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Key Points A negative feedback loop, integrin–PI3K–ARAP3–integrin, controls integrin inactivation. Integrin inactivation promotes neutrophil transendothelial migration and recruitment., Neutrophils are abundant circulating leukocytes that are rapidly recruited to sites of inflammation in an integrin-dependent fashion. Contrasting with the well-characterized regulation of integrin activation, mechanisms regulating integrin inactivation remain largely obscure. Using mouse neutrophils, we demonstrate in this study that the GTPase activating protein ARAP3 is a critical regulator of integrin inactivation; experiments with Chinese hamster ovary cells indicate that this is not restricted to neutrophils. Specifically, ARAP3 acts in a negative feedback loop downstream of PI3K to regulate integrin inactivation. Integrin ligand binding drives the activation of PI3K and of its effectors, including ARAP3, by outside-in signaling. ARAP3, in turn, promotes localized integrin inactivation by negative inside-out signaling. This negative feedback loop reduces integrin-mediated PI3K activity, with ARAP3 effectively switching off its own activator, while promoting turnover of substrate adhesions. In vitro, ARAP3-deficient neutrophils display defective PIP3 polarization, adhesion turnover, and transendothelial migration. In vivo, ARAP3-deficient neutrophils are characterized by a neutrophil-autonomous recruitment defect to sites of inflammation.

Neutrophils, the most abundant circulating leukocytes in humans have key roles in host defense and in the inflammatory response. Agonist-activated phosphoinositide 3-kinases (PI3Ks) are important regulators of many facets of neutrophil biology. PIP3 is subject to dephosphorylation by several 5’ phosphatases, including SHIP family phosphatases, which convert the PI3K product and lipid second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3) into PI(3,4)P2, a lipid second messenger in its own right. In addition to the leukocyte restricted SHIP1, neutrophils express the ubiquitous SHIP2. This study analyzed mice and isolated neutrophils carrying a catalytically inactive SHIP2, identifying an important regulatory function in neutrophil chemotaxis and directionalityin vitroand in neutrophil recruitment to sites of sterile inflammationin vivo, in the absence of major defects of any other neutrophil functions analyzed, including, phagocytosis and the formation of reactive oxygen species. Mechanistically, this is explained by a subtle effect on global 3-phosphorylated phosphoinositide species. This work identifies a non-redundant role for the hitherto overlooked SHIP2 in the regulation of neutrophils, and specifically, neutrophil chemotaxis/trafficking. It completes an emerging wider understanding of the complexity of PI3K signaling in the neutrophil, and the roles played by individual kinases and phosphatases within.

We study the effect of unemployment on birth outcomes by exploiting geographical variation in the unemployment rate across local areas in England, and comparing siblings born to the same mother via family fixed effects. Using rich individual data from hospital administrative records between 2003 and 2012, babies' health is found to be strongly pro-cyclical. A one-percentage point increase in the unemployment rate leads to an increase in low birth weight and preterm babies of respectively 1.3 and 1.4%, and a 0.1% decrease in foetal growth. We find heterogenous responses: unemployment has an effect on babies' health which varies from strongly adverse in the most deprived areas, to mildly favourable in the most prosperous areas. We provide evidence of three channels that can explain the overall negative effect of unemployment on new-born health: maternal stress; unhealthy behaviours - namely excessive alcohol consumption and smoking; and delays in the take-up of prenatal services. While the heterogenous effects of unemployment by area of deprivation seem to be explained by maternal behaviour. Most importantly, we also show for the first time that selection into fertility is the main driver for the previously observed, opposite counter-cyclical results, e.g., Dehejia and Lleras-Muney (2004). Our results are robust to internal migration, different geographical aggregation of the unemployment rate, the use of gender-specific unemployment rates, and potential endogeneity of the unemployment rate which we control for by using a shift-share instrumental variable approach.

Attempts to control hospital expenditure by managing down General Practitioner (GP) referrals are reoccurring features of UK health policy. However, despite the best efforts of GPs to benchmark referral criteria, patient health may be damaged and other costs created by constraining referrals to targets. This paper adopts an indirect method to indicate whether rationing practice referrals may damage population health by distorting the use of health resources away from patients' interests. We utilise a comprehensive database at practice level that allows us to explore the relationship between referrals and emergency admissions, using a panel fixed effects model of admissions that allows for the endogeneity of referrals. We find that practice referrals are positively and partially correlated with emergency admissions, which is consistent with time-varying practice-level sickness shocks driving the relationship between referrals and emergency care, rather than shocks to the practice willingness to refer, or to system reforms. In this environment, government policy to constrain referrals may make the elective care less responsive to practice-level variations in illness, and thereby lower health.

BackgroundRecent studies have found an association between access to primary care and accident and emergency attendances, with better access associated with fewer attendances. Analyses of an association with emergency admissions, however, have produced conflicting findings.AimThis study investigated whether emergency admission rates in an area are associated with 1) the number of GPs, and 2) mean size of GP practice.Design and settingAnalysis was conducted utilising Hospital Episode Statistics, the numbers of GPs and GP practices, Office for National Statistics population data, Quality and Outcomes Framework prevalence data, and Index of Multiple Deprivation data, from 2004/2005 to 2011/2012, for all practices in England.MethodRegression analysis of panel data with fixed effects to address 1) a potential two-way relationship between the numbers of GPs and emergency admissions, and 2) unobservable characteristics of GP practices.ResultsThere is not a statistically significant relationship between the number of GPs in a primary care trust area and the number of emergency admissions, when analysing all areas. In deprived areas, however, a higher number of GPs is associated with lower emergency admissions. There is also a lower emergency admission rate in areas in which practices are on average larger, holding GP supply constant.ConclusionAn increase in GPs was found to reduce emergency admissions in deprived areas, but not elsewhere. Areas in which GPs are concentrated into larger practices showed reduced levels of emergency admissions, all else being equal.

Inflammation is a complex biological response that serves to protect the body's tissues following harmful stimuli such as infection, irritation or injury and initiates tissue repair. At the start of an inflammatory response, pro-inflammatory mediators induce changes in the endothelial lining of the blood vessels and in leukocytes. This results in increased vascular permeability and increased expression of adhesion proteins, and promotes adhesion of leukocytes, especially neutrophils to the endothelium. Adhesion is a prerequisite for neutrophil extravasation and chemoattractant-stimulated recruitment to inflammatory sites, where neutrophils phagocytose and kill microbes, release inflammatory mediators and cross-talk with other immune cells to co-ordinate the immune response in preparation for tissue repair. Many signalling proteins are critically involved in the complex signalling processes that underpin the inflammatory response and cross-talk between endothelium and leukocytes. As key regulators of cell–cell and cell–substratum adhesion, small GTPases (guanosine triphosphatases) act as important controls of neutrophil-endothelial cell interactions as well as neutrophil recruitment to sites of inflammation. Here, we summarise key processes that are dependent upon small GTPases in leukocytes during these early inflammatory events. We place a particular focus on the regulation of integrin-dependent events and their control by Rho and Rap family GTPases as well as their regulators during neutrophil adhesion, chemotaxis and recruitment.

Neutrophils are short-lived, abundant peripheral blood leukocytes that provide a first line of defense against bacterial and fungal infections whilst also being a key part of the inflammatory response. Chemokines induce neutrophil recruitment to inflammatory sites, where neutrophils perform a number of diverse functions that are aimed at fighting infections. Neutrophil effector functions are tightly regulated processes that are governed by an array of intracellular signaling pathways and initiated by receptor-ligand binding events. Dysregulated, neutrophil activation can result in excessive inflammation and host damage, as is evident in a number of autoimmune diseases. Rho family small GTPases and agonist-activated phosphoinositide 3-kinases (PI3Ks) represent two classes of key regulators of the highly specialized neutrophil. Here we review cross-talk between these important signaling intermediates in the context of neutrophil functions. We include PI3K-dependent activation of Rho family small GTPases and of their guanine nucleotide exchange factors and GTPase activating proteins, as well as Rho GTPase-dependent regulation of PI3K.

BackgroundThe English NHS faces financial pressures that may render the growth rates of elective admissions seen between 2001/2 and 2011/12 unsustainable. A better understanding of admissions growth, and the influence of policy, are needed to minimise the impact on health gain for patients.ObjectivesThis project had several objectives: (1) to better understand the determinants of elective activity and policy to moderate growth at minimum health loss for patients; (2) to build a rich data set integrating health, practice and local area data to study general practitioner (GP) referrals and resulting admissions; (3) to predict patients whose treatment is unlikely to be cost-effective using patient-reported outcomes and to examine variation in provider performance; and (4) to study how policies that aim to reduce elective admissions may change demand for emergency care. The main drivers of elective admissions growth have increased either supply of or demand for care, and could include, for example, technical innovations or increased awareness of treatment benefits. Of the factors studied, neither system reform nor population ageing appears to be a key driver. The introduction of the prospective payment tariff ‘Payment by Results’ appears to have led to primary care trusts (PCTs) having increasingly similar lengths of stay. In deprived areas, increasing GP supply appears to moderate elective admissions. Reducing the incidence of single-handed practices tends to reduce referrals and admissions. Policies to reduce referrals are likely to reduce admissions but treatments may be particularly reduced in the lowest referring practices, in which resulting health loss may be greatest. In this model, per full-time equivalent, female and highly experienced GPs identify more patients admitted by specialists.ResultsIt appears from our studies that some patient characteristics are associated with not achieving sufficient patient gain to warrant cost-effective treatment. The introduction of independent sector treatment centres is estimated to have caused an increase in emergency activity rates at local PCTs. The explanations offered for increasing elective admissions indicate that they are manageable by health policy.ConclusionsFurther work is required to understand some of the results identified, such as whether or not high-volume Clinical Commissioning Groups are fulfilling unmet need; why some practices refer at low rates relative to admissions; why the period effect, which results from factors that equally affect all in the study at a point in time, dominates in the age–period–cohort analysis; and exactly how the emergency and elective sections of hospital treatment interact. This project relies on the analysis of secondary data. This type of research does not easily facilitate the important input of clinical experts or service users. It would be beneficial if other methods, including surveys and consultation with key stakeholders, could be incorporated into future research now that we have uncovered important questions.FundingThe National Institute for Health Research Health Services and Delivery Research programme.

Neuropathic pain is a common side-effect of chemotherapy. Although precise mechanisms are unclear, oxidative stress and mitochondrial damage are involved. We investigated whether the mitochondria targeted antioxidant, MitoVitE, provided better protection against paclitaxel-induced mitochondrial damage in rat dorsal root ganglion (DRG) cells, than a non-targeted form of vitamin E, Trolox. We also determined whether MitoVitE, compared with duloxetine, could limit paclitaxel-induced mechanical hypersensitivity in rats.Mitochondrial function was measured in DRG cells exposed to paclitaxel with and without MitoVitE or Trolox. The effect of MitoVitE or Trolox on paclitaxel-induced cell killing in cancer cell lines was also determined. Rats received a cumulative dose of 8 mg kgPaclitaxel caused loss of membrane potential in DRG cells. At 100 µM paclitaxel median [range] change was 61[44-78]%, P 0.0001, which was ameliorated by MitoVitE (86[62-104]%) but not Trolox (46[46-57]%). Similarly, loss of metabolic activity and glutathione induced by paclitaxel (both P 0.0001) were reduced by MitoVitE but not Trolox. Cytotoxicity of paclitaxel was not affected by co-exposure of ovarian cancer cells to either MitoVitE or Trolox, but was slightly reduced against breast cancer cells, in the presence of Trolox. Mean (SD) areas under the curve of withdrawal thresholds at 6 h after injection in rats given paclitaxel + control, or + MitoVitE (P 0.0001) or + duloxetine (P 0.0001) were 110 (5), 145 (10) and 156 (13) respectively.Paclitaxel affected mitochondrial function and glutathione in DRG cells, which was abrogated by MitoVitE but not Trolox, without decreasing cancer cell cytotoxicity. In rats, paclitaxel-induced mechanical hypersensitivity was ameliorated by MitoVitE treatment to an extent similar to duloxetine. These data confirm mitochondria as a mechanistic target for paclitaxel-induced damage and suggest mitochondria targeted antioxidants as future therapeutic strategies.

We analyze how two key factors contribute to the high cost of healthcare in the US relative to the UK: (i) the higher private cost of medical education, and (ii) the higher risk of malpractice litigation. To assess the role of these factors we formulate, calibrate and simulate an equilibrium model of physician wages and the supply of medical graduates, work hours and treatment decisions of practicing physicians, and malpractice risk and malpractice insurance pricing. Consistent with prior work, we find direct costs of malpractice fines and insurance explain little of the high cost of healthcare in the US. However, the high private cost of medical education interacts with high malpractice risk in an interesting way: It leads doctors to (i) demand high wages and (ii) use excessive diagnostics to mitigate risk (“defensive medicine”). The agency problem that arises because patients cannot judge the efficacy of tests allows them to be over-prescribed. Together, these factors increase costs far more than direct malpractice costs. Specifically, physician salaries plus diagnostic tests comprise 4.04% of GDP in the US, compared to only 2.3% in the UK. The mechanisms emphasized in our model can largely explain the difference. Our policy simulations imply that more generous medical education subsidies would lead to both improved patient welfare and reduced overall health care costs in the US system (a Pareto improvement). We also find policies to (i) reduce malpractice risk, or (ii) induce doctors to internalize a small part of diagnostic costs, would have similar efficacious effects.

The national picture of the comparative costs and diagnoses of hospitalised homeless patients are examined using the 'no fixed abode' flag in English hospital statistics. Comparable studies sample patients in single cities, eg New York and Toronto. The most common diagnosis is substance misuse; the share of homeless NHS patients with this diagnosis is rising, and now equals that found in North American cities. About half of the cost of homeless patients relates to diagnoses of mental illness, although these comprise a much smaller share of homeless patients than in North America. Hospital costs for homeless patients - both total and per admission - have fallen significantly in recent years, primarily because of fewer admissions and shorter lengths of stay for mentally ill patients. Aims to reduce NHS costs at the level of individual institutions have often shaped policy. Broader policy to prevent and reduce homelessness offers substantial long-term reductions in the cost of chronic care.

There is strong policy interest, in England as elsewhere, in slowing the growth in emergency hospital admissions, which for older people increased by 3.3% annually between 2001/2 and 2012/3. Resource constrains have increased the importance of understanding rising emergency admissions, which in policy discourse is often explained by population aging. This study examines how far the rise in emergency admissions of people over 65 was due to population ageing, how far to the changing likelihood of entering hospital at each age, and how far to other factors which might be more amenable to policy measures. It shows that: admission rates rose with age from age 40 upward but each successive birth cohort experienced lower emergency admission rates after standardising for age and other effects. This downward cohort effect largely offset the consequences of an older and larger population aged over 65. Other factors which could explain increasing admissions, such as new technologies or rising expectations, appear more important than the changing size and age structure of the population as drivers of rising emergency admissions in old age. These findings suggest that stemming the rate of increase in emergency admissions of older people may be feasible, if challenging, despite population ageing.

Homeless people have complex problems. GP enhanced care (Pathway) has shown benefits. We performed a randomised, -parallel arm trial at two large inner city hospitals. Inpatient homeless adults were randomly allocated to either standard care (all management by the hospital-based clinical team) or enhanced care with input from a homeless care team. The hospital data system provided healthcare usage information, and we used questionnaires to assess quality of life. 206 patients were allocated to enhanced care and 204 to usual care. Length of stay (up to 90 days after admission) did not differ between groups (standard care 14.0 days, enhanced care 13.3 days). Average reattendance at the emergency department within a year was 5.8 visits in the standard care group and 4.8 visits with enhanced care, but this decrease was not significant. -Quality of life scores after discharge (in 108 patients) improved with enhanced care (EQ-5D-5L score increased by 0.12 [95% CI 0.032 to 0.22] compared wtih 0.03 [-0.1 to 0.15; p=0.076] with standard care). The proportion of people sleeping on the streets after discharge was 14.6% in the standard care arm and 3.8% in the enhanced care arm (p=0.034). The quality-of-life cost per quality-adjusted life-year was £26,000. The Pathway approach doesn't alter length of stay but improves quality of life and reduces street -homelessness.

© The Author 2015. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. Background: Hospital standardized mortality rates (HSMRs) are considered to identify unsafe hospital care, but are criticized for disregarding unmeasured variations of both coding practice and outside of hospital palliative provision. Methods: The validity of HSMR methods is explored by examining whether the additional deaths implied by a Primary Care Trust (PCT) HSMR, as supplied by Dr Foster, are (i) detectable in English PCT mortality data and (ii) correlated with the percentage of PCT deaths out of hospital. Results: Higher PCT HSMRs were positively associated with higher area mortality, although this effect was significantly smaller than the HSMR model implies. There was a significant negative association between PCT HSMR and the percentage of deaths outside of hospital. Conclusions: This evidence suggests that the PCT HSMR is associated with all-cause area mortality, but it overstates the in-hospital mortality attributed to unsafe care. It also suggests that this overstatement is partially explained by the PCT HSMR reflecting the adverse case mix associated with a high share of deaths in hospital, i.e. the HSMR does not only reflect quality failings. Policy analyses that compare HSMRs to measure quality change may be biased by unbalanced samples of hospital patients.

ObjectiveVarious studies find that the share of emergencies in hospital admissions is higher in deprived areas, but both the explanation and policy implications are unclear. We estimate the extent to which this finding is due to a different disease mix in deprived areas, rather than other explanations such as patient behaviour and general practitioner effectiveness.DesignSecondary analysis using English Hospital Episode Statistics data, with disease for elective and emergency admissions in 2008/2009 coded at 186 blocks or 1230 categories and aggregated to lower layer super output area of residence. It is then linked to an appropriate measure of deprivation.Outcome measuresThe difference in the share of emergencies in hospital admissions between communities in the highest and lowest deciles of deprivation; and the percentage of this difference that is explained if areas in the least deprived decile have the same disease mix as those in the most deprived decile.ResultsUsing the finest disease classification scheme (1230 categories), 71% of the higher share of admissions that were emergencies in decile 1 areas relative to decile 10, is explained by the “adverse” case mix (CM) in deprived areas. The remainder reflects the higher relative use of emergency care in deprived areas for the same conditions. Higher incidence of respiratory and circulatory diseases in deprived areas explains about 30% of the CM contribution. Diseases of the digestive system and abdomen have a high relative use of emergency care in deprived areas.ConclusionsThe higher use of emergency care in deprived areas is primarily a symptom of the higher prevalence of diseases which have high national rates of emergency to elective care—especially respiratory diseases—rather than an indication of less effective primary care. Nevertheless, there is a higher share of emergency care in admissions in deprived areas for several diseases, most notably of the digestive system.

Chemotherapy-induced neuropathic pain is a debilitating and common side effect of cancer treatment. Mitochondrial dysfunction associated with oxidative stress in peripheral nerves has been implicated in the underlying mechanism. We investigated the potential of melatonin, a potent antioxidant that preferentially acts within mitochondria, to reduce mitochondrial damage and neuropathic pain resulting from the chemotherapeutic drug paclitaxel. In vitro, paclitaxel caused a 50% reduction of mitochondrial membrane potential and metabolic rate, independent of concentration (20-100μM). Mitochondrial volume was increased dose-dependently by paclitaxel (200% increase at 100μM). These effects were prevented by co-treatment with 1μM melatonin. Paclitaxel cytotoxicity against cancer cells was not affected by co-exposure to 1μM melatonin of either the breast cancer cell line MCF-7, or the ovarian carcinoma cell line A2780. In a rat model of paclitaxel-induced painful peripheral neuropathy, pre-treatment with oral melatonin (5/10/50mg/kg), given as a daily bolus dose, was protective, dose-dependently limiting development of mechanical hypersensitivity (19/43/47% difference from paclitaxel control, respectively). Melatonin (10mg/kg/day) was similarly effective when administered continuously in drinking water (39% difference). Melatonin also reduced paclitaxel-induced elevated 8-isoprostane F2 α levels in peripheral nerves (by 22% in sciatic; 41% in saphenous) and limited paclitaxel-induced reduction of C fibre activity-dependent slowing (by 64%). Notably melatonin limited the development of mechanical hypersensitivity in both male and female animals (by 50/41%, respectively) and an additive effect was found when melatonin was given with the current treatment, duloxetine (75/62% difference, respectively). Melatonin is therefore a potential treatment to limit the development of painful neuropathy resulting from chemotherapy treatment. This article is protected by copyright. All rights reserved.