Correlation of the in vitro biotransformation of H3B-6527 in dog and human hepatocytes with the in vivo metabolic profile of 14C-H3B-6527 in a dog mass balance study.

1. H3B-6527 is an orally available covalent small molecule inhibitor of FGFR4 undergoing evaluation in adults with hepatocellular carcinoma. Absorption, metabolism, transport and elimination of H3B-6527 were investigated in vitro and in a 14C-H3B-6527 beagle dog mass balance study.2. Following intravenous dosing in dogs, unchanged 14C-H3B-6527 represents only 1.6% of the total dose in excreta. The low amount of radioactivity in the dog urine (4.9% of the administered dose), suggests that renal elimination is a minor pathway of clearance for H3B-6527. A majority of the radioactivity was observed in the feces up to 5 days after dose administration, suggesting that drug-related material was secreted in the bile, and that H3B-6527 clearance was mostly driven by metabolism.3. In vitro, H3B-6527 is a substrate of GSTs, CYP3A and P-glycoprotein.4. The major pathways of metabolism were similar in human and dog hepatocytes, and occurred via glutathione (GSH) conjugations and sequential hydrolysis, N-deethylation and hydroxylation.5. The metabolic profile of H3B-6527 was qualitatively similar in dog hepatocytes and plasma/excreta.

Spectroscopic gas detection using a Bragg grating - stabilized external cavity laser, custom written in planar integrated silica-on-silicon.

We present the development of an external cavity Bragg grating stabilized laser for tunable diode laser spectroscopy (TDLS). Our design uses a planar integrated silica-on-silicon platform incorporating a custom written Bragg grating as the wavelength-selective element of the laser cavity. We have developed a prototype singlemode laser at 1651 nm and performed a detailed characterization of its performance for the purpose of spectroscopic measurement of methane at this wavelength using a 25 cm path-length single-pass cell. Mode hop-free tuning of 0.13 nm has been demonstrated at frequencies of up to 10 kHz. A single-point limit of detection for TDLS of ΔI/I0 = 8.3 × 10-5 AU was achieved, which is consistent with the performance of standard distributed feedback lasers. The new device exhibits a side-mode suppression ratio of -40 dB and a low RIN of <-150 dB/Hz, and thus avoids the high levels of noise or instability normally associated with larger, mechanically driven external cavity lasers. The silica-on-silicon platform has the potential for low-volume manufacturing of special lasers at the custom wavelengths required for gas detection, without the need for investment in foundry solutions.

Integrated reconfigurable photonic filters based on interferometric fractional Hilbert transforms.

In this paper, we present integrated reconfigurable photonic filters using fractional Hilbert transformers (FrHTs) and optical phase tuning structure within the silica-on-silicon platform. The proposed structure, including grating-based FrHTs, an X-coupler, and a pair of thermal tuning filaments, is fabricated through the direct UV grating writing technique. The thermal tuning effect is realized by the controllable microheaters located on the two arms of the X-coupler. We investigate the 200 GHz maximum bandwidth photonic FrHTs based on apodized planar Bragg gratings, and analyze the reflection spectrum responses. Through device integration and thermal modulation, the device could operate as photonic notch filters with 5 GHz linewidth and controllable single sideband suppression filters with measured 12 dB suppression ratio. A 50 GHz instantaneous frequency measuring system using this device is also schematically proposed and analyzed with potential 3 dB measurement improvement. The device could be configured with these multiple functions according to need. The reconfigurable structure has great potential in ultrafast all-optical signal processing fields.

Ultra-wide detuning planar Bragg grating fabrication technique based on direct UV grating writing with electro-optic phase modulation.

A direct UV grating writing technique based on phase-controlled interferometry is proposed and demonstrated in a silica-on-silicon platform, with a wider wavelength detuning range than any previously reported UV writing technology. Electro-optic phase modulation of one beam in the interferometer is used to manipulate the fringe pattern and thus control the parameters of the Bragg gratings and waveguides. Various grating structures with refractive index apodization, phase shifts and index contrasts of up to 0.8 × 10(-3) have been demonstrated. The method offers significant time/energy efficiency as well as simplified optical layout and fabrication process. We have shown Bragg gratings can be made from 1200 nm to 1900 nm exclusively under software control and the maximum peak grating reflectivity only decreases by 3 dBover a 250 nm (~32 THz) bandwidth.

Terahertz bandwidth photonic Hilbert transformers based on synthesized planar Bragg grating fabrication.

Terahertz bandwidth photonic Hilbert transformers are proposed and experimentally demonstrated. The integrated device is fabricated via a direct UV grating writing technique in a silica-on-silicon platform. The photonic Hilbert transformer operates at bandwidths of up to 2 THz (~16 nm) in the telecom band, a 10-fold greater bandwidth than any previously reported experimental approaches. Achieving this performance requires detailed knowledge of the system transfer function of the direct UV grating writing technique; this allows improved linearity and yields terahertz bandwidth Bragg gratings with improved spectral quality. By incorporating a flat-top reflector and Hilbert grating with a waveguide coupler, an ultrawideband all-optical single-sideband filter is demonstrated.

Phase controlled integrated interferometric single-sideband filter based on planar Bragg gratings implementing photonic Hilbert transform.

The monolithically integrated all-optical single-sideband (SSB) filter based on photonic Hilbert transform and planar Bragg gratings is proposed and experimentally demonstrated. An SSB suppression of 12 dB at 6 GHz and sideband switching are achieved via thermal tuning. An X-coupler, photonic Hilbert transformer, flat top reflector, and a micro heater are incorporated in a single silicon-on-silica substrate. The device can be thermally tuned by the micro heater on top of the channel waveguide. The device is fabricated using a combination of direct UV grating writing technology and photolithography.

Demonstration of UV-written waveguides, Bragg gratings and cavities at 780 nm, and an original experimental measurement of group delay.

We present direct UV-written waveguides and Bragg gratings operating at 780 nm. By combining two gratings into a Fabry-Perot cavity we have devised and implemented a novel and practical method of measuring the group delay of Bragg gratings.

Meeting Report: WHO Workshop on modelling global mortality and aetiology estimates of enteric pathogens in children under five. Cape Town, 28-29th November 2018.

Investment in vaccine product development should be guided by up-to-date and transparent global burden of disease estimates, which are also fundamental to policy recommendation and vaccine introduction decisions. For low- and middle-income countries (LMICs), vaccine prioritization is primarily driven by the number of deaths caused by different pathogens. Enteric diseases are known to be a major cause of death in LMICs. The two main modelling groups providing mortality estimates for enteric diseases are the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Seattle and the Maternal Child Epidemiology Estimation (MCEE) group, led by Johns Hopkins Bloomberg School of Public Health. Whilst previous global diarrhoea mortality estimates for under five-year-olds from these two groups were closely aligned, more recent estimates for 2016 have diverged, particularly with respect to numbers of deaths attributable to different enteric pathogens. This has impacted prioritization and investment decisions for vaccines in the development pipeline. The mission of the Product Development for Vaccines Advisory Committee (PDVAC) at the World Health Organisation (WHO) is to accelerate product development of vaccines and technologies that are urgently needed and ensure they are appropriately targeted for use in LMICs. At their 2018 meeting, PDVAC recommended the formation of an independent working group of subject matter experts to explore the reasons for the difference between the IHME and MCEE estimates, and to assess the respective strengths and limitations of the estimation approaches adopted, including a review of the data on which the estimates are based. Here, we report on the proceedings and recommendations from a consultation with the working group of experts, the IHME and MCEE modelling groups, and other key stakeholders. We briefly review the methodological approaches of both groups and provide a series of proposals for investigating the drivers for the differences in enteric disease burden estimates.

Phase-controlled integrated photonic quantum circuits.

Scalable photonic quantum technologies are based on multiple nested interferometers. To realize this architecture, integrated optical structures are needed to ensure stable, controllable, and repeatable operation. Here we show a key proof-of-principle demonstration of an externallycontrolled photonic quantum circuit based upon UV-written waveguide technology. In particular, we present non-classical interference of photon pairs in a Mach-Zehnder interferometer constructed with X couplers in an integrated optical circuit with a thermo-optic phase shifter in one of the interferometer arms.

Predictability of the UK variant Creutzfeldt-Jakob disease epidemic.

Back-calculation analysis of the variant Creutzfeldt-Jakob disease epidemic in the United Kingdom is used to estimate the number of infected individuals and future disease incidence. The model assumes a hazard of infection proportional to the incidence of bovine spongiform encephalopathy in the United Kingdom and accounts for precautionary control measures and very wide ranges of incubation periods. The model indicates that current case data are compatible with numbers of infections ranging from a few hundred to several millions. In the latter case, the model suggests that the mean incubation period must be well beyond the human life-span, resulting in disease epidemics of at most several thousand cases.

Pre-vaccination screening strategies for the use of the CYD-TDV dengue vaccine: A meeting report.

The first licensed dengue vaccine, CYD-TDV (Dengvaxia) is efficacious in seropositive individuals, but increases the risk for severe dengue in seronegative persons about two years after administration of the first dose. For countries considering the introduction of Dengvaxia, WHO recommends a pre-vaccination screening strategy whereby only persons with evidence of a past dengue infection would be vaccinated. Policy-makers need to consider the risk-benefit of vaccination strategies based on such screening tests, the optimal age to introduce the vaccine, communication and implementation strategies. To address these questions, the Global Dengue and Aedes-transmitted diseases Consortium (GDAC) organized a 3-day workshop in January 2019 with country representatives from Asia and Latin America. The meeting discussions highlighted many challenges in introducing Dengvaxia, in terms of screening test characteristics, costs of such tests combined with a 3-dose schedule, logistics, achieving high coverage rates, vaccine confidence and communication; more challenges than for any other vaccine introduction programme. A screening test would require a high specificity to minimize individual risk, and at the same time high sensitivity to maximize individual and population benefit. The underlying seroprevalence dependent positive predictive value is the best indicator for an acceptable safety profile of a pre-vaccination screening strategy. The working groups discussed many possible implementation strategies. Addressing the bottlenecks in school-based vaccine introduction for Dengvaxia will also benefit other vaccines such as HPV and booster doses for tetanus and pertussis. Levels of public trust are highly variable and context specific, and understanding of population perceptions and concerns is essential to tailor interventions, monitor and mitigate risks.

Remodeling of uterine innervation.

This minireview reports current hypotheses concerning the remodeling of sympathetic innervation in rodent and human uterus during the estrous cycle and gestation. Neural modulation in this organ is related to sexual hormone concentrations, and a reduction in nerve density is observed when estrogen levels are high during the estrous cycle. Estrogen receptor alpha is considered to be the major receptor mediating the action of estrogen. In the uterus, the expression of neurotrophins, such as nerve growth factor, which are involved in the survival and growth of nerve fibers, changes in response to steroid levels. Despite much research, further studies are necessary to clarify various aspects of nerve growth control under diverse physiological conditions. These studies could be of importance, since alterations of the biological mechanisms of uterus innervation may play significant roles in various pathologies, such as infertility and spontaneous abortion.

Line defects and temperature effects in liquid crystal tunable planar Bragg gratings.

Liquid crystal tunable planar Bragg Gratings produced by Direct UV Writing are capable of wavelength tuning of over 100GHz. However, such devices exhibit non-linear tuning curves with threshold points and hysteresis. We show that these effects are due to the formation of disclination structures in the liquid crystal and discuss the role of electrode defects and sample temperature on wavelength tuning.

Regular drug use and cancer.

An extensive survey study of 25,000 patients admitted to 24 Boston-area hospitals during the first 10 months of 1972 provided data which were used to estimate the proportion of cancer that is likely to be due to recent regular intake of drugs normally used to treat illness. Cancer was diagnosed for the first time in some 800 patients. The regular drug use before admissions among these patients was compared to that of 3,443 non-cancer patients admitted for conditions thought to be unrelated to any regular drug use. Controlling for age and sex, the risk ratio point estimate for any regular drug use among cancer patients was 0.88 when compared to that of reference patients. The 90% upper confidence bound was 1.02. These data indicate with 90% confidence that less than 1% of the cancers identified in this study were likely to have been caused by any recent regular use of drugs.

Burkitt's lymphoma in the Mengo Districts of Uganda: epidemiologic features and their relationship to malaria.

An epidemiologic study of 123 patients residing in the Mengo Districts of Uganda, with onset of symptoms of diagnosed Burkitt's lymphoma (BL) in the period 1959-68, revealed a substantial decline in incidence of BL during that decade. Other significant findings included differences by ethnic group in age of patient at onset of BL, a change in the proportions of patients by ethnic group over the decade, a lower incidence rate of BL in the countries of higher altitude, and a seasonal pattern of onset. There was no evidence of the time space clustering previously reported for BL in Uganda. The changing pattern of BL in the Mengo Districts was consistent with the hypothesis that severe malaria infection not only is important in the development of BL but also precipitates onset.

Current epidemiological evidence for transmission of Hodgkin's disease.

The epidemiological evidence relating to the possibility of person-to-person transmission of Hodgkin's disease is reviewed. A number of studies are found to be difficult to interpret because of the absence of control data. It is concluded that, although certain studies are consistent with the hypothesis of person-to-person transmission, the evidence is a present weak and further epidemiological studies are needed.

Epstein-Barr virus-malaria interaction models for Burkitt's lymphoma: implications for preventive trials.

Infections with both Epstein-Barr virus (EBV) and malaria have been implicated as causal factors in the pathogenesis of Burkitt's lymphoma (BL). Proposed trials of preventive measures for both infections are receiving serious consideration as possible means of establishing a causal relationship with BL. In this paper we examine certain models for the interaction of EBV and malaria in the induction of BL, and also review the aims of the longitudinal, population-based study being conducted in the West Nile District of Uganda. Given existing knowledge, the outcome of preventive trials, even for the most simple interaction models, is unpredictable and, under certain circumstances, trials of an EBV vaccine could actually increase the incidence of BL. It is suggested that trials of an EBV vaccine at this time would be premature and should be delayed at least until the results from the West Nile prospective study are clear.

Childhood pneumonia and crowding, bed-sharing and nutrition: a case-control study from The Gambia.

SETTING: Greater Banjul and Upper River Regions, The Gambia. OBJECTIVE: To investigate tractable social, environmental and nutritional risk factors for childhood pneumonia. DESIGN: A case-control study examining the association of crowding, household air pollution (HAP) and nutritional factors with pneumonia was undertaken in children aged 2-59 months: 458 children with severe pneumonia, defined according to the modified WHO criteria, were compared with 322 children with non-severe pneumonia, and these groups were compared to 801 neighbourhood controls. Controls were matched by age, sex, area and season. RESULTS: Strong evidence was found of an association between bed-sharing with someone with a cough and severe pneumonia (adjusted OR [aOR] 5.1, 95%CI 3.2-8.2, P < 0.001) and non-severe pneumonia (aOR 7.3, 95%CI 4.1-13.1, P < 0.001), with 18% of severe cases estimated to be attributable to this risk factor. Malnutrition and pneumonia had clear evidence of association, which was strongest between severe malnutrition and severe pneumonia (aOR 8.7, 95%CI 4.2-17.8, P < 0.001). No association was found between pneumonia and individual carbon monoxide exposure as a measure of HAP. CONCLUSION: Bed-sharing with someone with a cough is an important risk factor for severe pneumonia, and potentially tractable to intervention, while malnutrition remains an important tractable determinant.

Frequency dependence of the frog skin impedance.

At frequencies between 20 Hz and 1 kHz the impedance locus of the isolated frog skin is circular; below 20 Hz the resistive component of the impedance is frequently greater than would be expected from extrapolation of the high-frequency locus. At frequencies greater than twice the highest frequency at which there are deviations from the circular locus the variation of impedance Z with angular frequency omega is closely described by the equation Z equals r1 plus r o/[1 plus (j omega tau)1-alpha], where j is square root--1, r 1 and r 0 are resistances, tau is a time constant and alpha a constant in the range 0.02-0.14.

The epidemiology of variant Creutzfeldt-Jakob disease.

Variant Creutzfeldt-Jakob disease (vCJD) was identified as a new disease in 1996. It was linked to infection with the bovine spongiform encephalopathy (BSE) agent although the epidemiological evidence for this was not strong, but later strain typing studies confirmed the association. The disease has affected predominantly young adults whose dietary and other characteristics are unexceptional compared to control groups, other than that all patients to date have been methoinine homozygous at codon 129 of the prion protein gene and the incidence has been about two times higher in the North of the UK. The number of cases in the 7 years after first identification of the disease has been considerably lower than initially feared, given the likely widespread exposure of the UK population to the BSE agent through contaminated beef products. Predictions of the possible future course of the epidemic have many associated uncertainties, but current mathematical models suggest that more than a few thousand cases is unlikely. Such modelling is limited by the absence of a test for infection with the vCJD agent. The development of a test that could be used on easily accessible tissue to detect infection early in the incubation period would not only advance understanding of the epidemiology of infection with the agent but would also aid the implementation of control measures to prevent potential iatrogenic spread.