Impact of HPV testing in opportunistic cervical screening: Support for primary HPV screening in the United States.

Human papillomavirus (HPV) testing for cervical screening increases diagnosis of precancer and reduces the incidence of cervical cancer more than cytology alone. However, real-world evidence from diverse practice settings is lacking for the United States (U.S.) to support clinician adoption of primary HPV screening. Using a population-based registry, which captures all cervical cytology (with or without HPV testing) and all cervical biopsies, we conducted a real-world evidence study of screening in women aged 30 to 64 years across the entire state of New Mexico. Negative cytology was used to distinguish cotests from reflex HPV tests. A total of 264 198 cervical screening tests (with exclusions based on clinical history) were recorded as the first screening test between 2014 and 2017. Diagnoses of cervical intraepithelial neoplasia grades 2 or 3 or greater (CIN2+, CIN3+) from 2014 to 2019 were the main outcomes. Of cytology-negative screens, 165 595 (67.1%) were cotests and 4.8% of these led to biopsy within 2 years vs 3.2% in the cytology-only group. Among cytology-negative, HPV tested women, 347 of 398 (87.2%) CIN2+ cases were diagnosed in HPV-positive women, as were 147 of 164 (89.6%) CIN3+ cases. Only 29/921 (3.2%) CIN3+ and 67/1964 (3.4%) CIN2+ cases were diagnosed in HPV-negative, cytology-positive women with biopsies. Under U.S. opportunistic screening, across a diversity of health care delivery practices, and in a population suffering multiple disparities, we show adding HPV testing to cytology substantially increased the yield of CIN2+ and CIN3+. CIN3+ was rarely diagnosed in HPV-negative women with abnormal cytology, supporting U.S. primary HPV-only screening.

Microenterprise and home care for older adults in England and Wales: A partial revolution?

Paid carers play an important role in helping older adults with care needs to remain living in their own homes. This paper examines changes in the home care field, specifically the emergence of self-employed care entrepreneurs ('microentrepreneurs'). To do this, it employs Bourdieu's concepts of field, capital and habitus. Drawing on 105 semi-structured interviews with stakeholders working in home care, the paper describes how the interaction of changes to field structures, and altered practices of care have challenged the taken-for-granted acceptance of traditional, transactional forms of care provision. This process has been highly dependent on local state actors, their ability to mobilise relevant forms of capital and the factors which shaped their habitus. It should be seen within the context of changes to local field structures and the hierarchical classification processes which underpin them. These changes threaten the distribution of capital in the home care field in ways that are beneficial to microentrepreneurs. Bourdieu might categorise these developments as 'partial revolutions', which do not challenge the fundamental axioms of the field. However, for care entrepreneurs, formerly employed as low-paid home-care workers, a revolution that is only partial may be better than none at all.

Uptake of co-testing with HPV and cytology for cervical screening: A population-based evaluation in the United States.

OBJECTIVES: Human papillomavirus (HPV) testing for cervical screening has been shown to increase the yield of precancerous disease and reduce the incidence of cervical cancer more than cytology alone. Here we document the state-wide uptake of co-testing with HPV and cytology in women aged 30-64 years as recommended by national and international bodies. METHODS: Registry-based study of all screening cytology and HPV tests in New Mexico from 2008 to 2019 among women aged 21-64 years, with a focus on cytology negative tests to distinguish co-testing from reflex HPV testing to triage equivocal or mildly abnormal cytology. RESULTS: A total of 1,704,055 cervical screening tests from 681,440 women aged 21-64 years in the state of New Mexico were identified. The proportion of screening tests which were co-tests rose from 5.6% in 2008 to 84.3% in 2019 among women aged 30-64 years with a marked change from the near exclusive use of the Hybrid Capture II HPV test, (a signal amplified test method) to the use of target amplified HPV tests. The largest increases were seen between 2013 and 2015, reflecting the introduction and adoption of new clinical guidelines. Increases in co-testing were also seen in younger women. CONCLUSIONS: Co-testing is now well established in women aged 30-64 years, but smaller increases have also been seen at younger ages, although this is not currently recommended. The impact of co-testing on cervical disease outcomes and number of colposcopies and biopsies in routine population settings remain important, especially in young women.

Assembling the Healthopolis: Competitive city-regionalism and policy boosterism pushing Greater Manchester further, faster.

Health and care policy is increasingly promoted within visions of the competitive city-region. This paper examines the importance of policy boosterism within the political construction of city-regions in the context of English devolution. Based on a two-year case study of health and social care devolution in Greater Manchester, England, we trace the relational and territorial geographies of policy across and through new "devolved" city-regional arrangements. Contributing to geographical debates on policy assemblages and city-regionalism, we advance a conceptual framework linking crisis and opportunity, emulation and exceptionalism, and evidence and experimentation. The paper makes two key contributions. First, we argue health and care policy is increasingly drawn towards the logic of global competitiveness without being wholly defined by neoliberal political agendas. Fostering transnational policy networks helped embed global "best practice" policies while simultaneously hailing Greater Manchester as a place beyond compare. Second, we caution against positioning the city-region solely at the receiving end of devolutionary austerity. Rather, we illustrate how the urgency of devolution was conditioned by crisis, yet concomitantly framed as a unique opportunity by the local state harnessing policy to negotiate a more fluid politics of scale. In doing so, the paper demonstrates how attempts to resolve the "local problem" of governing health and care under austerity were rearticulated as a "global opportunity" to forge new connections between place, health, and economy. Consequently, we foreground the multiple tensions and contradictions accumulating through turning to health and care to push Greater Manchester further, faster. The paper concludes by asking what the present crisis might mean for city-regions in good health and turbulent times.

The impact of a combinatorial digital and organisational intervention on the management of long-term conditions in UK primary care: a non-randomised evaluation.

BACKGROUND: Better management of long-term conditions remains a policy priority, with a focus on improving outcomes and reducing use of expensive hospital services. A number of interventions have been tested, but many have failed to show benefit in rigorous comparative research. In 2016, the NHS Test Beds scheme was launched to implement and test interventions combining digital technologies and pathway redesign in routine health care settings, with each intervention comprising multiple innovations to better realise benefit from their 'combinatorial' effect. We present the evaluation of one of the NHS Test Beds, which combined risk stratification algorithms, practice-based quality improvement and health monitoring and coaching to improve management of long-term conditions in a single health economy in the north-west of England. METHODS: The NHS Test Bed was implemented in one clinical commissioning group in the north-west of England (patient population 235,800 served by 36 general practices). Routine administrative data on hospital use (the primary outcome) and a selection of secondary outcomes (data from both hospital and primary care) were collected in the intervention site, and from a comparator area in the same region. We used difference-in-differences analysis to compare outcomes in the NHS Test Bed area and the comparator after initiation of the combinatorial intervention. RESULTS: Tests confirmed the existence of parallel trends in the intervention and comparator sites for hospital outcomes for the period April 2016 to March 2017, and for some of the planned primary care outcomes. Based on 10 months of post-intervention secondary care data and 13 months post-intervention primary care data, we found no significant impact on primary outcomes between the intervention and comparator site, and a significant impact on only one secondary outcome. CONCLUSION: A combinatorial digital and organisational intervention to improve the management of long-term conditions was implemented across a whole health economy, but we found no evidence of a positive impact on health care utilisation outcomes in hospital and primary care.

Understanding behaviour change in context: examining the role of midstream social marketing programmes.

This research examines how midstream social marketing programmes that adopt a relational and community-based approach create opportunities for individuals to make incremental changes to health behaviour. Specifically, it applies Bourdieusian theory to explore how interactions between community healthcare workers (CHWs) and members of the public generate impetus for change and foster individual agency for improved health. Qualitative interviews were carried out with members of the public and CHWs engaged in a Smokefree home and cars initiative. The findings suggest that although CHWs are challenged by resource constraints, their practices in working with individuals and families build trust and enable dialogue that bridges smoking-related health insight with home logics. These interactions can promote individual agency with a transformative effect through small changes to smoking-related dispositions, norms and practices. However, tensions with the habitus of other household members and other capital deficits can inhibit progress towards embedding new practices. The study concludes that interventions built upon community relationships show potential for addressing limitations of information-focused campaigns but there is a need to also respond to key social structures relating to the field of action for new health dispositions to become embedded in practice.

Regional assemblage and the spatial reorganisation of health and care: the case of devolution in Greater Manchester, England.

In this paper, we examine how space is integral to the practices and politics of restructuring health and care systems and services and specifically how ideas of assemblage can help understand the remaking of a region. We illustrate our arguments by focusing on health and social care devolution in Greater Manchester, England. Emphasising the open-ended political construction of the region, we consider the work of assembling different actors, organisations, policies and resources into a new territorial formation that provisionally holds together without becoming a fixed totality. We highlight how the governing of health and care is shaped through the interplay of local, regional and national actors and organisations coexisting, jostling and forging uneasy alliances. Our goal is to show that national agendas continued to be firmly embedded within the regional project, not least the politics of austerity. Yet through keeping the region together as if it was an integrated whole and by drawing upon new global policy networks, regional actors strategically reworked national agendas in attempts to leverage and compete for new resources and powers. We set out a research agenda that foregrounds how the political reorganisation of health and care is negotiated and contested across multiple spatial dimensions simultaneously.

Long-term effect of hospital pay for performance on mortality in England.

BACKGROUND: A pay-for-performance program based on the Hospital Quality Incentive Demonstration was introduced in all hospitals in the northwest region of England in 2008 and was associated with a short-term (18-month) reduction in mortality. We analyzed the long-term effects of this program, called Advancing Quality. METHODS: We analyzed 30-day in-hospital mortality among 1,825,518 hospital admissions for eight conditions, three of which were covered by the financial-incentive program. The hospitals studied included the 24 hospitals in the northwest region that were participating in the program and 137 elsewhere in England that were not participating. We used difference-in-differences regression analysis to compare risk-adjusted mortality for an 18-month period before the program was introduced with subsequent mortality in the short term (the first 18 months of the program) and the longer term (the next 24 months). RESULTS: Throughout the short-term and the long-term periods, the performance of hospitals in the incentive program continued to improve and mortality for the three conditions covered by the program continued to fall. However, the reduction in mortality among patients with these conditions was greater in the control hospitals (those not participating in the program) than in the hospitals that were participating in the program (by 0.7 percentage points; 95% confidence interval [CI], 0.3 to 1.2). By the end of the 42-month follow-up period, the reduced mortality in the participating hospitals was no longer significant (-0.1 percentage points; 95% CI, -0.6 to 0.3). From the short term to the longer term, the mortality for conditions not covered by the program fell more in the participating hospitals than in the control hospitals (by 1.2 percentage points; 95% CI, 0.4 to 2.0), raising the possibility of a positive spillover effect on care for conditions not covered by the program. CONCLUSIONS: Short-term relative reductions in mortality for conditions linked to financial incentives in hospitals participating in a pay-for-performance program in England were not maintained.

Does capitation affect the delivery of oral healthcare and access to services? Evidence from a pilot contact in Northern Ireland.

BACKGROUND: In May 2009, the Northern Ireland government introduced General Dental Services (GDS) contracts based on capitation in dental practices newly set up by a corporate dental provider to promote access to dental care in populations that had previously struggled to secure service provision. Dental service provision forms an important component of general health services for the population, but the implications of health system financing on care delivered and the financial cost of services has received relatively little attention in the research literature. The aim of this study is to evaluate the policy effect capitation payment in recently started corporate practices had on the delivery of primary oral healthcare in Northern Ireland and access to services. METHODS: We analysed the policy initiative in Northern Ireland as a natural experiment to find the impact on healthcare delivery of the newly set up corporate practices that use a prospective capitation system to remunerate primary care dentists. Data was collected from GDS claim forms submitted to the Business Services Organisation (BSO) between April 2011 and October 2014. Health and Social Care Board (HSCB) practices operating within a capitation system were matched to a control group, who were remunerated using a retrospective fee-for-service system. RESULTS: No evidence of patient selection was found in the HSCB practices set up by a corporate provider and operated under capitation. However, patients were less likely to visit the dentist and received less treatment when they did attend, compared to those belonging to the control group (P < 0.05). The extent of preventive activity offered and the patient payment charge revenue did not differ between the two practice groups. CONCLUSION: Although remunerating NHS primary care dentists in newly set up corporate practices using a prospective capitation system managed costs within healthcare, there is evidence that this policy may have reduced access to care of registered patients.

Sensemaking and the co-production of safety: a qualitative study of primary medical care patients.

This study explores the ways in which patients make sense of 'safety' in the context of primary medical care. Drawing on qualitative interviews with primary care patients, we reveal patients' conceptualisation of safety as fluid, contingent, multi-dimensional, and negotiated. Participant accounts drew attention to a largely invisible and inaccessible (but taken for granted) architecture of safety, the importance of psycho-social as well as physical dimensions and the interactions between them, informal strategies for negotiating safety, and the moral dimension of safety. Participants reported being proactive in taking action to protect themselves from potential harm. The somewhat routinised and predictable nature of the primary medical care consultation, which is very different from 'one off' inpatient spells, meant that patients were not passive recipients of care. Instead they had a stock of accumulated knowledge and experience to inform their actions. In addition to highlighting the differences and similarities between hospital and primary care settings, the study suggests that a broad conceptualisation of patient safety is required, which encompasses the safety concerns of patients in primary care settings.

Reduced mortality with hospital pay for performance in England.

BACKGROUND: Pay-for-performance programs are being adopted internationally despite little evidence that they improve patient outcomes. In 2008, a program called Advancing Quality, based on the Hospital Quality Incentive Demonstration in the United States, was introduced in all National Health Service (NHS) hospitals in the northwest region of England (population, 6.8 million). METHODS: We analyzed 30-day in-hospital mortality among 134,435 patients admitted for pneumonia, heart failure, or acute myocardial infarction to 24 hospitals covered by the pay-for-performance program. We used difference-in-differences regression analysis to compare mortality 18 months before and 18 months after the introduction of the program with mortality in two comparators: 722,139 patients admitted for the same three conditions to the 132 other hospitals in England and 241,009 patients admitted for six other conditions to both groups of hospitals. RESULTS: Risk-adjusted, absolute mortality for the conditions included in the pay-for-performance program decreased significantly, with an absolute reduction of 1.3 percentage points (95% confidence interval [CI], 0.4 to 2.1; P=0.006) and a relative reduction of 6%, equivalent to 890 fewer deaths (95% CI, 260 to 1500) during the 18-month period. The largest reduction, for pneumonia, was significant (1.9 percentage points; 95% CI, 0.9 to 3.0; P<0.001), with nonsignificant reductions for acute myocardial infarction (0.6 percentage points; 95% CI, -0.4 to 1.7; P=0.23) and heart failure (0.6 percentage points; 95% CI, -0.6 to 1.8; P=0.30). CONCLUSIONS: The introduction of pay for performance in all NHS hospitals in one region of England was associated with a clinically significant reduction in mortality. As compared with a similar U.S. program, the U.K. program had larger bonuses and a greater investment by hospitals in quality-improvement activities. Further research is needed on how implementation of pay-for-performance programs influences their effects. (Funded by the NHS National Institute for Health Research.).

Prevalence and outcomes of renal transplantation in children with intellectual disability.

To describe the prevalence and outcomes of renal transplantation in children with ID we performed a retrospective cohort analysis of all children receiving a first kidney-alone transplant in the UNOS dataset from 2008 to 2011. Recipients with definite, probable, and without ID were compared using chi-square tests. Kaplan-Meier curves were constructed for patient and graft survival. Cox proportional hazard models were used to estimate the association between ID and graft failure and patient survival. Over the study period, 332 children with definite (117) or probable (215) ID underwent first renal transplant, accounting for 16% of all first pediatric renal transplants (n = 2076). Children with definite ID were not significantly different from children without ID with respect to sex, ethnicity, or prevalence of acute rejection. ID was associated with increased likelihood of deceased donor source. ID was not significantly associated with decreased graft or patient survival. In this first large-scale study, up to 16% of first pediatric renal transplants were performed in children with ID. Short-term graft and patient survival after transplant were equivalent between children with and without ID. Further research is needed to examine long-term outcomes of transplant in this population.

'Bourdieu', medical elites and 'social class': a qualitative study of 'desert island' doctors.

Sociologists of professions draw on Weberian theories of closure. However they have tended to ignore Bourdieu's work, which rejects Weberian notions of class and status groups as distinct ideal types and sees these concepts as inextricably linked. Bourdieu emphasises the importance of a class-based habitus which generates orientations, inclinations and dispositions that organise practices and the perception of practice. For Bourdieu, because individuals perceive one another primarily through the status that attaches to their practices (through a symbolic veil of honour) they fail to perceive the real basis of these practices: the forms of capital that underlie the different habitus and enable their realisation. This article draws on interviews with 17 elite doctors appearing on a national (UK) radio show during which they choose eight discs to take to a desert island. According to Bourdieu, 'nothing more clearly affirms one's "class", nothing more infallibly classifies, than one's taste in music'. An analysis of the doctors' musical tastes and their mode of acquisition (largely, for these elites, via their family and education at independent schools), as well as other insights into their cultural capital reveals the importance of linking class and status when exploring professional status and prestige.

The clinical impact of humoral immunity in pediatric renal transplantation.

The development of anti-donor humoral responses after transplantation associates with higher risks for acute rejection and 1-year graft survival in adults, but the influence of humoral immunity on transplant outcomes in children is not well understood. Here, we studied the evolution of humoral immunity in low-risk pediatric patients during the first 2 years after renal transplantation. Using data from 130 pediatric renal transplant patients randomized to steroid-free (SF) or steroid-based (SB) immunosuppression in the NIH-SNSO1 trial, we correlated the presence of serum anti-HLA antibodies to donor HLA antigens (donor-specific antibodies) and serum MHC class 1-related chain A (MICA) antibody with both clinical outcomes and histology identified on protocol biopsies at 0, 6, 12, and 24 months. We detected de novo antibodies after transplant in 24% (23% of SF group and 25% of SB group), most often after the first year. Overall, 22% developed anti-HLA antibodies, of which 6% were donor-specific antibodies, and 6% developed anti-MICA antibody. Presence of these antibodies de novo associated with significantly higher risks for acute rejection (P=0.02), chronic graft injury (P=0.02), and decline in graft function (P=0.02). In summary, antibodies to HLA and MICA antigens appear in approximately 25% of unsensitized pediatric patients, placing them at greater risk for acute and chronic rejection with accelerated loss of graft function. Avoiding steroids does not seem to modify this incidence. Whether serial assessments of these antibodies after transplant could guide individual tailoring of immunosuppression requires additional study.

Solid tumors following kidney transplantation in children.

Kidney transplant recipients have an increased risk of cancer. Data on non-LPD malignancies (solid tumors) in pediatric renal transplant recipients are limited. We performed a cohort study using the NAPRTCS transplant registry to describe the incidence of non-LPD malignancy compared with the general pediatric population. The observed incidence rate of non-LPD malignancy in the NAPRTCS transplant registry was 72.1 per 100,000 person-years (SIR 6.7; 95% CI, 5.3, 8.5); a 6.7-fold increased risk compared with the general pediatric population (10.7 cases per 100,000 person-years). Non-LPD malignancy was diagnosed in 35 subjects at a median of 726 days post-transplant. The most common type of malignancy was renal cell carcinoma. The increased risk of non-LPD malignancy was seen in all patients regardless of age, gender, race, etiology of end-stage kidney disease, and transplant era. The specific type of immunosuppression was not identified as a risk factor. In this first large-scale study of North American pediatric renal transplant recipients, we observed a 6.7-fold increased risk of non-LPD malignancy compared with the general pediatric population. Further examination of this unique patient population may provide greater insight into the impact of transplant and immunosuppression on malignancy risk.

Determining the optimal model for role-substitution in NHS dental services in the United Kingdom.

BACKGROUND: Role-substitution describes a model of dental care where Dental Care Professionals (DCPs) provide some of the clinical activity previously undertaken by General Dental Practitioners. This has the potential to increase technical efficiency, the capacity to care and reduce costs. Technical efficiency is defined as the production of the maximum amount of output from a given amount of input so that the service operates at the production frontier i.e. optimal level of productivity. Academic research into technical efficiency is becoming increasingly utilised in health care, although no studies have investigated the efficiency of NHS dentistry or role-substitution in high-street dental practices. The aim of this study is to examine the barriers and enablers that exist for role-substitution in general dental practices in the NHS and to determine the most technically efficient model for role-substitution. METHODS/DESIGN: A screening questionnaire will be sent to DCPs to determine the type and location of role-substitutive models employed in NHS dental practices in the United Kingdom (UK). Semi-structured interviews will then be conducted with practice owners, DCPs and patients at selected sites identified by the questionnaire. Detail will be recorded about the organisational structure of the dental team, the number of NHS hours worked and the clinical activity undertaken. The interviews will continue until saturation and will record the views and attitudes of the members of the dental team. Final numbers of interviews will be determined by saturation.The second work-stream will examine the technical efficiency of the selected practices using Data Envelopment Analysis and Stochastic Frontier Modeling. The former is a non-parametric technique and is considered to be a highly flexible approach for applied health applications. The latter is parametric and is based on frontier regression models that estimate a conventional cost function. DISCUSSION: Maximising health for a given level and mix of resources is an ethical imperative for health service planners. This study will determine the technical efficiency of role-substitution and so address one of the key recommendations of the Independent Review of NHS dentistry in England.

Spillover effects of financial incentives for providers onto non-targeted patients: daycase surgery in English hospitals.

BACKGROUND: Incentives for healthcare providers may also affect non-targeted patients. These spillover effects have important implications for the full impact and evaluation of incentive schemes. However, there are few studies on the extent of such spillovers in health care. We investigated whether incentives to perform surgical procedures as daycases affected whether other elective procedures in the same specialties were also treated as daycases. DATA: 8,505,754 patients treated for 92 non-targeted procedures in 127 hospital trusts in England between April and March 2016. METHODS: Interrupted time series analysis of the probability of being treated as a daycase for non-targeted patients treated in six specialties where targeted patients were also treated and three specialties where they were not. RESULTS: The daycase rate initially increased (1.04 percentage points, SE: 0.30) for patients undergoing a non-targeted procedure in incentivised specialties but then reduced over time. Conversely, the daycase rate gradually decreased over time for patients treated in a non-incentivised specialty. DISCUSSION: Spillovers from financial incentives have variable effects over different activities and over time. Policymakers and researchers should consider the possibility of spillovers in the design and evaluation of incentive schemes.

Persistent frequent attenders in primary care: costs, reasons for attendance, organisation of care and potential for cognitive behavioural therapeutic intervention.

BACKGROUND: The top 3% of frequent attendance in primary care is associated with 15% of all appointments in primary care, a fivefold increase in hospital expenditure, and more mental disorder and functional somatic symptoms compared to normal attendance. Although often temporary if these rates of attendance last more than two years, they may become persistent (persistent frequent or regular attendance). However, there is no long-term study of the economic impact or clinical characteristics of regular attendance in primary care. Cognitive behaviour formulation and treatment (CBT) for regular attendance as a motivated behaviour may offer an understanding of the development, maintenance and treatment of regular attendance in the context of their health problems, cognitive processes and social context. METHODS/DESIGN: A case control design will compare the clinical characteristics, patterns of health care use and economic costs over the last 10 years of 100 regular attenders (≥30 appointments with general practitioner [GP] over 2 years) with 100 normal attenders (6-22 appointments with GP over 2 years), from purposefully selected primary care practices with differing organisation of care and patient demographics. Qualitative interviews with regular attending patients and practice staff will explore patient barriers, drivers and experiences of consultation, and organisation of care by practices with its challenges. Cognitive behaviour formulation analysed thematically will explore the development, maintenance and therapeutic opportunities for management in regular attenders. The feasibility, acceptability and utility of CBT for regular attendance will be examined. DISCUSSION: The health care costs, clinical needs, patient motivation for consultation and organisation of care for persistent frequent or regular attendance in primary care will be explored to develop training and policies for service providers. CBT for regular attendance will be piloted with a view to developing this approach as part of a multifaceted intervention.

Persistent rhinitis and epithelial remodeling induced by cyclic ozone exposure in the nasal airways of infant monkeys.

Children chronically exposed to high levels of ozone (O(3)), the principal oxidant pollutant in photochemical smog, are more vulnerable to respiratory illness and infections. The specific factors underlying this differential susceptibility are unknown but may be related to air pollutant-induced nasal alterations during postnatal development that impair the normal physiological functions (e.g., filtration and mucociliary clearance) serving to protect the more distal airways from inhaled xenobiotics. In adult animal models, chronic ozone exposure is associated with adaptations leading to a decrease in airway injury. The purpose of our study was to determine whether cyclic ozone exposure induces persistent morphological and biochemical effects on the developing nasal airways of infant monkeys early in life. Infant (180-day-old) rhesus macaques were exposed to 5 consecutive days of O(3) [0.5 parts per million (ppm), 8 h/day; "1-cycle"] or filtered air (FA) or 11 biweekly cycles of O(3) (FA days 1-9; 0.5 ppm, 8 h/day on days 10-14; "11-cycle"). The left nasal passage was processed for light microscopy and morphometric analysis. Mucosal samples from the right nasal passage were processed for GSH, GSSG, ascorbate (AH(2)), and uric acid (UA) concentration. Eleven-cycle O(3) induced persistent rhinitis, squamous metaplasia, and epithelial hyperplasia in the anterior nasal airways of infant monkeys, resulting in a 39% increase in the numeric density of epithelial cells. Eleven-cycle O(3) also induced a 65% increase in GSH concentrations at this site. The persistence of epithelial hyperplasia was positively correlated with changes in GSH. These results indicate that early life ozone exposure causes persistent nasal epithelial alterations in infant monkeys and provide a potential mechanism for the increased susceptibility to respiratory illness exhibited by children in polluted environments.

Postnatal episodic ozone results in persistent attenuation of pulmonary and peripheral blood responses to LPS challenge.

Early life is a dynamic period of growth for the lung and immune system. We hypothesized that ambient ozone exposure during postnatal development can affect the innate immune response to other environmental challenges in a persistent fashion. To test this hypothesis, we exposed infant rhesus macaque monkeys to a regimen of 11 ozone cycles between 30 days and 6 mo of age; each cycle consisted of ozone for 5 days (0.5 parts per million at 8 h/day) followed by 9 days of filtered air. Animals were subsequently housed in filtered air conditions and challenged with a single dose of inhaled LPS at 1 yr of age. After completion of the ozone exposure regimen at 6 mo of age, total peripheral blood leukocyte and polymorphonuclear leukocyte (PMN) numbers were reduced, whereas eosinophil counts increased. In lavage, total cell numbers at 6 mo were not affected by ozone, however, there was a significant reduction in lymphocytes and increased eosinophils. Following an additional 6 mo of filtered air housing, only monocytes were increased in blood and lavage in previously exposed animals. In response to LPS challenge, animals with a prior history of ozone showed an attenuated peripheral blood and lavage PMN response compared with controls. In vitro stimulation of peripheral blood mononuclear cells with LPS resulted in reduced secretion of IL-6 and IL-8 protein in association with prior ozone exposure. Collectively, our findings suggest that ozone exposure during infancy can result in a persistent effect on both pulmonary and systemic innate immune responses later in life.