Structural visual metrics associate with moderate to vigorous physical activity in youth with pediatric onset neuroinflammatory disorders.

BACKGROUND: Higher levels of moderate to vigorous physical activity (MVPA) associate with disease activity in pediatric multiple sclerosis (MS). Further, measures of retinal integrity associate with lower brain atrophy, yet the relationship of retinal integrity with MVPA has not been investigated. OBJECTIVE: To determine the relationship between MVPA and retinal nerve fibre layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness in patients with MS, myelin oligodendrocyte glycoprotein-associated disorders (MOGAD), neuromyelitis optica spectrum disorder (NMOSD), and monophasic acquired demyelinating syndromes (monoADS). METHODS: 150 consecutive children ≤18 y.o with neuroinflammatory disorders were included. Outcomes included the Godin Leisure Time Activity Questionnaire (GLTEQ) modeled as both a continuous and categorical variable (any vs no MVPA/Strenuous activity), and RNFL and GCIPL using linear mixed models (JASP 0.14.1). RESULTS: An association was identified between MVPA with RNFL thickness (F (1,133) = 8.40, p = .004) and GCIPL thickness (F(1, 131) = 7.68, p = .006). In the MS cohort, any strenuous physical activity was associated with greater RNFL (F(1,35) = 7.30, p = .011) and GCIPL thickness (F(1,35) = 8.73, p =.006). CONCLUSIONS: Any MVPA participation is associated with higher RNFL and GCIPL thickness across neuroinflammatory disorders.

Impact of temperature on hospital admission for acute lower respiratory infection (ALRI) among pre-school children in Ho Chi Minh City, Vietnam.

Changes in ambient temperature have been reported as an important risk factor for respiratory diseases among pre-school children. However, there have been few studies so far on the effects of temperature on children respiratory health in developing countries including Vietnam. This study examined the impact of short-term changes in ambient temperature on hospital admissions for acute lower respiratory infection (ALRI) among children aged less than 5 years old in Ho Chi Minh City (HCMC), Vietnam. Data on daily hospital admissions from 2013 to 2017 were collected from two large paediatric hospitals of the city. Daily meteorological data of the same period were also collected. Time series analysis was performed to evaluate the association between risk of hospitalisations and temperatures categorised by seasons, age, and causes. We found that a 1 °C increase in maximum temperature was associated with 4.2 and 3.4% increase in hospital admission for ALRI among children 3-5 years old during the dry season and the rainy season, respectively. Surprisingly, in the rainy season, a rise of 1°C diurnal temperature range (DTR) was significantly associated with a decrease from 2.0 to 2.5% risk of hospitalisation for ALRI among children <3 years old. These findings suggested that although high temperature is a risk factor for hospital admissions among children in general, other modifiable factors such as age, exposure time, air conditioning usage, wearing protective clothing, socioeconomic status, and behaviour may influence the overall effect of high temperature on hospital admissions of children <5 years old in HCMC. The findings of this study have provided evidence for building public health policies aimed at preventing and minimizing the adverse health effects of temperature on children in HCMC.

A Phase I Dose-Escalation Study to Evaluate the Safety and Tolerability of Evofosfamide in Combination with Ipilimumab in Advanced Solid Malignancies.

PURPOSE: As hypoxia can mediate resistance to immunotherapy, we investigated the safety, tolerability, and efficacy of combining evofosfamide, a prodrug that alleviates hypoxia, with ipilimumab, an immune checkpoint inhibitor, in immunologically "cold" cancers, which are intrinsically insensitive to immunotherapy, as well as in "hot/warm" metastatic cancers that are, atypical of such cancers, resistant to immunotherapy. PATIENTS AND METHODS: In a phase I, 3+3 dose-escalation trial (NCT03098160), evofosfamide (400-640 mg/m2) and ipilimumab (3 mg/kg) were administered in four 3-week cycles. The former was administered on days 1 and 8 of cycles 1-2, while the latter was administered on day 8 of cycles 1-4. Response was assessed using immune-related RECIST and retreatment was allowed, if deemed beneficial, after completion of cycle 4 or at progression. RESULTS: Twenty-two patients were enrolled, of whom 21 were evaluable, encompassing castration-resistant prostate cancer (n = 11), pancreatic cancer (n = 7), immunotherapy-resistant melanoma (n = 2), and human papillomavirus-negative head and neck cancer (n = 1). Drug-related hematologic toxicities, rash, fever, nausea, vomiting, and elevation of liver enzymes were observed in > 10% of patients. The most common drug-related grade 3 adverse event was alanine aminotransferase elevation (33.3%). Two patients discontinued ipilimumab and 4 required evofosfamide deescalation due to toxicity. Of 18 patients with measurable disease at baseline, 3 (16.7%) achieved partial response and 12 (66.7%) achieved stable disease. The best responses were observed at 560 mg/m2 evofosfamide. Preexisting immune gene signatures predicted response to therapy, while hypermetabolic tumors predicted progression. Responders also showed improved peripheral T-cell proliferation and increased intratumoral T-cell infiltration into hypoxia. CONCLUSIONS: No new or unexpected safety signals were observed from combining evofosfamide and ipilimumab, and evidence of therapeutic activity was noted.

Late-life depression and increased risk of dementia: a longitudinal cohort study.

Late-life depression (LLD) is associated with an increased risk of developing dementia; however, it is not known whether individuals with a history of LLD exhibit a more rapid rate of cognitive decline. We aimed to determine whether those with LLD experienced faster cognitive decline compared with never-depressed control (NDC) participants from the community and whether stratification of LLD into early-onset depression (EOD) and late-onset depression (LOD) subtypes revealed differing rates and domain-specific expression of cognitive decline. We conducted a prospective, longitudinal study where 185 participants with LLD (remitted) and 114 NDC were followed for 5 years on average. EOD was defined as having first lifetime depressive episode at <60years and LOD at ≥60years. Every year, participants underwent comprehensive neuropsychological assessment. Composite scores for each cognitive domain were calculated through averaging standardized scores across tests. LLD compared to NDC demonstrated significant baseline impairment but did not decline more rapidly. EOD were significantly impaired in attention/processing speed and global cognitive function at baseline but did not experience more rapid decline as compared to NDC. Those with LOD compared to both NDC and EOD performed worse in all domains at baseline and experienced more rapid decline in verbal skills and delayed memory ability. Our findings suggest that baseline impairment may lower the threshold for those with LLD to develop dementia. EOD and LOD may represent distinct phenotypes of cognitive impairment with differing neural substrates. LOD may represent a distinct phenotype with a more rapid decline in verbal skills and delayed memory.

[Radiochemotherapy for the treatment ofmuscle invasive bladder tumors in a west african radiotherapy service]. / Radiochimiotherapie pour le traitement des tumeurs de vessie infiltrant lemuscle dans un service de radiotherapie ouest africaine.

OBJECTIF: The aim of this study was to describe the results of radiochemotherapy in patients after transurethral resection of muscle invasive bladder tumors. MATERIAL AND METHODS: A retrospective study from May 2014 to May 2016 in the radiotherapy department of the Mali Hospital. Have been included, all patients with bladder cancer infiltrating the muscle. Secondary cancers of the bladder and metastatic forms have been excluded from our study. Transurethral resection of bladder was performed. Neoadjuvant chemotherapy with paclitaxel- carboplatin was administered every three weeks in all patients, then external phototherapy 6 MV at a dose of 66 Gy due to 2 Gy of 5 sessions per week 6MV photon of external beam radiotherapy at a dose of 66 Gy due to 2 Gy of 5 sessions per week associated with concomitant cisplatin at dose of 40mg / m2 / week. RESULTS: Eight patients were included in ourstudy. The average age of 53.75 ± 14.84 years. The male sex was predominant 87.5% (n = 7). The history of chronic smoking wasfound in four patients. The main carcinogenic risk factor identified in our patients was urogenital bilharzia (6 cases / 8).The histological type found was urothelial carcinomain 12.5% (n = 1) and invasive squamous cell carcinomain 87.5% (n = 7). Transurethral resection of the tumor was performed in 62.5% (n = 5). Endoscopic biopsy was performed in 37.5% (n = 3). The tumor was classified pT2N0M0 in 50% (n = 4), pT3aN0M0 in 37.5% (n = 3) and pT3bN0M0 in 12.5% (n = 1). Neoadjuvant chemotherapy with paclitaxel - carboplatin every three weeks was administered to all patients. The results of radiochemotherapy (see Table: evolution). CONCLUSION: Concomitant radiochemotherapy is a conservative curative treatment that can be proposed as a replacement for cystectomy, for non-metastatic infiltrating tumors after the most complete endoscopic resection.

OBJECTIF: Le but de cette étude était de décrire les résultats d'une radiochimiothérapie chez les patients après résection transurétrale des tumeurs de vessie infiltrant le muscle. MATÉRIEL ET MÉTHODES: Une étude rétrospective allant de mai 2014 à mai 2016 au service de radiothérapie de l'hôpital du Mali. Ont été inclus, tous les patients présentant un cancer de vessie infiltrant le muscle. Les cancers secondaires de la vessie ainsi que les formes métastatiques ont été exclus de notre étude. La résection transurétrale de vessie a été réalisée. La chimiothérapie néoadjuvante à base de paclitaxel ­ carboplatine a été administrée toutes les trois semaines. La radiothérapie externe au photon 6MV à la dose de 66 Gy en raison de 2 Gy de 5 séances par semaine associée à la chimiothérapie concomitante à base de cisplatine (CDDP) 40mg/m2/semaine a été réalisée. RÉSULTATS: Au total huit patients ont été inclus dans notre étude. L'âge moyen de 53,75±14,84 ans. Le sexe masculin était prédominant 87.5% (n=7). L'antécédent de tabagisme chronique était retrouvé chez quatre patients. Le principal facteur de risque cancérigène identifié chez nos patients était la bilharziose urogénitale (6cas/8). Le type histologique retrouvé était le carcinome urothelial dans 12.5% (n=1) et le carcinome épidermoïde infiltrant dans 87.5% (n=7). La résection transurétrale de la tumeur a été réalisée dans 62.5% (n=5). La biopsie par voie endoscopique été réalisée dans 37.5% (n=3). La tumeur été classée pT2N0M0 dans 50% (n= 4), pT3aN0M0 dans 37.5% (n=3) et pT3bN0M0 dans 12.5% (n= 1). La chimiothérapie néoadjuvante à base de paclitaxel ­ carboplatine chaque trois semaines a été administrée chez tous les malades.Les résultats de la radiochimiothérapie (cf. Tableau: évolution). CONCLUSION: La radiochimiothérapie concomitante est un traitement curatif conservateur qui peut être proposée en remplacement à la cystectomie pour les tumeurs infiltrantes non métastatiques après une résection endoscopique la plus complète possible.

When worry may be good for you: Worry severity and limbic-prefrontal functional connectivity in late-life generalized anxiety disorder.

BACKGROUND: Late-life generalized anxiety disorder (GAD) is one of the most common anxiety disorders in older adults. However, its neural markers have received relatively little attention. In this study, we explored the association between worry severity and limbic-prefrontal connectivity during emotional reactivity in late-life GAD. METHODS: We recruited 16 anxious (GAD) and 20 non-anxious (HC) older adults to perform the faces/shapes emotional reactivity task during functional magnetic resonance imaging (fMRI). We investigated the functional connectivity of both the amygdala and the bed nucleus of stria terminalis (BNST) with the prefrontal cortex (PFC) using generalized psychophysiological interaction (gPPI) analysis. We tested for (1) group differences in connectivity, (2) association between worry severity and connectivity, and (3) interaction between group and worry severity and its association with connectivity. RESULTS: Amygdala-PFC and BNST-PFC functional connectivity were associated with worry severity in an inverse U-shape, and was independent of depression severity, global anxiety, neuroticism, and general cognitive function. LIMITATIONS: Our limitations include slightly skewed PSWQ distributions, lack of non-anxious individuals with high worry, small sample size, and low depression comorbidity in a sample of late-life GAD that may not generalize to GAD in younger populations. CONCLUSIONS: This suggests that moderate worry is associated with maximum engagement of the limbic-PFC connectivity, while severe worry is associated with failure of the limbic-PFC emotional regulation circuit. This may explain the aberrant and exaggerated responses to negative stimuli observed in participants with pathological worry.

Impact of ambient air pollution and wheeze-associated disorders in children in Southeast Asia: a systematic review and meta-analysis.

Several systematic reviews have been conducted so far to examine the effect of air pollution on respiratory diseases, but there has not been a corresponding meta-analysis to estimate the effect sizes for wheeze-associated diseases/disorders, which is one of the leading causes of emergency department visits and hospitalizations for children worldwide. The aim of this review is to systematically evaluate the relationship between air pollution and risk of wheeze-associated disorders in children in Southeast Asia. We searched the relevant computerized databases (PubMed, EMBASE, Web of Science, Scopus and Cochrane library) for indexed publications up to July 2018. Finally, eight studies were qualified for performing a random-effect meta-analysis to compute the pooled effect sizes. The results show that each increase of 10 µg/m3 in concentrations of PM2.5, PM1 was associated with 1-2% increase in risk of wheeze-associated disorders. Positive associations were found for PM10, SO2, NO2, NOx but no association was found for CO and O3. We confirmed the strong effect of fine particulate matters on respiratory health and recommend an updated meta-analysis should be done when more studies are available.

[Neoadjuvant chemotherapy in locally advanced cervical cancer in patients receiving a concomitant chemoradiotherapy in a low income country]. / Chimiotherapie neo adjudante dans les cancers localement avances du col uterin chez des patientes recevant une radiochimiotherapie concomitante dans pays aux ressources limitees.

PURPOSE: Delays to access to radiotherapy are long in our context. The purpose of this study was to analyze the effect of neoadjuvant chemotherapy to concomitant chemoradiotherapy in locally advanced cervical cancers. PATIENTS AND METHODS: We conducted a retrospective study from April 2014 to April 2016 at the radiotherapy center of "Hopital du Mali" in Bamako, Mali. Patients were allocated according to age, histological type, tumor size and the 2002 classification of the FIGO. Experimental protocol was the administration of a neoadjuvante chemotherapy with association of Paclitaxel 175mg/m2 + Carboplatine AUC 5 every 3 weeks and radiothérapy cure with avec linac 6 MV at 70 Gy due to 5 sessions of 2 Gy per week associated with a concomitant chemotherapy with cisplatin at 40 mg/m2/week. The clinical response was assessed at the end of neoadjuvant chemotherapy and of concomitant chemoradiotherapy. RESULTS: Thirty patients were included in the study. The mean age was 53.63 ± 8.9 years. The mean size of the tumor was 5.17 cm (2 to 7 cm). According to the 2002 classification of the FIGO stages IIB were 33% (n = 10); IIIB were 57% (n = 17) and IVA were 10% (n = 3). Clinical evaluation at the end of neoadjuvant chemotherapy found: complete response 17 % (n = 5), partial response 10% (n = 3) and stable disease 73 % (n = 22). Evaluation at the end of the concomitant chemoradiotherapy had found the complete response in 90% (n = 27) and stable disease in 10% (n = 3). CONCLUSION: Neoadjuvant chemotherapy to concomitant chemoradiotherapy in locally advanced cervical cancer allows stabilization of the tumor and improves local control. Due to long delays to access to radiotherapy treatment in our context; neoadjuvant chemotherapy is an alternative to stabilize the disease and prevent distant metastasis from locally advanced cervical cancers.

OBJECTIF: Les délais d'attente pour accéder à la radiothérapie sont longs dans note contexte. L'objet de cette étude était d'analyser le résultat de la chimiothérapie néo adjuvante à la radiothérapie dans les cancers localement avancés du col utérin. PATIENTS ET MÉTHODES: Nous avons réalisé une étude rétrospective allant d'avril 2014 à avril 2016 au centre de radiothérapie de l'hôpital du Mali. Les patients ont été regroupés selon l'âge, le type histologique, la taille de la tumeur, la classification de la FIGO 2002. Le schéma thérapeutique était une chimiothérapie néo adjuvante associant Paclitaxel 175 mg/m2 et Carboplatine AUC 5 toutes les 3 semaines suivie d'une radiothérapie avec linac 6 MV à la dose de 70 Gy en raison de 5 séances de 2 Gy par semaine faite concomitamment à une chimiothérapie avec du cisplatine à la dose de 40 mg/m2/semaine. La réponse clinique était évaluée à la fin de la chimiothérapie néoadjuvante et de la radiochimiothérapie concomitante. RÉSULTATS: Trente patientes ont été incluses dans l'étude. L'âge moyen était de 53.63 ± 8.9 ans. La taille moyenne de la tumeur était de 5,17 cm (2 à 7 cm). Selon la classification FIGO 2002, 10 (33%) étaient en stade IIB distal, 17 (57%) étaient en stade IIIB et 3 (10%) en stade IVA. L'évaluation clinique à la fin de la chimiothérapie néo adjuvante avait retrouvé 17 % de réponses complètes (n=5), 10% de réponses partielles (n=3) 73 % d'évolutions stables (n=22). L'évaluation à la fin de la radiochimiothérapie concomitante avait trouvé une réponse complète chez 27 patientes (90%) et une maladie stable chez 3 (10%). CONCLUSION: La chimiothérapie néo adjuvante à la chimioradiothérapie concomitante dans les cancers localement avancés du col utérin permet la stabilisation de la tumeur et améliore le control local. En raison des délais d'attente longs pour accéder à la radiothérapie, la chimiothérapie néo adjuvante est une alternative pour stabiliser la maladie et réduire le risque de métastases à distance des cancers du col utérin localement avancés.

Effects of temperature on hospitalisation among pre-school children in Hanoi, Vietnam.

This study examined the effect of short-term changes in ambient temperature on hospital admissions among children aged less than 5 years old in Hanoi, Vietnam. Data on daily hospital admissions from January 2010 to June 2014 were collected from two hospitals. Daily meteorological data were obtained for the same period. We applied time series analysis to evaluate the risk of hospitalisation related to hot and cold weather by age and causes. We found that a 1 °C decrease in minimum temperature during the cold weather months was associated with 2.2% increase in hospital admission for respiratory infection among children 3-5 years old. A 1 °C increase in diurnal temperature range (DTR) in cold weather was associated with an increase of 1.9% and 1.7% in hospitalisation for all causes and respiratory infection, respectively, among children < 3 years old and an increase of 1.8% and 3.4% in hospitalisation for all causes and respiratory infection, respectively, among children of 3-5 years old. Negative associations between hot weather and hospital admissions were demonstrated. These findings suggested that low temperature and DTRs in winter are important risk factors for hospital admissions among children aged < 5 years old in Hanoi. Other factors may have modified the effect of high temperature on hospital admissions of children in Hanoi.

Novel Enzyme Actions for Sulphated Galactofucan Depolymerisation and a New Engineering Strategy for Molecular Stabilisation of Fucoidan Degrading Enzymes.

Fucoidans from brown macroalgae have beneficial biomedical properties but their use as pharma products requires homogenous oligomeric products. In this study, the action of five recombinant microbial fucoidan degrading enzymes were evaluated on fucoidans from brown macroalgae: Sargassum mcclurei, Fucus evanescens, Fucus vesiculosus, Turbinaria ornata, Saccharina cichorioides, and Undaria pinnatifida. The enzymes included three endo-fucoidanases (EC 3.2.1.-GH 107), FcnA2, Fda1, and Fda2, and two unclassified endo-fucoglucuronomannan lyases, FdlA and FdlB. The oligosaccharide product profiles were assessed by carbohydrate-polyacrylamide gel electrophoresis and size exclusion chromatography. The recombinant enzymes FcnA2, Fda1, and Fda2 were unstable but were stabilised by truncation of the C-terminal end (removing up to 40% of the enzyme sequence). All five enzymes catalysed degradation of fucoidans containing α(1→4)-linked l-fucosyls. Fda2 also degraded S. cichorioides and U. pinnatifida fucoidans that have α(1→3)-linked l-fucosyls in their backbone. In the stabilised form, Fda1 also cleaved α(1→3) bonds. For the first time, we also show that several enzymes catalyse degradation of S. mcclurei galactofucan-fucoidan, known to contain α(1→4) and α(1→3) linked l-fucosyls and galactosyl-ß(1→3) bonds in the backbone. These data enhance our understanding of fucoidan degrading enzymes and their substrate preferences and may assist development of enzyme-assisted production of defined fuco-oligosaccharides from fucoidan substrates.

Dynamic changes of circulating miRNAs induced by the Ebola virus vaccine VSV-EBOV.

VSV-EBOV is a replication-competent Ebola virus (EBOV) vaccine, which was tested in clinical trials as response to the Ebola virus disease (EVD) outbreak 2013-2016. It is the most advanced EBOV candidate currently in the licensure process. The experimental vaccine was again administered as response to outbreaks in the Democratic Republic of Congo. However, underlying molecular mechanisms that convey protection remain incompletely understood. MicroRNAs (miRNAs) are known key regulators that influence gene expression on a post-transcriptional level. The miRNA-mediated control has emerged as a critical regulatory principle in the immune system, which strongly influences the balance of innate and adaptive immune responses by modulation of signaling pathways critical for differentiation of immune cells. We investigated expression levels of circulating miRNAs (c-miRNAs) in plasma from healthy vaccinees, as they may reflect cellular dynamics following VSV-EBOV immunization and additionally may serve as potential biomarkers for vaccine efficacy. As part of the WHO-led VEBCON consortium, we investigated safety and immunogenicity of VSV-EBOV in a phase I trial. A comprehensive analysis of expression levels on c-miRNAs from plasma samples following VSV-EBOV immunization (day 0, 1, 3 post vaccination) was conducted using RT-qPCR assays. Potential biological relevance was assessed using in silico analyses. Additionally, we correlated dynamics of miRNA expressions with our previously reported data on vaccine-induced antibody and cytokine responses and finally evaluated the prognostic power by generating ROC curves. We identified four promising miRNAs (hsa-miR-146a, hsa-miR-126, hsa-miR-199a, hsa-miR-484), showing a strong association with adaptive immune responses, exhibited favourable prognostic performance and are implicated in immunology-related functions. Our results provide evidence that miRNAs may serve as useful biomarkers for prediction of vaccine-induced immunogenicity. Furthermore, our unique data set provides insight into molecular mechanisms that underlie VSV-EBOV-mediated protective immune responses, which may help to decipher VSV-EBOV immune signature and accelerate strategic vaccine design or personalized approaches.

Seasonal association between ambient ozone and hospital admission for respiratory diseases in Hanoi, Vietnam.

BACKGROUND: Many studies have indicated the detrimental effect of ambient ozone to respiratory health in different countries. The levels of ozone in Hanoi, Vietnam are frequently above the WHO guideline but very few studies on the effects of ambient ozone on human health have been conducted in this location. This study aimed to examine the effects of ozone on hospital admission for respiratory diseases in Hanoi, by diseases, ages and seasons. METHODS: Hospital admissions, air pollutants and meteorological data were collected from January 2010 to June 2014. We used generalized linear models and distributed lag linear model to assess the association. In addition to full year analysis, we conducted restricted analysis of the data for two summer (from June-August) and winter (from December-February) seasons and grouped hospital admissions by diseases and ages (all ages, children 0 to 5 years and elderly >65 years). The delayed effect of ozone was assessed using lags of up to 5 days. RESULTS: Ozone has a stronger effect on the risk of hospital admission for respiratory diseases and wheeze-associated disorders in the winter. For respiratory diseases, children were affected by ozone more than other age groups in both winter and summer. Each increase of 10 µg/m3 of ozone is associated with an increase of 6.2% risk of admission for respiratory disease among children in the winter and 1.2% in the summer. For wheeze-associated disorders, the elderly group seemed to be more affected by ozone in full year and winter but no significant association was found between ozone and admission for wheeze-associated diseases in any age group. CONCLUSIONS: Ozone is a risk factor for respiratory admission, especially amongst children under 5 years old in Hanoi, and ozone has a stronger effect in the winter than in the summer in this city.

Dynamics of Erythropoietic Biomarkers in Response to Treatment With Erythropoietin in Belgrade Rats.

Recombinant human erythropoietin (rHuEPO) is used effectively in the treatment of various anemic disorders. Belgrade rat is a useful animal model of anemia caused by defect in iron utilization. The objective of the present study was to investigate the dynamics of erythropoietic biomarkers in Belgrade rats receiving rHuEPO. Pharmacokinetics of rHuEPO was evaluated in Belgrade rats and normal rats after intravenous administration of single doses of the drug (100 and 1350 IU/kg). Pharmacodynamic biomarkers included levels of red blood cells, hemoglobin, and reticulocytes following administration of a single intravenous dose of rHuEPO (100 IU/kg). Red blood cell survival was assessed after treatment with rHuEPO (450 IU/kg), three times a week for 2 weeks. It was found that rHuEPO exhibited non-linear pharmacokinetics in both Belgrade and control rats. At the low dose, plasma concentrations and AUC (area under the curve) were significantly lower while clearance and volume of distribution were higher in Belgrade rats (p < 0.05). At the higher dose, there was no difference in pharmacokinetics between the two groups. Erythropoietic effect of rHuEPO was negligible in Belgrade rats at the dose of 100 IU/kg whereas all studied erythropoietic biomarkers were increased in normal rats. The levels of red blood cells, hemoglobin were significantly lower whereas the percentage of reticulocytes was higher in Belgrade rats compared to that in normal rats (p < 0.05). RHuEPO increased red blood cell survival in both animal groups. In conclusion, rHuEPO effect on erythropoietic biomarkers was stronger in normal rats than Belgrade rats at the studied doses. The findings from this study may provide further insights into understanding of anemic disorders resulting from mutations in the divalent metal transporter.

Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma.

Background: Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme-arginine deiminase-conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and patients: Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2 : 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4-5.6 months increase in median OS (one-sided α = 0.025). Secondary end points included progression-free survival, safety, and arginine correlatives. Results: A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P = 0.88, HR = 1.02) and median progression-free survival 2.6 months versus 2.6 (P = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in <5% of patients. Two patients on ADI-PEG 20 had ≥grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion: ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway. Clinical Trial number: www.clinicaltrials.gov (NCT 01287585).

Hepatitis B surface antigen loss and sustained viral suppression in Asian chronic hepatitis B patients: A community-based real-world study.

Community-based real-world outcomes on effectiveness of antiviral therapies for chronic hepatitis B virus (CHB) in Asians are limited. Whether hepatitis B surface antigen (HBsAg) loss correlates with undetectable virus and alanine aminotransferase (ALT) normalization on treatment or what predicts risk of seroreversion or detectable virus after stopping therapy is unclear. We aim to evaluate rates and predictors of HBsAg loss, seroconversion, ALT normalization and undetectable HBV DNA, including HBsAg seroreversion or re-emergence of HBV DNA among Asian CHB patients. We retrospectively evaluated 1072 CHB adults on antiviral therapy at two community gastroenterology clinics from 1997 to 2015. Rates of HBsAg loss, ALT normalization, achieving undetectable HBV DNA and developing surface antibody (anti-HBs) were stratified by HBeAg status. Following HBsAg loss, HBsAg seroreversion or re-emergence of detectable HBV DNA was analysed. With median treatment of 76.7 months, the overall rate of HBsAg loss was 4.58%, with similar HBsAg loss rates between HBeAg-positive and HBeAg-negative patients (4.44% vs 4.71%, P=.85) in a predominantly Asian population (98.1%). Among HBsAg loss patients, 33.3% developed anti-HBs, 95.8% achieved undetectable virus and 66.0% normalized ALT. No significant baseline or on-treatment predictors of HBsAg loss were observed. While six patients who achieved HBsAg loss had seroreversion with re-emergence of HBsAg positivity, viral load remained undetectable, demonstrating the sustainability of viral suppression. Among a large community-based real-world cohort of Asian CHB patients treated with antiviral therapy, rate of HBsAg loss was 4.58%. Despite only 33.3% of HBsAg loss patients achieving anti-HBs, nearly all patients achieved sustained undetectable virus.

Community-based real-world treatment outcomes of sofosbuvir/ledipasvir in Asians with chronic hepatitis C virus genotype 6 in the United States.

Sofosbuvir/ledipasvir (SOF/LDV) is the first all-oral ribavirin-free treatment approved for chronic hepatitis C virus (HCV) genotype 6, offering a safe and highly efficacious treatment option. Large studies evaluating real-world outcomes of this regimen are lacking. We aim to evaluate real-world treatment outcomes for HCV genotype 6. A retrospective cohort study evaluated 65 adults (age ≥18) with chronic HCV genotype 6 treated with SOF/LDV without ribavirin at a community gastroenterology clinic in the United States from November 2014 to May 2016. Rates of undetectable virus at week 4 on treatment, at end of treatment (EOT) and SVR12 were stratified by the presence of cirrhosis and prior treatment (treatment naïve vs treatment experienced). Among 65 patients with chronic HCV genotype 6 treated with SOF/LDV (52.3% male, mean age 66.3 years [SD 9.7], 41.5% cirrhosis and 15.4% treatment experienced), 97.3% had undetectable virus at week 4 on treatment, 96.9% had undetectable virus at EOT and 95.3% achieved SVR12. SVR12 was 100% in females vs 91.2% in males, P=.096, and 92.3% in patients with cirrhosis vs 97.4% in those without cirrhosis, P=.347. Resistance testing of treatment failures was attempted but unsuccessful due to lack of conforming primers to define the possible resistance mutations. Among the largest U.S. community-based real-world cohort of Asian chronic HCV genotype 6 patients treated with all-oral SOF/LDV without ribavirin, SVR12 was similar to SVR12 reported in clinical trials, confirming the safety and effectiveness of this regimen and validating current HCV genotype 6 treatment guideline recommendations.

The association between particulate air pollution and respiratory admissions among young children in Hanoi, Vietnam.

While the effects of ambient air pollution on health have been studied extensively in many developed countries, few studies have been conducted in Vietnam, where the population is exposed to high levels of airborne particulate matter. The aim of our study was to examine the short-term effects of PM10, PM2.5, and PM1 on respiratory admissions among young children in Hanoi. Data on daily admissions from the Vietnam National Hospital of Paediatrics and daily records of PM10, PM2.5, PM1 and other confounding factors as NO2, SO2, CO, O3 and temperature were collected from September 2010 to September 2011. A time-stratified case-crossover design with individual lag model was applied to evaluate the associations between particulate air pollution and respiratory admissions. Significant effects on daily hospital admissions for respiratory disease were found for PM10, PM2.5 and PM1. An increase in 10µg/m3 of PM10, PM2.5 or PM1 was associated with an increase in risk of admission of 1.4%, 2.2% or 2.5% on the same day of exposure, respectively. No significant difference between the effects on males and females was found in the study. The study demonstrated that infants and young children in Hanoi are at increased risk of respiratory admissions due to the high level of airborne particles in the city's ambient air.

Oral sex and oropharyngeal cancer: The role of the primary care physicians.

BACKGROUND: We aimed to study the prevalence of oral sex and its possible association with human papillomavirus (HPV) 16 infection in the development of oropharyngeal cancer in the US population for possible prevention. METHODS: We conduct a systemic review on the prevalence of oral sex among Americans among different age groups, the prevalence of HPV 16 infection reported in oropharyngeal cancer, and correlation between oral sex and oropharyngeal cancer. RESULTS: Oral sex is prevalent among adolescents and sexually active adults. Sixty percent of oropharyngeal cancer reported in the United States is associated with HPV 16 infections. Individuals who practiced oral sex with multiple partners are at risk for developing oropharyngeal cancer and need to be informed about practicing safe sex or getting vaccination. CONCLUSION: Family physicians will play a key role in prevention and educating the public about the risk of oral sex.

Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer.

PURPOSE: The primary objective was to determine safety, toxicity, and a recommended phase II dose regimen of LY2606368, an inhibitor of checkpoint kinase 1, as monotherapy. PATIENTS AND METHODS: This phase I, nonrandomized, open-label, dose-escalation trial used a 3 + 3 dose-escalation scheme and included patients with advanced solid tumors. Intravenous LY2606368 was dose escalated from 10 to 50 mg/m(2) on schedule 1 (days 1 to 3 every 14 days) or from 40 to 130 mg/m(2) on schedule 2 (day 1 every 14 days). Safety measures and pharmacokinetics were assessed, and pharmacodynamics were measured in blood, hair follicles, and circulating tumor cells. RESULTS: Forty-five patients were treated; seven experienced dose-limiting toxicities (all hematologic). The maximum-tolerated doses (MTDs) were 40 mg/m(2) (schedule 1) and 105 mg/m(2) (schedule 2). The most common related grade 3 or 4 treatment-emergent adverse events were neutropenia, leukopenia, anemia, thrombocytopenia, and fatigue. Grade 4 neutropenia occurred in 73.3% of patients and was transient (typically < 5 days). Febrile neutropenia incidence was low (7%). The LY2606368 exposure over the first 72 hours (area under the curve from 0 to 72 hours) at the MTD for each schedule coincided with the exposure in mouse xenografts that resulted in maximal tumor responses. Minor intra- and intercycle accumulation of LY2606368 was observed at the MTDs for both schedules. Two patients (4.4%) had a partial response; one had squamous cell carcinoma (SCC) of the anus and one had SCC of the head and neck. Fifteen patients (33.3%) had a best overall response of stable disease (range, 1.2 to 6.7 months), six of whom had SCC. CONCLUSION: An LY2606368 dose of 105 mg/m(2) once every 14 days is being evaluated as the recommended phase II dose in dose-expansion cohorts for patients with SCC.

Air pollution and risk of respiratory and cardiovascular hospitalizations in the most populous city in Vietnam.

Air pollution has become an alarming issue in Vietnam recently; however, there was only one study so far on the effects of ambient air pollution on population health. Our study aimed to investigate the short-term effects of air pollutants including PM10, NO2, SO2, and O3 on respiratory and cardiovascular hospitalizations in Ho Chi Minh City (HCMC), the largest city in Vietnam. Data on hospitalization from the two largest hospitals in HCMC and daily records of PM10, NO2, SO2, O3 and meteorological data were collected from February 2004 to December 2007. A time-series regression analysis with distributed lag model was applied for data analysis. Changes in levels of NO2 and PM10 were strongly associated with hospital admissions for both respiratory and cardiovascular diseases (CVD); whereas levels of SO2 were only moderately associated with respiratory and CVD hospital admissions and O3 concentration was not associated with any of them. For a 10µg/m(3) increase of each air pollutant, the risk of respiratory admissions increased from 0.7% to 8% while the risk of CVD admissions increased from 0.5% to 4%. Females were found to be more sensitive than males to exposure to air pollutants in regard to respiratory diseases. In regard to CVD, females (RR, 1.04, 95% CI, 1.01-1.07) had a slightly higher risk of admissions than males (RR, 1.03, 95% CI, 1-1.06) to exposure to NO2. In contrast, males (RR, 1.007, 95%CI, 1-1.01) had a higher risk of admission than females (RR, 1.004, 95%CI, 1.001-1.007) to exposure to PM10. People in the age group of 5-65year-olds had a slightly higher risk of admissions caused by air pollutants than the elderly (65+years old) except for a significant effect of PM10 on the risk of cardiovascular admissions was found for the elderly only.