Comparison of a novel potentiator of CFTR channel activity to ivacaftor in ameliorating mucostasis caused by cigarette smoke in primary human bronchial airway epithelial cells.

BACKGROUND: Cystic Fibrosis causing mutations in the gene CFTR, reduce the activity of the CFTR channel protein, and leads to mucus aggregation, airway obstruction and poor lung function. A role for CFTR in the pathogenesis of other muco-obstructive airway diseases such as Chronic Obstructive Pulmonary Disease (COPD) has been well established. The CFTR modulatory compound, Ivacaftor (VX-770), potentiates channel activity of CFTR and certain CF-causing mutations and has been shown to ameliorate mucus obstruction and improve lung function in people harbouring these CF-causing mutations. A pilot trial of Ivacaftor supported its potential efficacy for the treatment of mucus obstruction in COPD. These findings prompted the search for CFTR potentiators that are more effective in ameliorating cigarette-smoke (CS) induced mucostasis. METHODS: Small molecule potentiators, previously identified in CFTR binding studies, were tested for activity in augmenting CFTR channel activity using patch clamp electrophysiology in HEK-293 cells, a fluorescence-based assay of membrane potential in Calu-3 cells and in Ussing chamber studies of primary bronchial epithelial cultures. Addition of cigarette smoke extract (CSE) to the solutions bathing the apical surface of Calu-3 cells and primary bronchial airway cultures was used to model COPD. Confocal studies of the velocity of fluorescent microsphere movement on the apical surface of CSE exposed airway epithelial cultures, were used to assess the effect of potentiators on CFTR-mediated mucociliary movement. RESULTS: We showed that SK-POT1, like VX-770, was effective in augmenting the cyclic AMP-dependent channel activity of CFTR. SK-POT-1 enhanced CFTR channel activity in airway epithelial cells previously exposed to CSE and ameliorated mucostasis on the surface of primary airway cultures. CONCLUSION: Together, this evidence supports the further development of SK-POT1 as an intervention in the treatment of COPD.

Method for Identification of Aberrations in Operational Data of Maritime Vessels and Sources Investigation.

Sensing data from vessel operations are of great importance in reflecting operational performance and facilitating proper decision-making. In this paper, statistical analyses of vessel operational data are first conducted to compare manual noon reports and autolog data from sensors. Then, new indicators to identify data aberrations are proposed, which are the errors between the reported values from operational data and the expected values of different parameters based on baseline models and relevant sailing conditions. A method to detect aberrations based on the new indicators in terms of the reported power is then investigated, as there are two independent measured power values. In this method, a sliding window that moves forward along time is implemented, and the coefficient of variation (CV) is calculated for comparison. Case studies are carried out to detect aberrations in autolog and noon data from a commercial vessel using the new indicator. An analysis to explore the source of the deviation is also conducted, aiming to find the most reliable value in operations. The method is shown to be effective for practical use in detecting aberrations, having been initially tested on both autolog and noon report from four different commercial vessels in 14 vessel years. Approximately one triggered period per vessel per year with a conclusive deviation source is diagnosed by the proposed method. The investigation of this research will facilitate a better evaluation of operational performance, which is beneficial to both the vessel operators and crew.

Comparison of a novel potentiator of CFTR channel activity to ivacaftor in ameliorating mucostasis caused by cigarette smoke in primary human bronchial airway epithelial cells.

Background: Cystic Fibrosis causing mutations in the gene CFTR , reduce the activity of the CFTR channel protein, and leads to mucus aggregation, airway obstruction and poor lung function. A role for CFTR in the pathogenesis of other muco-obstructive airway diseases such as Chronic Obstructive Pulmonary Disease (COPD) has been well established. The CFTR modulatory compound, Ivacaftor (VX-770), potentiates channel activity of CFTR and certain CF-causing mutations and has been shown to ameliorate mucus obstruction and improve lung function in people harbouring these CF-causing mutations. A pilot trial of Ivacaftor supported its potential efficacy for the treatment of mucus obstruction in COPD. These findings prompted the search for CFTR potentiators that are more effective in ameliorating cigarette-smoke (CS) induced mucostasis. Methods: A novel small molecule potentiator (SK-POT1), previously identified in CFTR binding studies, was tested for its activity in augmenting CFTR channel activity using patch clamp electrophysiology in HEK-293 cells, a fluorescence-based assay of membrane potential in Calu-3 cells and in Ussing chamber studies of primary bronchial epithelial cultures. Addition of cigarette smoke extract (CSE) to the solutions bathing the apical surface of Calu-3 cells and primary bronchial airway cultures was used to model COPD. Confocal studies of the velocity of fluorescent microsphere movement on the apical surface of CSE exposed airway epithelial cultures, were used to assess the effect of potentiators on CFTR-mediated mucociliary movement. Results: We showed that SK-POT1, like VX-770, was effective in augmenting the cyclic AMP-dependent channel activity of CFTR. SK-POT-1 enhanced CFTR channel activity in airway epithelial cells previously exposed to CSE and ameliorated mucostasis on the surface of primary airway cultures. Conclusion: Together, this evidence supports the further development of SK-POT1 as an intervention in the treatment of COPD.

Impact of selective licensing schemes for private rental housing on mental health and social outcomes in Greater London, England: a natural experiment study.

OBJECTIVES: To assess primary impact of selective Licensing (SL), an area-based intervention in the private rented housing market, on individual self-reported anxiety and neighbourhood mental health (MHI-Mental Healthcare Index) and secondary impacts on antisocial behaviour (ASB), population turnover and self-reported well-being. DESIGN: Difference-in-difference (DiD) was used to evaluate effects of SL schemes initiated 2012-2018. 921 intervention areas (lower super output areas) were matched 3:1 using propensity scores derived from sociodemographic and housing variables (N=3.684 including controls). Average treatment effect on treated (ATT) was calculated for multiple time period DiD in area-level analyses. Canonical DiD was used for individual-level analysis by year of treatment initiation while adjusting for age, sex, native birth and occupational class. SETTING: Intervention neighbourhoods and control areas in Greater London, UK, 2011-2019. PARTICIPANTS: We sampled 4474 respondents renting privately in intervention areas (N=17 347 including controls) in Annual Population Survey and obtained area-level MHI population data. INTERVENTIONS: Private landlords in SL areas must obtain a licence from the local authority, allow inspection and maintain minimum housing standards. RESULTS: ATT after 5 years was significantly lower for MHI (-7.5%, 95% CI -5.6% to -8.8%) than controls. Antidepressant treatment days per population reduced by -5.4% (95% CI -3.7% to -7.3), mental health benefit receipt by -9.6% (95% CI -14% to -5.5%) and proportion with depression by -12% (95% CI -7.7% to -16.3%). ASB reduced by -15% (95% CI -21% to -8.2%). Population turnover increased by 26.5% (95% CI 22.1% to 30.8%). Sensitivity analysis suggests overlap with effects of London 2012 Olympic regeneration. No clear patterns were observed for self-reported anxiety. CONCLUSIONS: We found associations between SL and reductions in area-based mental healthcare outcomes and ASB, while population turnover increased. A national evaluation of SL is feasible and necessary.

Assessing the impact of selective licencing schemes for private rental housing on mental health and well-being: protocol for a mixed-method natural experiment study in Greater London, UK.

INTRODUCTION: The UK private rental housing market has poorer quality housing compared with other sectors and is subjected to calls for better regulation. Poor quality housing poses risks to mental and physical health, and housing improvement can potentially benefit health and well-being. Local authorities have powers to implement selective licencing (SL) schemes in specific localities. Such schemes involve landlord registration, payment of licence fees, local authority inspection and requirements that landlords conduct any necessary renovation works to ensure housing standards are met. We aim to evaluate SL in Greater London and to test the feasibility of a national evaluation. METHODS AND ANALYSIS: We will measure individual-level and area-level impacts of SL in Greater London between 2011 and 2019. A difference-in-differences approach with propensity score-matched controls will be used. We propose to exploit data from the Annual Population Survey (APS) and health and social benefit registers to measure mental health and well-being at individual (self-reported anxiety) and area (Small Area Mental Health Index) level. We estimate 633 APS participants in our intervention groups compared with 1899 participants in control areas (1:3 ratio of intervention to control). Secondary outcomes will be self-reported well-being and residential stability at the individual level and incidence of police-recorded antisocial behaviour calls and population turnover at the area level. The study size of the area-level analyses will be 3684 lower layer super output areas (including controls). Qualitative semistructured interviews with lead implementers in several London boroughs will produce insights into variations and commonalities between schemes. ETHICS AND DISSEMINATION: Ethical approval was obtained from London School of Hygiene and Tropical Medicine's Ethics Committee (reference number 26481) and London Borough of Hackney. All interviewees will be asked for informed written consent. Study findings will be published in a peer-reviewed journal.

British surname origins, population structure and health outcomes-an observational study of hospital admissions.

Population structure is a confounder on pathways linking genotypes to health outcomes. This study examines whether the historical, geographical origins of British surnames are associated with health outcomes today. We coded hospital admissions of over 30 million patients in England between 1999 and 2013 to their British surname origin and divided their diagnoses into 125 major disease categories (of which 94 were complete-case). A base population was constructed with patients' first admission of any kind. Age- and sex-standardised odds ratios were calculated with logistic regression using patients with ubiquitous English surnames such as "Smith" as reference (alpha = .05; Benjamini-Hochberg false discovery rate (FDR) = .05). The results were scanned for "signals", where a branch of related surname origins all had significantly higher or lower risk. Age- and sex-standardised admission (alpha = .05) was calculated for each signal across area deprivation and surname origin density quintiles. Signals included three branches of English surnames (disorders of teeth and jaw, fractures, upper gastrointestinal disorders). Although the signal with fractures was considered unusual overall, 2 out of the 9 origins in the branch would only be significant at a FDR > .05: OR 0.92 (95% confidence interval 0.86-0.98) and 0.70 (0.55-0.90). The risk was only different in the quintile with the highest density of that group. Differential risk remained when studied across quintiles of area deprivation. The study shows that surname origins are associated with diverse health outcomes and thus act as markers of population structure over and above area deprivation.

Ethnic disparities in preventable hospitalisation in England: an analysis of 916 375 emergency admissions.

OBJECTIVES: To study ethnic inequalities in ambulatory care sensitive conditions (ACSC) in England. DESIGN: Observational study of inpatient hospital admission database enhanced with ethnicity coding of patient surnames. The primary diagnosis of the first episode in spells with emergency admission were coded with definitions for acute ACSC, chronic ACSC and vaccine-preventable diseases. SETTING: National Health Service England. PARTICIPANTS: 916 375 ACSC emergency admissions in 7 39 618 patients were identified between April 2011 and March 2012. MAIN OUTCOME MEASURES: ORs of ACSC for each ethnic group relative to the White British majority group adjusted for age, sex and area deprivation. RESULTS: Acute ACSC admission risk adjusted for age and sex was particularly high among Other (OR 1.73; 95% CI 1.69 to 1.77) and Pakistani (1.51; 95% CI 1.48 to 1.54) compared with White British patients. For chronic ACSC, high risk was found among Other (2.02; 95% CI 1.97 to 2.08), Pakistani (2.07; 95% CI 2.02 to 2.12) and Bangladeshi (1.36; 95% CI 1.30 to 1.42). For vaccine-preventable diseases, other (2.42; 95% CI 2.31 to 2.54), Pakistani (1.94; 95% CI 1.85 to 2.04), Bangladeshi (1.48; 95% CI 1.36 to 1.62), Black African (1.45; 95% CI 1.36 to 1.54) and white other (1.38; 95% CI 1.33 to 1.43) groups. Elevated risk was only partly explained in analyses also adjusting for area deprivation. CONCLUSIONS: ACSC admission was especially high among individuals of Bangladeshi, Pakistani, Black African, white other or other background with up to twofold differences compared with the white British group. This suggests that these ethnic groups are not receiving optimal primary care.

Ultrafast Rotational and Translational Energy Relaxation in Neat Liquids.

The excess energy flow pathways during rotational and translational relaxation induced by rotational or translational excitation of a single molecule of and within each of four different neat liquids (H2O, MeOH, CCl4, and CH4) are studied using classical molecular dynamics simulations and energy flux analysis. For all four liquids, the relaxation processes for both types of excitation are ultrafast, but the energy flow is significantly faster for the polar, hydrogen-bonded (H-bonded) liquids H2O and MeOH. Whereas the majority of the initial excess energy is transferred into hindered rotations (librations) for rotational excitation in the H-bonded liquids, an almost equal efficiency for transfer to translational and rotational motions is observed in the nonpolar, non-H-bonded liquids CCl4 and CH4. For translational excitation, transfer to translational motions dominates for all liquids. In general, the energy flows are quite local; i.e., more than 70% of the energy flows directly to the first solvent shell molecules, reaching almost 100% for CCl4 and CH4. Finally, the determined validity of linear response theory for these nonequilibrium relaxation processes is quite solvent-dependent, with the deviation from linear response most marked for rotational excitation and for the nonpolar liquids.

Ethnic inequalities in hospital admissions in England: an observational study.

BACKGROUND: Ethnic inequalities in health are well-known and partly explained by social determinants such as poorer living and working conditions, health behaviours, discrimination, social exclusion, and healthcare accessibility factors. Inequalities are known both for self-reported health and for diseases such as diabetes, cardiovascular diseases, respiratory diseases, and non-specific chest pains. Most studies however concern individual diseases or self-reported health and do not provide an overview that can detect gaps in existing knowledge. The aim of this study is thus to identify ethnic inequalities in inpatient hospital admission for all major disease categories in England. METHODS: Observational study of the inpatient hospital admission database in England enhanced with ethnicity coding of participants' surnames. The primary diagnosis was coded to Level 1 of the Global Burden of Disease groups. For each year, only the first admission for each condition for each participant was included. If a participant was readmitted within two days only the first admission was counted. Admission risk for all major disease groups for each ethnic group relative to the White British group were calculated using logistic regression adjusting for age and area deprivation. RESULTS: 40,928,105 admissions were identified between April 2009 and March 2014. Ethnic inequalities were found in cardiovascular diseases, respiratory diseases, chest pain, and diabetes in line with previous studies. Additional inequalities were found in nutritional deficiencies, endocrine disorders, and sense organ diseases. CONCLUSIONS: The results of this study were consistent with known inequalities, but also found previously unreported disparities in nutritional deficiencies, endocrine disorders, and sense organ diseases. Further studies would be required to map out the relevant care pathways for ethnic minorities and establish whether preventive measures can be strengthened.

Names-based ethnicity enhancement of hospital admissions in England, 1999-2013.

BACKGROUND: Accurate recording of ethnicity in electronic healthcare records is important for the monitoring of health inequalities. Yet until the late 1990s, ethnicity information was absent from more than half of records of patients who received inpatient care in England. In this study, we report on the usefulness of a names-based ethnicity classification, Ethnicity Estimator (EE), for addressing this gap in the hospital records. MATERIALS AND METHODS: Data on inpatient hospital admissions were obtained from Hospital Episode Statistics (HES) between April 1999 and March 2014. The data were enhanced with ethnicity coding of participants' surnames using the EE software. Only data on the first episode for each patient each year were included. RESULTS: A total of 111,231,653 patient-years were recorded between April 1999 and March 2014. The completeness of ethnicity records improved from 59.5 % in 1999 to 90.5 % in 2013 (financial year). Biggest improvement was seen in the White British group, which increased from 55.4 % in 1999 to 73.9 % in 2013. The correct prediction of NHS-reported ethnicity varied by ethnic group (2013 figures): White British (89.8 %), Pakistani (81.7 %), Indian (74.6 %), Chinese (72.9 %), Bangladeshi (63.4 %), Black African (57.3 %), White Other (50.5 %), White Irish (45.0 %). For other ethnic groups the prediction success was low to none. Prediction success was above 70 % in most areas outside London but fell below 40 % in parts of London. CONCLUSION: Studies of ethnic inequalities in hospital inpatient care in England are limited by incomplete data on patient ethnicity collected in the 1990s and 2000s. The prediction success of a names-based ethnicity classification tool has been quantified in HES for the first time and the results can be used to inform decisions around the optimal analysis of ethnic groups using this data source.

Primary care use and cardiovascular disease risk in Russian 40-69 year olds: a cross-sectional study.

BACKGROUND: The Russian Federation has very high cardiovascular disease (CVD) mortality rates compared with countries of similar economic development. This cross-sectional study compares the characteristics of CVD-free participants with and without recent primary care contact to ascertain their CVD risk and health status. METHODS: A total of 2774 participants aged 40-69 years with no self-reported CVD history were selected from a population-based study conducted in Arkhangelsk and Novosibirsk, Russian Federation, 2015-2018. A range of co-variates related to socio-demographics, health and health behaviours were included. Recent primary care contact was defined as seeing primary care doctor in the past year or having attended a general health check under the 2013 Dispansarisation programme. RESULTS: The proportion with no recent primary care contact was 32.3% (95% CI 29.7% to 35.0%) in males, 16.3% (95% CI 14.6% to 18.2%) in females, and 23.1% (95% CI 21.6% to 24.7%) overall. In gender-specific age-adjusted analyses, no recent contact was also associated with low education, smoking, very good to excellent self-rated health, no chest pain, CVD 10-year SCORE risk 5+%, absence of hypertension control, absence of hypertension awareness and absence of care-intensive conditions. Among those with no contact: 37% current smokers, 34% with 5+% 10-year CVD risk, 32% untreated hypertension, 20% non-anginal chest pain, 18% problem drinkers, 14% uncontrolled hypertension and 9% Grade 1-2 angina. The proportion without general health check attendance was 54.6%. CONCLUSION: Primary care and community interventions would be required to proactively reach sections of 40-69 year olds currently not in contact with primary care services to reduce their CVD risk through diagnosis, treatment, lifestyle recommendations and active follow-up.

Untreated hypertension in Russian 35-69 year olds - a cross-sectional study.

BACKGROUND: The Russian Federation has among the highest rates of cardiovascular disease (CVD) in the world and a high rate of untreated hypertension remains an important risk factor. Understanding who is at greatest risk is important to inform approaches to primary prevention. METHODS: 2,353 hypertensive 35-69 year olds were selected from a population-based study, Know Your Heart, conducted in Arkhangelsk and Novosibirsk, Russian Federation, 2015-2018. The associations between untreated hypertension and a range of co-variates related to socio-demographics, health, and health behaviours were examined. RESULTS: The age-standardised prevalence of untreated hypertension was 51.1% (95% CI 47.8-54.5) in males, 28.8% (25.4-32.5) in females, and 40.0% (37.5-42.5) overall. The factors associated with untreated hypertension relative to treated hypertension were younger ages, self-rated general health as very good-excellent, not being obese, no history of CVD events, no evidence of diabetes or chronic kidney disease, and not seeing a primary care doctor in the past year as well as problem drinking for women and working full time, lower education, and smoking for men. CONCLUSION: The study found relatively high prevalence of untreated hypertension, especially, in men. Recent initiatives to strengthen primary care provision and implementation of a general health check programme (dispansarisation) are promising, although further studies should evaluate other, potentially more effective strategies tailored to the particular circumstances of this population.

Uncontrolled and apparent treatment resistant hypertension: a cross-sectional study of Russian and Norwegian 40-69 year olds.

BACKGROUND: Uncontrolled hypertension is a major cardiovascular risk factor. We examined uncontrolled hypertension and differences in treatment regimens between a high-risk country, Russia, and low-risk Norway to gain better understanding of the underlying factors. METHODS: Population-based survey data on 40-69 year olds with hypertension defined as taking antihypertensives and/or having high blood pressure (140+/90+ mmHg) were obtained from Know Your Heart Study (KYH, N = 2284), Russian Federation (2015-2018) and seventh wave of The Tromsø Study (Tromsø 7, N = 5939), Norway (2015-2016). Uncontrolled hypertension was studied in the subset taking antihypertensives (KYH: N = 1584; Tromsø 7: 2792)and defined as having high blood pressure (140+/90+ mmHg). Apparent treatment resistant hypertension (aTRH) was defined as individuals with uncontrolled hypertension on 3+ OR controlled on 4+ antihypertensive classes in the same subset. RESULTS: Among all those with hypertension regardless of treatment status, control of blood pressure was achieved in 22% of men (KYH and Tromsø 7), while among women it was 33% in Tromsø 7 and 43% in KYH. When the analysis was limited to those on treatment for hypertension, the percentage uncontrolled was higher in KYH (47.8%, CI 95 44.6-50.9%) than Tromsø 7 (38.2, 36.1-40.5%). The corresponding figures for aTRH were 9.8% (8.2-11.7%) and 5.7% (4.8-6.8%). Antihypertensive monotherapies were more common than combinations and used by 58% in Tromsø 7 and 44% in KYH. In both KYH and Tromsø 7, untreated hypertension was higher in men, those with no GP visit in the past year and problem drinkers. In both studies, aTRH was associated with older age, CVD history, obesity, and diabetes. In Tromsø 7, also male gender and any drinking. In KYH, also chronic kidney disease. CONCLUSION: There is considerable scope for promoting combination therapies in line with European treatment guidelines in both study populations. The factors associated with untreated hypertension overlap with known correlates of treatment non-adherence and health check non-attendance. In contrast, aTRH was characterised by obesity and underlying comorbidities potentially complicating treatment.

Pre-travel malaria enquiries to the United Kingdom national travel advice line 2016: Advice mainly needed on malaria maps and risk groups.

BACKGROUND: Malaria prevention in travellers can be complex and requires consideration of a number of factors. UK healthcare professionals providing pre-travel malaria advice can access specialist support from the National Travel Health Network and Centre (NaTHNaC) telephone advice line. The aim of this study is to characterise queries to the NaTHNaC telephone advice line regarding pre-travel malaria advice. METHOD: Telephone calls received to NaTHNaC's advice line are recorded using an online data capture form. All calls relating to malaria advice during 2016 were selected and data extracted. Analysis was undertaken using Microsoft Excel and STATA. RESULTS: During 2016, 1803 malaria-related calls were received; the majority from general practice and calls were from across the UK. The most common type of pre-travel malaria query was country-specific followed by travellers with special health needs. Many queries related to pregnant and breastfeeding travellers, children under 5 years and travellers over 60 years. CONCLUSIONS: This review presents a large and exceptional dataset and reflects the ambiguity amongst some healthcare professionals regarding malaria advice. We have identified potential knowledge gaps, and as a result will strengthen future guidance, enhance existing malaria maps, and inform the development of future clinical educational activity.

Computation of the S1 ← S0 Vibronic Absorption Spectrum of Formaldehyde by Variational Gaussian Wavepacket and Semiclassical IVR Methods.

The vibronic absorption spectrum of the electric dipole forbidden and vibronically allowed S1(1 A2) ← S0(1 A1) transition of formaldehyde is calculated by Gaussian wavepacket and semiclassical methods, along with numerically exact reference calculations, using the potential energy surface of Fu, Shepler, and Bowman ( J. Am. Chem. Soc. 2011, 133, 7957). Specifically, the variational multiconfigurational Gaussian (vMCG) approach and the Herman-Kluk semiclassical initial value representation (HK-SCIVR) are compared to assess the accuracy and convergence of these methods, benchmarked against numerically exact time-dependent wavepacket propagation (TDWP) on the reference potential energy surface. The vMCG calculation is shown to converge quite well with about 100 variationally evolving Gaussian functions and using a local cubic expansion instead of the conventional local harmonic approximation. By contrast, the HK-SCIVR approach with ∼105 trajectories reproduces the vibrationally structured spectral envelope correctly but yields a strongly broadened spectrum. The comparison of the computed absorption spectrum with experiment shows that the relevant vibronic progressions are reasonably reproduced by all computations, but deviations of the order of 10-100 cm-1 occur, underscoring that both electronic structure calculations and dynamical approaches remain challenging in the calculation of typical small-molecule excited-state spectra by trajectory-based methods.

Instantaneous Tunneling Flight Time for Wavepacket Transmission through Asymmetric Barriers.

The time it takes a particle to tunnel through the asymmetric Eckart barrier potential is investigated using Gaussian wavepackets, where the barrier serves as a model for the potential along a chemical reaction coordinate. We have previously shown that the, in principle experimentally measurable, tunneling flight time, which determines the time taken by the transmitted particle to traverse the barrier, vanishes for symmetric potentials like the Eckart and square barrier [ Petersen , J. ; Pollak , E. J. Phys. Chem. Lett. 2017 , 9 , 4017 ]. Here we show that the same result is obtained for the asymmetric Eckart barrier potential, and therefore, the zero tunneling flight time seems to be a general result for one-dimensional time-independent potentials. The wavepacket dynamics is simulated using both an exact quantum mechanical method and a classical Wigner prescription. The excellent agreement between the two methods shows that quantum coherences are not important in pure one-dimensional tunneling and reinforces the conclusion that the tunneling flight time vanishes.

Quantum coherence in the reflection of above barrier wavepackets.

The quantum phenomenon of above barrier reflection is investigated from a time-dependent perspective using Gaussian wavepackets. The transition path time distribution, which in principle is experimentally measurable, is used to study the mean flight times ⟨t⟩R and ⟨t⟩T associated with the reflection and the transmission over the barrier paying special attention to their dependence on the width of the barrier. Both flight times, and their difference Δt, exhibit two distinct regimes depending on the ratio of the spatial width of the incident wavepacket and the length of the barrier. When the ratio is larger than unity, the reflection and transmission dynamics are coherent and dominated by the resonances above the barrier. The flight times ⟨t⟩R/T and the flight time difference Δt oscillate as a function of the barrier width (almost in phase with the transmission probability). These oscillations reflect a momentum filtering effect related to the coherent superposition of the reflected and transmitted waves. For a ratio less than unity, the barrier reflection and transmission dynamics are incoherent and the oscillations are absent. The barrier width which separates the coherent and incoherent regimes is identified analytically. The oscillatory structure of the time difference Δt as a function of the barrier width in the coherent regime is absent when considered in terms of the Wigner phase time delays for reflection and transmission. We conclude that the Wigner phase time does not correctly describe the temporal properties of above barrier reflection. We also find that the structure of the reflected and transmitted wavepackets depends on the coherence of the process. In the coherent regime, the wavepackets can have an overlapping peak structure, but the peaks are not fully resolved. In the incoherent regime, the wavepackets split in time into distinct separated Gaussian like waves, each one reflecting the number of times the wavepacket crosses the barrier region before exiting. A classical Wigner approximation, using classical trajectories which upon reaching an edge of the barrier are reflected or transmitted as if the edge was a step potential, is quantitative in the incoherent regime. The implications of the coherence observed on resonance reactive scattering are discussed.

Amplification of perceived risk among users of a national travel health Web site during the 2013-2016 West African Ebola virus outbreak.

Timely outbreak information was paramount to public health bodies issuing travel advisories during the 2013-2016 West Africa Ebola virus outbreak. This article explores the potential for a syndromic system/Shewhart control chart based on the online interaction with a national travel health Web site in comparison with searches on the Google UK search engine. The study showed an amplification of perceived risk among users of a national travel health Web site months before the World Health Organization declared the outbreak a Public Health Emergency of International Concern and the initial surge in public interest on Google UK in August 2014.

3,5-Disubstituted-indole-7-carboxamides as IKKß Inhibitors: Optimization of Oral Activity via the C3 Substituent.

IκB kinase ß (IKKß or IKK2) is a key regulator of nuclear factor kappa B (NF-κB) and has received attention as a therapeutic target. Herein we report on the optimization of a series of 3,5-disubstituted-indole-7-carboxamides for oral activity. In doing so, we focused attention on potency, ligand efficiency (LE), and physicochemical properties and have identified compounds 24 and (R)-28 as having robust in vivo activity.