to adipose-rich tissues (DIR mean FL intensity (MFI) for greater and lesser omentum = 76570±17808 vs. mesentery MFI = 22326±2956; p = 0.0297). Efficacy studies showed that PUDCA-PTX was significantly more effective in inhibiting tumor progression (p = 0.0191) and, more importantly, in preventing recurrent disease compared to DMSO-PTX. Finally, PUDCA-PTX was able to significantly reduce omental-residual disease compared to DMSO-PTX (p=0.049). Conclusion: We demonstrate for the first time that PUDCA is able to target residual disease localized in adipocyte-rich tissues and that this significantly delays tumor progression and prevents recurrence. These results underscore the value of i.p.-delivered PUDCA as a drug delivery platform for enhanced targeting of cancer cells within adipose-rich tissues and its value in the management of ovarian cancer patients. Citation Format: Roslyn Tedja, Ayesha B. Alvero, Jung Seok Lee, Mary Pitruzzello, Tarek Fahmy, Gil G. Mor. Specific targeting of adipose tissue-associated metastasis using bile salt nanoparticles [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A01.

Background The dengue vaccination era began when Dengvaxia (CYD-TDV) became available in 2016. In addition, several second-generation vaccine candidates are currently in phase 3 trials, suggesting that a broader availability of dengue vaccines may be possible in the near future. Advancing on the recent WHO-SAGE recommendations for the safe and effective use of CYD-TDV at the regional level on average, this study investigates the vaccination impacts and cost-effectiveness of CYD-TDV and of a hypothetical new vaccine candidate (NVC) in a country-specific manner for three endemic countries: Vietnam, Thailand, and Colombia. Methods The vaccination impacts of CYD-TDV and NVC were derived by fitting the empirical seroprevalence rates of 9 year olds into an individual-based meta-population transmission model, previously used for the WHO-SAGE working group. The disability-adjusted life years were estimated by applying country-specific parametric values. The cost-effectiveness analyses of four intervention strategies in combination with routine and catch-up campaigns were compared for both vaccines to inform decision makers regarding the most suitable immunization program in each of the three countries. Results and conclusion Both CYD-TDV and NVC could be cost-effective at the DALY threshold cost of $2000 depending upon vaccination costs. With CYD-TDV, targeting 9 year olds in routine vaccination programs and 10–29 year olds as a one-off catch-up campaign was the most cost-effective strategy in all three countries. With NVC, while the most cost-effective strategy was to vaccinate 9–29 and 9–18 year olds in Vietnam and Thailand respectively, vaccinating younger age cohorts between 1 and 5 years old in Colombia was more cost-effective than other strategies. Given that three countries will soon face decisions regarding whether and how to incorporate CYD-TDV or future dengue vaccines into their budget-constrained national immunization programs, the current study outcomes can be used to help decision makers understand the expected impacts and cost-effectiveness of such vaccines.

Myasthenia gravis (MG) is an autoimmune disease associated with antibodies directed to the postsynaptic muscle components of the neuromuscular junction. The heterogeneous nature of the acetylcholine receptor (AChR) antibody response had led to the categorization of AChR antibodies into 3 types: binding, blocking, and modulating antibodies. The purpose of this study is to compare the AChR antibodies' type with the clinical severity of MG patients. The patients enrolled in the study had been tested for both binding and blocking antibodies and had disease duration exceeding 2 years since diagnosis. The patients were divided into five main classes by the Myasthenia Gravis Foundation of America clinical classification. Again, the enrolled patients were divided into ocular and generalized group. We compared the type and titer of antibodies and the thymus status between the ocular and generalized group. Thirty-five patients met the inclusion criteria. Of these, 16 patients (47 %) had both blocking and binding AChR antibodies, 11 patients (31 %) had only binding antibodies, and 8 patients (22 %) had only blocking antibodies. By defined clinical classification, the ocular and generalized groups included 10 and 25 patients, respectively. Sixteen patients in the generalized group possessed both AChR antibodies, with the remaining patients displaying only the binding antibody. All the patients with only blocking antibody were classified into ocular group. Use of binding and blocking antibodies' tests may, therefore, be more helpful in predicting the prognosis and diagnoses of MG patient.

Purpose The purpose of this study was to determine the effect of a newly designed titanium mesh (TM) for preserving the buccal bone around an immediately placed implant following tooth extraction in dogs. Materials and Methods Immediate implant placements were performed bilaterally in the mesial socket of the fourth premolar in five dogs. In one site, the TM was affixed to the fixture using its own stabilization components (TM group), and the contralateral site was left untreated (control group). All surgical sites were intended to be submerged with primary flap closure. Histologic and histomorphometric analyses were performed 16 weeks postoperatively. Results All implants were histologically osseointegrated, and buccal bone resorption was evident in both groups with the high rate of TM exposure (4/5). The most coronal level of bone-implant contact and the bone crest were not statistically different between the TM and the control group. A dense connective tissue layer consistently predominated under the TM, where mineralized tissue was not observed, and the vascularity and cellularity were minimal. Conclusions It can be conjectured that preservation of buccal plate by using the TM in immediate implantation was not predictable due to vulnerability to wound dehiscence and substantial pseudoperiosteum formation beneath the TM.

The insertion of a stent in diseased arteries is a common endovascular procedure that can be compromised by the development of short- and long-term inflammatory responses leading to restenosis and thrombosis, respectively. While treatment with drugs, either systemic or localized, has decreased the incidence of restenosis and thrombosis these complications persist and are associated with a high mortality in those that present with stent thrombosis. We reasoned that if stents could be made to undergo accelerated endothelialization in the deployed region, then such an approach would further decrease the occurrence of stent thrombosis and restenosis thereby improving clinical outcomes. Toward that objective, the first step necessitated efficient capture of progenitor stem cells, which eventually would become the new endothelium. To achieve this objective, we engineered intrinsic ferromagnetism within nonmagnetizable, biodegradable magnesium (Mg) bare metal stents. Mg stents were coated with biodegradable polylactide (PLA) polymer embedding magnetizable iron-platinum (FePt) alloy nanoparticles, nanomagnetic particles

Because of the complexity of cancer, an ideal anticancer strategy is better to target both cancer cells and the tumor microenvironment. In this study, for the first time, we demonstrated that zinc oxide nanoparticles (ZnO NPs) were able to target multiple cell types of cancer, including cancer cells, cancer stem cells (CSCs), and macrophages, and simultaneously perform several key functions, including inhibition of cancer proliferation, sensitization of drug-resistant cancer, prevention of cancer recurrence and metastasis, and resuscitation of cancer immunosurveillance. As a nanocarrier, the chemotherapy drug, doxorubicin (Dox), could be loaded to ZnO NPs and the Dox-loaded ZnO NPs (ZnO/Dox) possessed excellent physicochemical and pH-responsive drug release properties. ZnO/Dox could be effectively internalized by both drug-sensitive and multidrug resistant (MDR) cancer cells and penetrate more efficiently through three-dimensional (3D) cancer cell spheroids compared with free Dox. As a cytotoxic agent, ZnO NPs were more efficient to kill MDR cancer cells. Interestingly, neither ZnO nor Dox showed high cytotoxicity in the 3D cancer cell spheroids, whereas ZnO/Dox showed remarkable synergistic anticancer effects. More importantly, we demonstrated that ZnO NPs could effectively downregulate CD44, a key CSC surface marker, and decrease the stemness of CSCs, leading to the sensitization of the Dox treatment, inhibition of the cancer cell adhesion and migration, and prevention of the tumor (3D cancer cell spheroid) formation. As an immunomodulator, ZnO NPs could protect macrophages from the Dox-induced toxicity and boost the Dox-induced macrophage polarization toward an M1-like phenotype. The macrophage-conditioned medium could promote the cancer cell apoptosis in both cancer cell monolayers and 3D spheroids. The findings in this study indicated that ZnO NPs were a multifunctional and multitarget nanocarrier and nanomedicine that would have more profound effects on cancer treatment.

Objective— Pseudoaneurysms remain a significant complication after vascular procedures. We hypothesized that TGF-β (transforming growth factor-β) signaling plays a mechanistic role in the development of pseudoaneurysms. Approach and Results— Rat aortic pericardial patch angioplasty was associated with a high incidence (88%) of pseudoaneurysms at 30 days, with increased smad2 phosphorylation in small pseudoaneurysms but not in large pseudoaneurysms; TGF-β1 receptors were increased in small pseudoaneurysms and preserved in large pseudoaneurysms. Delivery of TGF-β1 via nanoparticles covalently bonded to the patch stimulated smad2 phosphorylation both in vitro and in vivo and significantly decreased pseudoaneurysm formation (6.7%). Inhibition of TGF-β1 signaling with SB431542 decreased smad2 phosphorylation both in vitro and in vivo and significantly induced pseudoaneurysm formation by day 7 (66.7%). Conclusions— Normal healing after aortic patch angioplasty is associated with increased TGF-β1 signaling, and recruitment of smad2 signaling may limit pseudoaneurysm formation; loss of TGF-β1 signaling is associated with the formation of large pseudoaneurysms. Enhancement of TGF-β1 signaling may be a potential mechanism to limit pseudoaneurysm formation after vascular intervention.

Background Dengue fever has been a major public health concern in Colombia, Thailand, and Vietnam. Unlike other infectious diseases, dengue vaccines had not been available for a long time, causing difficulties to control the disease. However, the first live attenuated, tetravalent dengue vaccine (CYD-TDV) became available in 2016 and has been already licensed in some dengue-endemic countries. Because several second-generation dengue vaccines are also in the pipeline, it is critical to understand the efficient allocation of dengue vaccines considering the geographical variation of the disease. Methods The Climate Risk Factor (CRF) index was created using the climate and non-climate factors in the three countries. A random-coefficient negative binomial model was chosen to validate the relationship between the CRF index and dengue incidence proxy. Given the statistical significance of the CRF index, high risk areas for dengue fever were identified at the 5 km by 5 km resolution and used to estimate vaccination coverage rates and the number of doses required for various types of vaccination scenarios by country. Results and conclusions Based upon a three-dose scheme, the estimated number of vaccines required for routine vaccination targeting 9 years old ranged from 1 to 2.6 million doses across the countries during the first year of introduction. A one-off catch-up campaign targeting the age group of 10–17 year olds would require 8 to 18 million additional doses. Routine vaccination (with or without a catch-up campaign) covered 63%, 90%, and 91% of the targeted age group populations in Colombia, Thailand, and Vietnam respectively. Given that many dengue-endemic countries face limited resources and that the costs for mass vaccination campaigns may not be trivial, the findings of this study can guide the decision makers in the three countries regarding the efficient distribution of vaccines by identifying populations at high risk at 5 km by 5 km resolution.

Background Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic cause of stroke. In addition to ischemic stroke, CADASIL predisposes to development of cerebral microbleeds (CMB). CMB and hypertension are known to be associated with intracerebral hemorrhage (ICH). The purpose of this study was to analyze the relationships among CMB, hypertension, and ICH in CADASIL. Materials and methods We enrolled 94 genetically confirmed CADASIL patients from 76 unrelated families at Jeju National University Hospital (Korea) between March 2012 and February 2015. We analyzed CMB presence, number, and distribution on susceptibility-weighted imaging MRI using the microbleed anatomical rating scale. Multiple logistic regression was used to determine factors associated with the presence of CMB and ICH. Results CMB were observed in 62 patients (66%), median number of CMB per patient was 4 (range 0–121). Twenty-two ICHs were found in 16 patients (17%). There was incongruence between the most common site of CMB (thalamus) and that of ICH (basal ganglia). Hypertension was independently associated with the presence of CMB (multiple regression OR, 2.71; 95% CI 1.02–7.18, p

Purpose This study was conducted to analyze specific RNA expression profiles in gingival tissue and saliva samples in periodontitis patients and healthy individuals, and to determine their correlations in light of the potential use of microarray-based analyses of saliva samples as a periodontal monitoring tool. Methods Gingival tissue biopsies and saliva samples from 22 patients (12 with severe periodontitis and 10 with a healthy periodontium) were analyzed using transcriptomic microarray analysis. Differential gene expression was assessed, and pathway and clustering analyses were conducted for the samples. The correlations between the results for the gingival tissue and saliva samples were analyzed at both the gene and pathway levels. Results There were 621 differentially expressed genes (DEGs; 320 upregulated and 301 downregulated) in the gingival tissue samples of the periodontitis group, and 154 DEGs (44 upregulated and 110 downregulated) in the saliva samples. Nine of these genes overlapped between the sample types. The periodontitis patients formed a distinct cluster group based on gene expression profiles for both the tissue and saliva samples. Database for Annotation, Visualization and Integrated Discovery analysis revealed 159 enriched pathways from the tissue samples of the periodontitis patients, as well as 110 enriched pathways In the saliva samples. Thirty-four pathways overlapped between the sample types. Conclusions The present results indicate the possibility of using the salivary transcriptome to distinguish periodontitis patients from healthy individuals. Further work is required to enhance the extraction of available RNA from saliva samples., Graphical Abstract

Summary Background No access to safe water is an important risk factor for typhoid fever, yet risk-level heterogeneity is unaccounted for in previous global burden estimates. Since WHO has recommended risk-based use of typhoid polysaccharide vaccine, we revisited the burden of typhoid fever in low-income and middle-income countries (LMICs) after adjusting for water-related risk. Methods We estimated the typhoid disease burden from studies done in LMICs based on blood-culture-confirmed incidence rates applied to the 2010 population, after correcting for operational issues related to surveillance, limitations of diagnostic tests, and water-related risk. We derived incidence estimates, correction factors, and mortality estimates from systematic literature reviews. We did scenario analyses for risk factors, diagnostic sensitivity, and case fatality rates, accounting for the uncertainty in these estimates and we compared them with previous disease burden estimates. Findings The estimated number of typhoid fever cases in LMICs in 2010 after adjusting for water-related risk was 11·9 million (95% CI 9·9–14·7) cases with 129 000 (75 000–208 000) deaths. By comparison, the estimated risk-unadjusted burden was 20·6 million (17·5–24·2) cases and 223 000 (131 000–344 000) deaths. Scenario analyses indicated that the risk-factor adjustment and updated diagnostic test correction factor derived from systematic literature reviews were the drivers of differences between the current estimate and past estimates. Interpretation The risk-adjusted typhoid fever burden estimate was more conservative than previous estimates. However, by distinguishing the risk differences, it will allow assessment of the effect at the population level and will facilitate cost-effectiveness calculations for risk-based vaccination strategies for future typhoid conjugate vaccine. Funding Bill and Melinda Gates Foundation.

The aim of this study was to characterize the healing process of extraction sockets with a periapical lesion following immediate graft with collagenated bovine bone mineral (CBBM) soaked with epigallocatechin-3-gallate (EGCG). Following induction of periapical lesions in premolars in five dogs, treatment of extraction sockets was divided into three groups: control (no treatment) and two test groups, CBBM with or without EGCG. 3D reconstruction and superimposition of the digital images were used to measure the dimensional changes in alveolar ridge. Histologic specimen was evaluated in all groups. The horizontal ridge widths at 4-mm level were wider in both test groups (3.3 ± 1.7 mm in CBBM; 3.0 ± 1.7 mm in CBBM+EGCG) than in the control group (1.7 ± 2.4 mm). Fibrosis and limited new bone formation were observed in the apical regions of test groups; however, the extent of fibrosis was less in the CBBM+EGCG group. Within the limitations of this study, it was conjectured that adjunctive use of EGCG with CBBM can be a candidate biomaterial in grafting of extraction socket with periapical lesion. Bone regeneration at the coronal region of the CBBM grafted socket might not be influenced by the presence of a periapical lesion. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 103B: 727–734, 2015.

Background Magnetic resonance imaging (MRI) is a useful tool to predict the diagnosis and progression of Alzheimer's disease (AD), especially for primary physicians. However, the correlation between baseline MRI findings and AD progression has not been fully established. Objective To investigate the correlation between hippocampal atrophy (HA) and white matter hyperintensities (WMH) on initial brain MRI images and the degree of cognitive decline and functional changes over 1 year. Methods In this prospective, 12-month observational study, dementia outpatients were recruited from 29 centers across South Korea. Baseline assessments of HA and WMH on baseline brain MRI were derived as well as cognitive function, dementia severity, activities of daily living, and acetylcholinesterase inhibitor (AChEI) use. Follow-up assessments were conducted at 6 and 12 months. Results Among 899 enrolled dementia patients, 748 were diagnosed with AD of whom 654 (87%) were taking AChEIs. Baseline WMH showed significant correlations with age, current alcohol consumption, and Clinical Dementia Rating score; baseline HA was correlated with age, family history, physical exercise, and the results of cognitive assessments. Among the AChEI group, changes in the Korean version of the Instrumental Activities of Daily Living (K-IADL) were correlated with the severity of HA on baseline brain MRI, but not with the baseline severity of WMH. In the no AChEI group, changes in K-IADL were correlated with the severity of WMH and HA at baseline. Conclusion Baseline MRI findings could be a useful tool for predicting future clinical outcomes by primary physicians, especially in relation to patients' functional status.

Background: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited microangiopathy caused by mutations in the Notch3 gene. In the present study, we aimed to analyze cognitive and neuroimaging profiles of CADASIL patients with R544C mutation. Methods: Fifty-eight consecutive patients with R544C mutation and 26 normal controls were investigated. The patients were divided into two groups depending on the presence (CADASIL with dementia: CADASIL-D) or absence of dementia (CADASIL no dementia: CADASIL-ND). We applied the same neuropsychological test to the three groups. Brain magnetic resonance images were obtained from 58 patients with R544C mutation. Linear regression models were used to assess the impact of lacunes and white matter hyperintensities on cognitive function in the CADASIL-ND group. Results: Compared to controls, the CADASIL-ND group demonstrated significant difficulties concerning measures of attention, executive function, and motor control. The CADASIL-D group was impaired in all cognitive domains that were assessed, except the language domain. After correction for age and educational level, the number of lacunes was associated with lower scores in the Alzheimer's Disease Assessment Scale cognitive subtest and Stroop color test in the CADASIL-ND group. Conclusions: Non-Caucasian CADASIL patients with R544C mutation and Caucasian CADASIL patients show similar patterns of cognitive impairment.

Background and aim There are variations of migraine prevalence in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) among different regions of the world. Previous studies on Asian CADASIL patients have not provided detailed descriptions of the characteristics of their headaches. The aims of this study were to determine prevalence and characteristics of headaches and to investigate associations between headache and other clinical symptoms or brain magnetic resonance imaging (MRI) findings among homogenous group of patients having the same R544C mutation. Methods In this cross-sectional study, we enrolled 53 CADASIL patients with the R544C mutation between May 2010 and April 2011. We obtained the history of headache using a structured questionnaire and detailed interview. Other clinical features and brain MRI findings were also assessed for potential associations. Results Overall headache prevalence was 45.3% (24 patients). Among them, 21 patients (87.5%) were classified as having tension-type headache, followed by migraine (two patients) and unclassifiable headaches (one patient). Except for alcohol consumption, no significant associations were observed between the headaches and other clinical features or brain MRI findings. Conclusion Migraine was found in only 3.8% of CADASIL patients with the R544C mutation. Such a low prevalence of migraine may hinder clinical detection of CADASIL among ethnically Asian patients.

Patients with epithelial ovarian cancer have the best overall survival when maximal surgical effort is accomplished. However, despite numerous technological advances, surgery still relies primarily on white-light reflectance and the surgeon’s vision. As such, micrometastases are usually missed and most patients clinically classified as a complete responder eventually recur and succumb to the disease. Our objective is to develop optical enhancers which can aid in the visualization of ovarian cancer micrometastasis. To this end we developed a nanoparticle (NP) platform, which is specifically targeted to the tumor microenvironment. Targeting is achieved by coating FDA-approved PLGA-PEG NP with the peptide sequence RGD, which binds with high affinity to αVβ3 integrins present in both the tumor-associated neovasculature and on the surface of ovarian cancer cells. Administration of the NP platform carrying fluorescent dyes to mice bearing intraperitoneal ovarian cancer allowed visualization of tumor-associated vasculature and its contrast against normal blood vessels. More importantly, we demonstrate the visualization of intraperitoneal ovarian cancer micrometastasis as small as 100 μm with optimal resolution. Finally, we demonstrate that the fluorescent dye cargo was able to penetrate intra-tumorally. Such modality could be used to allow microscopic surgical debulking to assure maximal surgical effort.

Background Dengue has been prevalent in Colombia with high risk of outbreaks in various locations. While the prediction of dengue epidemics will bring significant benefits to the society, accurate forecasts have been a challenge. Given competing health demands in Colombia, it is critical to consider the effective use of the limited healthcare resources by identifying high risk areas for dengue fever. Methods The Climate Risk Factor (CRF) index was constructed based upon temperature, precipitation, and humidity. Considering the conditions necessary for vector survival and transmission behavior, elevation and population density were taken into account. An Early Warning Signal (EWS) model was developed by estimating the elasticity of the climate risk factor function to detect dengue epidemics. The climate risk factor index was further estimated at the smaller geographical unit (5 km by 5 km resolution) to identify populations at high risk. Results From January 2007 to December 2015, the Early Warning Signal model successfully detected 75% of the total number of outbreaks 1 ~ 5 months ahead of time, 12.5% in the same month, and missed 12.5% of all outbreaks. The climate risk factors showed that populations at high risk are concentrated in the Western part of Colombia where more suitable climate conditions for vector mosquitoes and the high population level were observed compared to the East. Conclusions This study concludes that it is possible to detect dengue outbreaks ahead of time and identify populations at high risk for various disease prevention activities based upon observed climate and non-climate information. The study outcomes can be used to minimize potential societal losses by prioritizing limited healthcare services and resources, as well as by conducting vector control activities prior to experiencing epidemics. Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2577-4) contains supplementary material, which is available to authorized users.

Prosthetic grafts and patches are commonly used in cardiovascular surgery, however neointimal hyperplasia remains a significant concern, especially under low flow conditions. We hypothesized that delivery of rapamycin from nanoparticles (NP) covalently attached to patches allows sustained site-specific delivery of therapeutic agents targeted to inhibit localized neointimal hyperplasia. NP were covalently linked to pericardial patches using EDC/NHS chemistry and could deliver at least 360 ng rapamycin per patch without detectable rapamycin in serum; nanoparticles were detectable in the liver, kidney and spleen but no other sites within 24 hours. In a rat venous patch angioplasty model, control patches developed robust neointimal hyperplasia on the patch luminal surface characterized by Eph-B4-positive endothelium and underlying SMC and infiltrating cells such as macrophages and leukocytes. Patches delivering rapamycin developed less neointimal hyperplasia, less smooth muscle cell proliferation, and had fewer infiltrating cells but retained endothelialization. NP covalently linked to pericardial patches are a novel composite delivery system that allows sustained site-specific delivery of therapeutics; NP delivering rapamycin inhibit patch neointimal hyperplasia. NP linked to patches may represent a next generation of tissue engineered cardiovascular implants.

Cerebral microbleeds (CMB) are small MRI signal voids due to tiny hemosiderin deposits derived from red blood cell extravasation. The relationship between CMB and postthrombolysis intracerebral hemorrhage (ICH), the most feared complication of thrombolysis for acute ischemic stroke, has received considerable attention. Individual studies relating CMB and postthrombolysis ICH have generally failed to show a significant association. However, recent meta-analyses indicate that CMB presence or burden on pretreatment MRI is associated with postthrombolysis ICH. The exact nature of the CMB–postthrombolysis ICH relationship is complicated by the heterogeneous nature of CMB and their associated risk factors hypertension, cerebral amyloid angiopathy, and chronic kidney disease. CMB may be due to a primary disruption of the vessel wall (primary CMB) or may be a consequence of ischemic brain injury (secondary CMB). Clinicians making decisions regarding whether or not to offer intravenous thrombolysis to patients with acute ischemic stroke should attempt to distinguish primary from secondary CMB, as it is the former that likely create the greatest risk for postthrombolysis ICH.

Background While the global burden of typhoid fever has been often brought up for attention, the detailed surveillance information has only been available for the limited number of countries. As more efficacious vaccines will be available in the near future, it is essential to understand the geographically diverse patterns of typhoid risk levels and to prioritize the right populations for vaccination to effectively control the disease. Methods A composite index called the typhoid risk factor (TRF) index was created based on data with the Global Positioning System (GPS). Demographic and Health Surveys (DHS) and National Geographical Data Center (NGDC) satellite lights data were used for this analysis. A count model was adopted to validate the TRF index against the existing surveillance burden data. The TRF index was then re-estimated for 66 countries using the most recent data and mapped out for two geographical levels (sub-national boundary and grid-cell levels). Results The TRF index which consists of drinking water sources, toilet facility types, and population density appeared to be statistically significant to explain variation in the disease burden data. The mapping analysis showed that typhoid risk levels vary not only by country but also by sub-national region. The grid-cell level analysis highlighted that the distribution of typhoid risk factors is uneven within the sub-national boundary level. Typhoid risk levels are geographically heterogeneous. Conclusions Given the insufficient number of surveillance studies, the TRF index serves as a useful tool by capturing multiple risk factors of the disease into a single indicator. This will help decision makers identify high risk areas for typhoid as well as other waterborne diseases. Further, the study outcome can guide researchers to find relevant places for future surveillance studies. Electronic supplementary material The online version of this article (doi:10.1186/s12879-016-2074-1) contains supplementary material, which is available to authorized users.