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Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector (RRV). RRVs selectively infect cancer cells due to innate and adaptive immune response defects in cancers that allow virus replication, and the requirement for cell division for virus integration into the genome. Toca 511 spreads through tumors, stably delivering an optimized yeast cytosine deaminase gene that converts the prodrug Toca FC (investigational, extended-release 5-FC) into 5-FU within the tumor microenvironment. 5-FU kills infected dividing cancer cells and surrounding tumor, myeloid derived suppressor cells, and tumor associated macrophages, resulting in long-term tumor immunity in preclinical models. Data from a Phase 1 resection trial showed six durable CRs and extended mOS compared to historical controls. The FDA granted Breakthrough Therapy Designation for Toca 511 & Toca FC in the treatment of patients with rHGG. Toca 5 is an international, randomized, open-label Phase 3 trial (NCT02414165) of Toca 511 & Toca FC versus SOC in patients undergoing resection for first or second recurrence of rHGG. Patients will be stratified by IDH1 status, KPS, and geographic region. Primary endpoint is OS, and secondary endpoints are durable response rate, durable clinical benefit rate, duration of durable response, and 12-month survival rate. Key inclusion criteria are histologically proven GBM or AA, tumor size ≥1cm and ≤5cm, and KPS ≥70. Immune monitoring and molecular profiling will be performed. Approximately 380 patients will be randomized. An IDMC is commissioned to review the safety and efficacy data which includes 2 interim analyses. Enrollment is ongoing.
An experiment was carried out to evaluate the use of alkanes for estimating diet composition of goats and sheep offered three different dietary treatments. Twelve animals as two groups of 4 crossbred goats (G1, 24 kg live weight; G2, 22 kg) and 4 crossbred sheep (S, 26 kg live weight), were housed in metabolism pens. Animals were offered daily a total of 1 kg DM/100 kg live weight. G1 received 70% ryegrass (Lolium perenne) and 30% gorse (Ulex gallii), G2 received 70% ryegrass and 30% heather (Erica sp.) and S group ate 100% ryegrass. Diet composition was estimated from the alkane concentrations (using all alkanes from C23 to C36 or only odd-chain alkanes C27, C29, C31 and C33) in diet and faeces (with or without correction for incomplete faecal recoveries) using least-squares procedures.
Dietary treatment and animal species significantly affected alkane faecal recoveries, except for C24 and C36. When applying the faecal recovery corrections, there were no significant differences between measured proportions of dietary components and those estimated using all alkanes or odd-chain alkanes. In contrast, the proportions calculated without faecal recovery correction differed significantly (P<0.05) from the actual proportions and over-estimated the amount in the diet of those plant components with higher concentrations of long-chain alkanes (Erica sp. and Lolium perenne). The results indicate that alkanes are useful markers to estimate diet composition, however, it was observed that animal species and diet composition influenced the faecal recovery of alkanes. This suggests that the use of the alkane methodology for estimating the diet selection of grazing animals should be preceded by a calculation of the actual alkane faecal recoveries for each experimental condition.
Plants’ ability to rebuild their tiller population is affected by weather changes and management strategies. The hypothesis of the present study was that frequency and severity of defoliation alter Mulato grass (Brachiaria ruziziensis × Brachiaria brizantha cv. Marandu) sward development, and the proportion of aerial and basal tillers, interfering with sward stability. The objective was to evaluate aerial, basal and total tiller population density and changes in tillering dynamics. Treatments corresponded to strategies of rotational grazing characterized by combinations between two pre-grazing (95% and maximum canopy light interception during regrowth; LI95% and LIMax) and two post-grazing conditions (15 and 20 cm stubble height). The experimental period comprised four seasons of the year: summer 2008 (February–March 2008); autumn–early spring (April to mid-November 2008); late spring (mid-November–December 2008); and summer 2009 (January–March 2009). Density of aerial tillers decreased from summer 2008 to late spring. Tiller death decreased from summer 2008 to autumn–early spring. Aerial and total tiller death increased from late spring to summer 2009, mainly for the LI95% treatment. No differences were observed in the tiller population stability index of aerial tillers for LI treatments or post-grazing heights. The balance between tiller appearance and death for basal tillers remained relatively stable from summer 2008 to late spring. For aerial tillers the balance decreased to negative values from summer 2008 to autumn–early spring for both LI treatments. For total tiller population, the balance decreased to negative values from summer 2008 to autumn–early spring. Results indicated a strong seasonal effect on Mulato grass tillering and growth. Tillering dynamics were affected primarily by grazing frequency, which changed the relative importance of basal and aerial tillers. The results suggested that basal tillering was the predominant perennation pathway.
Urinary tract infection (UTI) is common in children aged <5 years with diarrhoea, but little is known about risk factors, aetiology and outcome of such children. We aimed to evaluate these knowledge gaps of UTI in children aged <5 years with diarrhoea. We enrolled all children aged <5 years with diarrhoea admitted to Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh, between May 2011 and April 2013, who had history of fever (⩾38 °C) and obtained a urine sample for culture. Diarrhoea with UTI (confirmed by culture) constituted cases (n = 26) and those without UTI constituted controls (n = 78). Threefold controls were randomly selected. The case-fatality rate was comparable in cases and controls (4% vs. 1%, P = 0·439). Escherichia coli (69%) and Klebsiella (15%) were the most commonly isolated pathogens. Persistent diarrhoea, pneumonia and prior antibiotics use were identified as risk factors for UTI in logistic regression analysis (P < 0·05 for all). Thus, children with diarrhoea presenting with persistent diarrhoea, pneumonia, and prior antibiotic use should be investigated for UTI for their prompt management that may reduce morbidity.
The Antarctic Roadmap Challenges (ARC) project identified critical requirements to deliver high priority Antarctic research in the 21st century. The ARC project addressed the challenges of enabling technologies, facilitating access, providing logistics and infrastructure, and capitalizing on international co-operation. Technological requirements include: i) innovative automated in situ observing systems, sensors and interoperable platforms (including power demands), ii) realistic and holistic numerical models, iii) enhanced remote sensing and sensors, iv) expanded sample collection and retrieval technologies, and v) greater cyber-infrastructure to process ‘big data’ collection, transmission and analyses while promoting data accessibility. These technologies must be widely available, performance and reliability must be improved and technologies used elsewhere must be applied to the Antarctic. Considerable Antarctic research is field-based, making access to vital geographical targets essential. Future research will require continent- and ocean-wide environmentally responsible access to coastal and interior Antarctica and the Southern Ocean. Year-round access is indispensable. The cost of future Antarctic science is great but there are opportunities for all to participate commensurate with national resources, expertise and interests. The scope of future Antarctic research will necessitate enhanced and inventive interdisciplinary and international collaborations. The full promise of Antarctic science will only be realized if nations act together.
The Dark Energy Survey is undertaking an observational programme imaging 1/4 of the southern hemisphere sky with unprecedented photometric accuracy. In the process of observing millions of faint stars and galaxies to constrain the parameters of the dark energy equation of state, the Dark Energy Survey will obtain pre-discovery images of the regions surrounding an estimated 100 gamma-ray bursts over 5 yr. Once gamma-ray bursts are detected by, e.g., the Swift satellite, the DES data will be extremely useful for follow-up observations by the transient astronomy community. We describe a recently-commissioned suite of software that listens continuously for automated notices of gamma-ray burst activity, collates information from archival DES data, and disseminates relevant data products back to the community in near-real-time. Of particular importance are the opportunities that non-public DES data provide for relative photometry of the optical counterparts of gamma-ray bursts, as well as for identifying key characteristics (e.g., photometric redshifts) of potential gamma-ray burst host galaxies. We provide the functional details of the DESAlert software, and its data products, and we show sample results from the application of DESAlert to numerous previously detected gamma-ray bursts, including the possible identification of several heretofore unknown gamma-ray burst hosts.
Salivary gland transfer surgery can reduce xerostomia in oropharyngeal squamous cell carcinoma patients undergoing primary chemoradiation. A potential drawback of salivary gland transfer is the treatment delay associated with the surgery, and its complications. This study aimed to determine whether the treatment delay affects patient survival and to evaluate patient quality of life after salivary gland transfer.
A retrospective analysis of 138 patients (salivary gland transfer group, n = 58; non-salivary gland transfer group, n = 80) was performed. Patient survival was compared between these groups using multivariate analysis. Salivary gland transfer patients were further evaluated for surgical complications and for quality of life using the head and neck module of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire.
Salivary gland transfer and non-salivary gland transfer patients had comparable baseline clinical characteristics. Salivary gland transfer patients experienced a median treatment delay of 16.5 days before chemoradiation (p = 0.035). Multivariate analysis showed that this did not, however, correspond to a survival disadvantage (p = 0.24 and p = 0.97 for disease-free and disease-specific survival, respectively). A very low complication rate was reported for the salivary gland transfer group (1.7 per cent). Questionnaire scores for the item ‘xerostomia’ were very low in salivary gland transfer patients.
The treatment delay associated with salivary gland transfer surgery does not negatively affect patient survival. Oropharyngeal squamous cell patients have an excellent quality of life after salivary gland transfer.
A cross-sectional survey was carried out in Bangladesh with the sampling of 514 Black Bengal goats on smallholdings to determine the presence of sorbitol non-fermenting (SNF) Shiga toxin-producing E. coli (STEC). Swab samples collected from the recto-anal junction were plated onto cefixime and potassium tellurite added sorbitol MacConkey (CT-SMAC) agar, a selective medium for STEC O157 serogroup, where this serogroup and other SNF STEC produce colourless colonies. The SNF E. coli (SNF EC) isolates obtained from the survey were investigated by PCR for the presence of Shiga toxin-producing genes, stx1 and stx2, and two other virulence genes, eae and hlyA that code for adherence factor (intimin protein) and pore-forming cytolysin, respectively. The SNF EC isolates were also assessed for the presence of the rfbO157 gene to verify their identity to O157 serogroup. The results revealed that the proportions of goats carrying SNF EC isolates and stx1 and stx2 genes were 6·2% (32/514) [95% confidence interval (CI) 4·4–8·7)], 1·2% (95% CI 0·5–2·6) and 1·2% (95% CI 0·5–2·6), respectively. All the SNF STEC tested negative for rfbO157, hlyA and eae genes. The risk for transmission of STEC from Black Bengal goats to humans is low.
Sorghum [Sorghum bicolor (L.) Moench] grown in India is of two adaptive types: rainy and post-rainy. The post-rainy sorghum is predominantly consumed by humans. While releasing new cultivars through multi-location testing, major emphasis is given to the superiority of new cultivars over existing cultivars, with very little emphasis on the genotype × environment interaction (GEI). To understand the complexity of GEI in post-rainy sorghum testing location trials, the multi-location evaluation data of two post-rainy seasons (2009/10 and 2010/11) under the All India Coordinated Sorghum Improvement Project were analysed. In both years, location explained the highest proportion of total sum of squares followed by the GEI effect and main effect of genotype. Additive main effects and multiplicative interaction (AMMI), stability values (ASV) and genotype + genotype × environment interaction (GGE) instability values recorded high correlation resulting in identification of the best performing cultivars. However, the rank correlations were lower, though still significant. A mixture of crossover and non-crossover GEI was a common occurrence in both years. ‘Which-won-where’ analysis suggested the existence of four possible mega-environments (ME) among post-rainy testing locations, with a few non-informative locations within ME. Mega-environments are characterized by soil type, rainfall pattern and moisture conservation practices. The present study indicated the possibility of reducing the number of test locations by eliminating non-representative highly correlated locations and suggested the need to breed for location-specific genotypes rather than genotypes with wider adaptability.
Human toxocarosis is a chronic tissue parasitosis most often caused by Toxocara canis. The seroprevalence can reach up to 50%, especially among children and adolescents. The anthelmintics used in the treatment have moderate efficacy. The aim of this study was to evaluate the in vitro and in vivo anthelmintic activity of quinones and their derivatives against T. canis larvae and the cytotoxicity of the larvicidal compounds. The compounds were evaluated at 1 mg mL−1 concentration in microculture plates containing third stage larvae in an Roswell Park Memorial Institute (RPMI) 1640 environment, incubated at 37 °C in 5% CO2 tension for 48 h. Five naphthoxiranes were selected for the cytotoxicity analysis. The cell viability evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays using murine peritoneal macrophages isolated from C57BL/6 mice revealed that the naphthoxiranes (1 and 3) were less cytotoxic at a concentration of 0·05 mg mL−1. The efficacy of naphthoxiranes (1 and 3) was examined in murine toxocarosis also. The anthelmintic activity was examined by evaluating the number of larvae in the brain, carcass, liver, lungs, heart, kidneys and eyes. Compound (3) demonstrated anthelmintic activity similar to that of albendazole by decreasing the number of larvae in the organs of mice and thus could form the basis of the development of a new anthelmintic drug.
In search of a suitable resource conservation technology under pigeonpea (Cajanus cajan L.)–wheat (Triticum aestivum L.) system in the Indo-Gangetic Plains, the effects of conservation agriculture (CA) on crop productivity and water-use efficiency (WUE) were evaluated during a 3-year study. The treatments were: conventional tillage (CT), zero tillage (ZT) with planting on permanent narrow beds (PNB), PNB with residue (PNB + R), ZT with planting on permanent broad beds (PBB) and PBB + R. The PBB + R plots had higher pigeonpea grain yield than the CT plots in all 3 years. However, wheat grain yields under all plots were similar in all years except for PBB + R plots in the second year, which had higher wheat yield than CT plots. The contrast analysis showed that pigeonpea grain yield of CA plots was significantly higher than CT plots in the first year. However, both pigeonpea and wheat grain yields during the last 2 years under CA and CT plots were similar. The PBB + R plots had higher system WUE than the CT plots in the second and third years. Plots under CA had significantly higher WUE and significantly lower water use than CT plots in these years. The PBB + R plots had higher WUE than PNB + R and PNB plots. Also, the PBB plots had higher WUE than PNB in the second and third years, despite similar water use. The interactions of bed width and residue management for all parameters in the second and third years were not significant. Those positive impacts under PBB + R plots over CT plots were perceived to be due to no tillage and significantly higher amount of estimated residue retention. Thus, both PBB and PBB + R technologies would be very useful under a pigeonpea–wheat cropping system in this region.
Obesity and osteoporosis may have their origins in early postnatal life. This study was designed to evaluate whether flaxseed flour use during lactation period bears effect on body adiposity and skeletal structure of male rat pups at weaning. At birth, male Wistar rats were randomly assigned to control and experimental (FF) groups, whose dams were treated with control or flaxseed flour diet, respectively, during lactation. At 21 days of age, pups were weaned to assess body mass, length and composition by dual-energy X-ray absorptiometry. The animals were then sacrificed to carry out analysis of serum profile, intra-abdominal adipocyte morphology and femur characteristics. Differences were considered significant when P<0.05. The FF group displayed the following characteristics (P<0.05): higher body mass, length, bone mineral content, bone area and concentrations of osteoprotegerin, osteocalcin and high-density lipoprotein cholesterol; higher levels of stearic, α-linolenic, eicosapentaenoic and docosapentaenoic acids and lower levels of arachidonic acid and cholesterol; smaller adipocyte area; and higher mass, epiphysis distance, diaphysis width, maximal load, break load, resilience and stiffness of femur. Flaxseed flour intake during lactation period promoted adipocyte hypertrophy down-regulation and contributed to pup bone quality at weaning.
Cholera is an important public health problem in Bangladesh. Interventions to prevent cholera depend on their cost-effectiveness which in turn depends on cholera incidence. Hospital-based diarrhoeal disease surveillance has been ongoing in six Bangladeshi hospitals where a systematic proportion of patients admitted with diarrhoea were enrolled and tested for Vibrio cholerae. However, incidence calculation using only hospital data underestimates the real disease burden because many ill persons seek treatment elsewhere. We conducted a healthcare utilization survey in the catchment areas of surveillance hospitals to estimate the proportion of severe diarrhoeal cases that were admitted to surveillance hospitals and estimated the population-based incidence of severe diarrhoea due to V. cholerae by combining both hospital surveillance and catchment area survey data. The estimated incidence of severe diarrhoea due to cholera ranged from 0·3 to 4·9/1000 population in the catchment area of surveillance hospitals. In children aged <5 years, incidence ranged from 1·0 to 11·0/1000 children. Diarrhoeal deaths were most common in the Chhatak Hospital's catchment area (18·5/100 000 population). This study provides a credible estimate of the incidence of severe diarrhoea due to cholera in Bangladesh, which can be used to assess the cost-effectiveness of cholera prevention activities.
Low-temperature stress is an important factor affecting the growth and development of rice in temperate and high-elevation areas. In this study, 220 germplasm lines were used for screening of tolerant genotypes, validation of molecular markers and identification of robust markers for seedling-stage chilling stress tolerance to be used in marker-assisted breeding (MAS) programme. The temperature regimes imposed in the growth chamber simulated cold-stress injuries at the seedling stages of the germplasm lines. The genotypes were classified into six classes: those having susceptible genotypes were classified into moderately and highly susceptible types, while tolerant types into moderately tolerant, tolerant, highly tolerant and very highly tolerant classes. Genotypes namely Langma, Umleng-1 and Geetanjali showed survival up to 25 d, which were better than the positive check Kalinga-III surviving up to 20 d under chilling stress. Ten simple sequence repeat (SSR) markers were tested for differentiation of genotypes. Individual use of SSR markers like RM284, RM286, RM85, RM341 and RM5746 can be applied in MAS breeding including combination use of non-pair markers like RM284, RM239 and RM85, which was even better than the combined use of RM284 and RM85. However, combined use of all ten markers can most effectively be employed for cold tolerance through MAS breeding.
In this work, we report on development of one-dimensional reaction-diffusion simulator needed to understand the kinetics of Cu-related metastabilities observed in CdTe PV devices. Evolution of intrinsic and Cu-related defects in CdTe solar cells has been studied in time-space domain self-consistently with free carrier transport. Resulting device performance was simulated as a function of stress time, thus showing pronounced effect that the evolution of associated acceptor and donor states can cause on device characteristics. Although 1D simulation has intrinsic limitations when applied to poly-crystalline films, the results presented confirm the validity and the potential of the approach presented in better understanding of the performance and metastabilities of CdTe photovoltaic devices.
The 2013 multistate outbreaks contributed to the largest annual number of reported US cases of cyclosporiasis since 1997. In this paper we focus on investigations in Texas. We defined an outbreak-associated case as laboratory-confirmed cyclosporiasis in a person with illness onset between 1 June and 31 August 2013, with no history of international travel in the previous 14 days. Epidemiological, environmental, and traceback investigations were conducted. Of the 631 cases reported in the multistate outbreaks, Texas reported the greatest number of cases, 270 (43%). More than 70 clusters were identified in Texas, four of which were further investigated. One restaurant-associated cluster of 25 case-patients was selected for a case-control study. Consumption of cilantro was most strongly associated with illness on meal date-matched analysis (matched odds ratio 19·8, 95% confidence interval 4·0–∞). All case-patients in the other three clusters investigated also ate cilantro. Traceback investigations converged on three suppliers in Puebla, Mexico. Cilantro was the vehicle of infection in the four clusters investigated; the temporal association of these clusters with the large overall increase in cyclosporiasis cases in Texas suggests cilantro was the vehicle of infection for many other cases. However, the paucity of epidemiological and traceback information does not allow for a conclusive determination; moreover, molecular epidemiological tools for cyclosporiasis that could provide more definitive linkage between case clusters are needed.
In this article, Conley’s connection matrix theory and a spectral sequence analysis of a filtered Morse chain complex
are used to study global continuation results for flows on surfaces. The briefly described unfoldings of Lyapunov graphs have been proved to be a well-suited combinatorial tool to keep track of continuations. The novelty herein is a global dynamical cancellation theorem inferred from the differentials of the spectral sequence
. The local version of this theorem relates differentials
to Smale’s theorem on cancellation of critical points.
Course and predictors of persistence of attention deficit hyperactivity disorder (ADHD) in adults are still largely unknown. Neurobiological and clinical differences between child and adult ADHD raise the need for follow-up studies of patients diagnosed during adulthood. This study investigates predictors of ADHD persistence and the possibility of full remission 7 years after baseline assessment.
A 7-year follow-up study of adults with ADHD (n = 344, mean age 34.1 years, 49.9% males) was conducted. Variables from different domains (social demographics, co-morbidities, temperament, medication status, ADHD measures) were explored with the aim of finding potential predictors of ADHD persistence.
Retention rate was 66% (n = 227). Approximately a third of the sample (n = 70, 30.2%) did not maintain ADHD criteria and 28 (12.4%) presented full remission (<4 symptoms), independently of changes in co-morbidity or cognitive demand profiles. Baseline predictors of diagnostic persistence were higher number of inattention symptoms [odds ratio (OR) 8.05, 95% confidence interval (CI) 2.54–25.45, p < 0.001], number of hyperactivity/impulsivity symptoms (OR 1.18, 95% CI 1.04–1.34, p = 0.01), oppositional defiant disorder (OR 3.12, 95% CI 1.20–8.11, p = 0.02), and social phobia (OR 3.59, 95% CI 1.12–11.47, p = 0.03).
Despite the stage of brain maturation in adults suggests stability, approximately one third of the sample did not keep full DSM-IV diagnosis at follow-up, regardless if at early, middle or older adulthood. Although full remission is less common than in childhood, it should be considered as a possible outcome among adults.
There is limited information on percent expenditure of household income due to childhood diarrhoea especially in rural Bangladesh. A total of 4205 children aged <5 years with acute diarrhoea were studied. Percent expenditure was calculated as total expenditure for the diarrhoeal episode divided by monthly family income, multiplied by 100. Overall median percent expenditure was 3·04 (range 0·01–94·35). For Vibrio cholerae it was 6·42 (range 0·52–82·85), for enterotoxigenic Escherichia coli 3·10 (range 0·22–91·87), for Shigella 3·17 (range 0·06–77·80), and for rotavirus 3·08 (range 0·06–48·00). In a multinomial logistic regression model, for the upper tertile of percent expenditure, significant higher odds were found for male sex, travelling a longer distance to reach hospital (⩾median of 4 miles), seeking care elsewhere before attending hospital, vomiting, higher frequency of purging (⩾10 times/day), some or severe dehydration and stunting. V. cholerae was the highest and rotavirus was the least responsible pathogen for percent expenditure of household income due to childhood diarrhoea.