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.

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.

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.

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.

Shunt surgery in idiopathic normal pressure hydrocephalus is cost-effective-a cost utility analysis.

BACKGROUND: The objective was to evaluate the cost-effectiveness of shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: Health-related quality of life was evaluated before and 6 months after surgery using the EQ-5D-3 L (EuroQOL group five-dimensions health survey) in 30 patients (median age, 71 years; range, 65-89 years) diagnosed with iNPH. The costs associated with shunt surgery were assessed by a detailed survey with interviews and extraction of register data concerning the cost of hospital care, primary care, residential care, home-care service and informal care. The cost of untreated patients was derived from the cost of dementia disorders in Sweden in 2012, as reported by the National Board of Health and Welfare. The cost effectiveness analysis used a decision-analytic Markov model. We used a societal perspective and a lifelong time horizon to estimate costs and effects. One-way sensitivity analysis and probabilistic sensitivity analysis were carried out to test the robustness of the model. RESULTS: The shunt surgery model as the standard treatment in iNPH resulted in a gain of 2.2 life years and 1.7 quality-adjusted life years (QALY), along with an incremental cost per patient of €7,500/QALY. The sensitivity analysis showed that the results were not sensitive to changes in uncertain parameters or assumptions. CONCLUSIONS: Shunt surgery in iNPH, an underdiagnosed condition severely impairing elderly patients, is not only an effective medical treatment, it is also cost-effective, adding 2.2 additional life years and 1.7 QALYs at a low cost, a remarkable gain for an individual aged around 70 years.

Danirixin: A Reversible and Selective Antagonist of the CXC Chemokine Receptor 2.

CXC chemokine receptor 2 (CXCR2) is a key receptor in the chemotaxis of neutrophils to sites of inflammation. The studies reported here describe the pharmacological characterization of danirixin, a CXCR2 antagonist in the diaryl urea chemical class. Danirixin has high affinity for CXCR2, with a negative log of the 50% inhibitory concentration (pIC50) of 7.9 for binding to Chinese hamster ovary cell (CHO)-expressed human CXCR2, and 78-fold selectivity over binding to CHO-expressed CXCR1. Danirixin is a competitive antagonist against CXCL8 in Ca2+-mobilization assays, with a KB (the concentration of antagonist that binds 50% of the receptor population) of 6.5 nM and antagonist potency (pA2) of 8.44, and is fully reversible in washout experiments over 180 minutes. In rat and human whole-blood studies assessing neutrophil activation by surface CD11b expression following CXCL2 (rat) or CXCL1 (human) challenge, danirixin blocks the CD11b upregulation with pIC50s of 6.05 and 6.3, respectively. Danirixin dosed orally also blocked the influx of neutrophils into the lung in vivo in rats following aerosol lipopolysaccharide or ozone challenge, with median effective doses (ED50s) of 1.4 and 16 mg/kg respectively. Thus, danirixin would be expected to block chemotaxis in disease states in which neutrophils are increased in response to inflammation, such as pulmonary diseases. In comparison with navarixin, a CXCR2 antagonist from a different chemical class, the binding characterization of danirixin is distinct. These observations may offer insight into the previously observed clinical differences in induction of neutropenia between these compounds.

Identifying and interpreting spatiotemporal variation in diagnoses of infectious syphilis among men, England: 2009 to 2013.

OBJECTIVES: Spatial clusters and variations in the trajectory of local epidemics were explored in relation to sexual orientation, demographic factors, stage of syphilis infection and HIV serostatus. METHODS: Kulldorff's scan statistics (SaTScan) was used to distinguish endemic and temporary clusters using a two-stage analysis. RESULTS: Endemic areas were found in London, Manchester, Brighton and Blackpool. Up to 40% of diagnoses were found within an 11 km radius of central London. Of men diagnosed with syphilis in London, 80% were men who have sex with men (MSM). Annual incidence in London increased from 24 cases (95% CI 23 to 26) per 100 000 male population in 2009 to 36 cases (95% CI 34 to38) in 2013. In comparison with clusters, endemic areas were characterised by a significantly higher (p<0.05) proportion of MSM (83% compared with 73%), increased HIV positivity (41% vs 15%), age 35 to 44 years (34% vs 23%), a lower proportion of patients born in the UK (50% vs 79%) and a lower proportion of primary stage infection (40% vs 47%). Space-time clusters outside endemic areas occurred in urban and rural areas and diagnoses fluctuated below 10 per month. Exponential increases in diagnoses resembling point source outbreaks were seen at two locations. CONCLUSION: Control of syphilis in endemic areas has proved elusive and clusters present unique intervention opportunities. Investigating the diversity of local epidemics provides information that can be used to predict outbreak structure, plan and evaluate sexual health services and guide public health investigation, hypothesis generation and research.

EGL-13/SoxD specifies distinct O2 and CO2 sensory neuron fates in Caenorhabditis elegans.

Animals harbor specialized neuronal systems that are used for sensing and coordinating responses to changes in oxygen (O2) and carbon dioxide (CO2). In Caenorhabditis elegans, the O2/CO2 sensory system comprises functionally and morphologically distinct sensory neurons that mediate rapid behavioral responses to exquisite changes in O2 or CO2 levels via different sensory receptors. How the diversification of the O2- and CO2-sensing neurons is established is poorly understood. We show here that the molecular identity of both the BAG (O2/CO2-sensing) and the URX (O2-sensing) neurons is controlled by the phylogenetically conserved SoxD transcription factor homolog EGL-13. egl-13 mutant animals fail to fully express the distinct terminal gene batteries of the BAG and URX neurons and, as such, are unable to mount behavioral responses to changes in O2 and CO2. We found that the expression of egl-13 is regulated in the BAG and URX neurons by two conserved transcription factors-ETS-5(Ets factor) in the BAG neurons and AHR-1(bHLH factor) in the URX neurons. In addition, we found that EGL-13 acts in partially parallel pathways with both ETS-5 and AHR-1 to direct BAG and URX neuronal fate respectively. Finally, we found that EGL-13 is sufficient to induce O2- and CO2-sensing cell fates in some cellular contexts. Thus, the same core regulatory factor, egl-13, is required and sufficient to specify the distinct fates of O2- and CO2-sensing neurons in C. elegans. These findings extend our understanding of mechanisms of neuronal diversification and the regulation of molecular factors that may be conserved in higher organisms.

Semiclassical initial value representation for the quantum propagator in the Heisenberg interaction representation.

One of the challenges facing on-the-fly ab initio semiclassical time evolution is the large expense needed to converge the computation. In this paper, we suggest that a significant saving in computational effort may be achieved by employing a semiclassical initial value representation (SCIVR) of the quantum propagator based on the Heisenberg interaction representation. We formulate and test numerically a modification and simplification of the previous semiclassical interaction representation of Shao and Makri [J. Chem. Phys. 113, 3681 (2000)]. The formulation is based on the wavefunction form of the semiclassical propagation instead of the operator form, and so is simpler and cheaper to implement. The semiclassical interaction representation has the advantage that the phase and prefactor vary relatively slowly as compared to the "standard" SCIVR methods. This improves its convergence properties significantly. Using a one-dimensional model system, the approximation is compared with Herman-Kluk's frozen Gaussian and Heller's thawed Gaussian approximations. The convergence properties of the interaction representation approach are shown to be favorable and indicate that the interaction representation is a viable way of incorporating on-the-fly force field information within a semiclassical framework.

Wave packet propagation across barriers by semiclassical initial value methods.

Semiclassical initial value representation (IVR) formulas for the propagator have difficulty describing tunneling through barriers. A key reason is that these formulas do not automatically reduce, in the classical limit, to the version of the Van Vleck-Gutzwiller (VVG) propagator required to treat barrier tunneling, which involves trajectories that have complex initial conditions and that follow paths in complex time. In this work, a simple IVR expression, that has the correct tunneling form in the classical limit, is derived for the propagator in the case of one-dimensional barrier transmission. Similarly, an IVR formula, that reduces to the Generalized Gaussian Wave Packet Dynamics (GGWPD) expression [D. Huber, E. J. Heller, and R. Littlejohn, J. Chem. Phys. 89, 2003 (1988)] in the classical limit, is derived for the transmitted wave packet. Uniform semiclassical versions of the IVR formulas are presented and simplified expressions in terms of real trajectories and WKB penetration factors are described. Numerical tests show that the uniform IVR treatment gives good results for wave packet transmission through the Eckart and Gaussian barriers in all cases examined. In contrast, even when applied with the proper complex trajectories, the VVG and GGWPD treatments are inaccurate when the mean energy of the wave packet is near the classical transmission threshold. The IVR expressions for the propagator and wave packet are cast as contour integrals in the complex space of initial conditions and these are generalized to potentially allow treatment of a larger variety of systems. A steepest descent analysis of the contour integral formula for the wave packet in the present cases confirms its relationship to the GGWPD method, verifies its semiclassical validity, and explains results of numerical calculations.

Complex time paths for semiclassical wave packet propagation with complex trajectories.

The use of complex-valued trajectories in semiclassical wave packet methods can lead to problems that prevent calculation of the wave function in certain regions of the configuration space. We investigate this so-called bald spot problem in the context of generalized Gaussian wave packet dynamics. The analysis shows that the bald spot phenomenon is essentially due to the complex nature of the initial conditions for the trajectories. It is, therefore, expected to be a general feature of several semiclassical methods that rely on trajectories with such initial conditions. A bald region is created when a trajectory, needed to calculate the wave function at a given time, reaches a singularity of the potential energy function in the complex plane at an earlier, real time. This corresponds to passage of a branch point singularity across the real axis of the complex time plane. The missing portions of the wave function can be obtained by deforming the time path for the integration of the equations of motion into the complex plane so that the singularity is circumvented. We present examples of bald spots, singularity times, and suitable complex time paths for one-dimensional barrier transmission in the Eckart and Gaussian systems. Although the bald regions for the Eckart system are often localized, they are found to be semi-infinite for the Gaussian system. For the case of deep tunneling, the bald regions for both systems may encompass the entire portion of space occupied by the transmitted wave packet. Thus, the use of complex time paths becomes essential for a treatment of barrier tunneling.

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.

Filming the birth of molecules and accompanying solvent rearrangement.

Molecules are often born with high energy and large-amplitude vibrations. In solution, a newly formed molecule cools down by transferring energy to the surrounding solvent molecules. The progression of the molecular and solute-solvent cage structure during this fundamental process has been elusive, and spectroscopic data generally do not provide such structural information. Here, we use picosecond X-ray liquidography (solution scattering) to visualize time-dependent structural changes associated with the vibrational relaxation of I(2) molecules in two different solvents, CCl(4) and cyclohexane. The birth and vibrational relaxation of I(2) molecules and the associated rearrangement of solvent molecules are mapped out in the form of a temporally varying interatomic distance distribution. The I-I distance increases up to ~4 Å and returns to the equilibrium distance (2.67 Å) in the ground state, and the first solvation cage expands by ~1.5 Å along the I-I axis and then shrinks back accompanying the structural change of the I(2) molecule.

Tyrosine urea muscarinic acetylcholine receptor antagonists: achiral quaternary ammonium groups.

Tyrosine ureas had been identified as potent muscarinic receptor antagonists with promising in vivo activity. Controlling the stereochemistry of the chiral quaternary ammonium center had proved to be a serious issue for this series, however. Herein we describe the preparation and SAR of tyrosine urea antagonists containing achiral quaternary ammonium centers. The most successful such moiety was the 2-methylimidazo[2,1-b][1,3]thiazol-7-ium group which yielded highly potent antagonists with long duration of action in an inhaled animal model of bronchoconstriction.

Design, synthesis and structure-activity relationship of N-substituted tropane muscarinic acetylcholine receptor antagonists.

A novel series of N-substituted tropane derivatives was characterized as potent muscarinic acetylcholine receptor antagonists (mAChRs). Kinetic washout studies showed that the N-endosubstituted analog 24 displayed much slower reversibility at mAChRs than the methyl-substituted parent molecule darotropium. In addition, it was shown that this characteristic appeared to translate into enhanced which duration of action in a mouse model of bronchonstriction.

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.

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.