Resources, methods, and data infrastructure to promote research in dementia care, caregiving, and services.

BACKGROUND: The National Institute on Aging, in conjunction with the Department of Health and Human Services as part of the National Alzheimer's Project Act, hosted a 2020 Dementia Care, Caregiving, and Services Research Summit Virtual Meeting Series on August 13, 2020. This article reflects three presentations related to Theme 6: Research Resources, Methods, and Data Infrastructure. Dr. Bynum discussed the challenges of identifying people for population- and healthcare-based research, including how definitions of dementia have changed over time, the opportunities and challenges inherent in the use of electronic data sources, and the need to fit data collection strategies to research goals and questions. Dr. Travison provided an overview on the growing use of embedded pragmatic clinical trials (ePCTs) and how to enhance their impact in dementia research. Dr. Wendler presented on the ethical considerations relevant to consent for dementia research, including assessment of decisional capacity and the role of decisional surrogates. CONCLUSIONS: The availability of claims data, electronic health records, and other sources of "existing" data has made the use and development of ePCTs both easier and more appealing. Among other things, they offer advantages in terms of lower cost and generalizability to real-world settings. This is turn has necessitated the use of informatic and analytic approaches to account for some of the limitations and complexities of such data, including multilevel clustering and the need to link and jointly analyze data from the person with dementia and those of their care partner. As part of this process, it will be important to broaden the scope of who is assessed for decisional capacity, make those assessments more study specific, and assist surrogates in making decisions based on what the individual would have chosen for themselves if capacitated (i.e., substituted judgment).

Optimising equity of access: how should we allocate slots to the most competitive trials in Cystic Fibrosis (CF)?

BACKGROUND: Trial participation can allow people with CF early access to CFTR modulator therapies, with high potential for clinical benefit. Therefore, the number of people wishing to participate can substantially exceed the number of slots available. We aimed to understand how the CF community thinks slots to competitive trials should be allocated across the UK and whether this should be driven by clinical need, patients' engagement/adherence or be random. For the latter, we explored site-level versus registry-based, national randomisation processes. METHODS: We developed an online survey, recruiting UK-based stakeholders through social media, newsletters and personal contacts. Closed questions were analysed for frequencies and percentages of responses. Free-text questions were analysed using thematic analysis. RESULTS: We received 203 eligible responses. Overall, 75% of stakeholders favoured allocation of slots to individual sites based on patient population size, although pharma favoured allocation based on previous metrics. Currently, few centres have defined strategies for allocating slots locally. At face-value, stakeholders believe all eligible participants should have an equal chance of getting a slot. However, further questioning reveals preference for prioritisation strategies, primarily perceived treatment adherence, although healthcare professionals were less likely to favour this strategy than other stakeholder groups. The majority of stakeholders would prefer to allocate slots and participate in trials locally but 80% said if necessary, they would engage in a system of national allocation. CONCLUSIONS: Fair allocation to highly competitive trials does not appear to have a universally acceptable solution. Therefore, transparency and empathy remain critical to negotiate this uncertain territory.

The relation between the flexion relaxation phenomenon onset angle and lumbar spine muscle reflex onset time in response to 30 min of slumped sitting.

Viscoelastic creep of spine tissue, induced by submaximal spine flexion in sitting, can delay the onset of the flexion-relaxation phenomenon (FRP) and low back reflexes (LBR). Theoretically, these two outcome measures should be correlated; however, no studies have investigated this. This study aims to determine whether 30 min of near-maximal spine flexion will affect the onset of FRP and LBR in the lumbar erector spinae (LS) and lumbar multifidus (LM), and to examine the relation between these parameters. 15 participants were recruited (9F, 6M). Spine angle (between L1 and S2) was monitored synchronously with bilateral muscle activity in the LS (L1) and the LM (L4). FRP onset and LBR were measured in a randomized order before and after 30 min of slouched sitting. No significant difference was found for any muscle LBR onset time between pre and post-sitting (p > 0.05). A significant increase in FRP onset was found in the RLM (p = 0.016) following sitting. No significant correlation was found between the FRP and the LBR for any muscle. These results suggest that the LBR onset might not be as sensitive as an outcome measure to investigate shorter exposures of sitting as FRP.

Local Health Jurisdiction Staff Deliver Health Promotion to Small Worksites, Washington.

CONTEXT: Worksites can serve as community sites for local health jurisdictions (LHJs) to assist with implementation of evidence-based interventions (EBIs) to prevent and control chronic diseases. OBJECTIVE: To assess the feasibility and effectiveness of using LHJ staff to disseminate Connect to Wellness (CtW), an effective dissemination package for increasing implementation of EBIs for chronic disease control by small worksites. DESIGN: Single-arm, multisite intervention trial, with measurement at baseline, after 6 months of intervention, and after a maintenance period of 6 months. SETTING: Six geographically dispersed counties in Washington State. Target worksites had 20 to 250 employees. PARTICIPANTS: Nine staff members from 6 LHJs delivered CtW to 35 worksites. INTERVENTION: Connect to Wellness seeks to increase worksites' implementation of 14 EBIs classified as communication, policy, or program approaches to increasing 4 behaviors: cancer screening, healthy eating, physical activity, and tobacco cessation. MAIN OUTCOME MEASURE: Evidence-based intervention implementation measured on a scale from 0% to 100%. RESULTS: Participating worksites showed a significant increase (P < .001, t test) in total mean implementation scores from baseline (33%) to 6-month follow-up (47%). Increases in implementation for communications, policy, healthy eating, and tobacco EBIs were statistically significant at 6 months and maintained at 12 months. Increased implementation at 6 months of a group physical activity program was not sustained after the program became unavailable, and total implementation scores at 12 months (38%) showed little change from baseline. CONCLUSIONS: Local health jurisdiction-delivered CtW increased worksites' implementation of EBIs at 6 months, and increased implementation in communication, policy, healthy eating, and tobacco was maintained at 12 months. This package, delivered by LHJ staff working part-time on CtW, was nearly as successful as prior delivery by staff working full-time on CtW.

Impact of rapid microbial identification on clinical outcomes in bloodstream infection: the RAPIDO randomized trial.

OBJECTIVES: Bloodstream infection has a high mortality rate. It is not clear whether laboratory-based rapid identification of the organisms involved would improve outcome. METHODS: The RAPIDO trial was an open parallel-group multicentre randomized controlled trial. We tested all positive blood cultures from hospitalized adults by conventional methods of microbial identification and those from patients randomized (1:1) to rapid diagnosis in addition to matrix-assisted desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) performed directly on positive blood cultures. The only primary outcome was 28-day mortality. Clinical advice on patient management was provided to members of both groups by infection specialists. RESULTS: First positive blood culture samples from 8628 patients were randomized, 4312 into rapid diagnosis and 4136 into conventional diagnosis. After prespecified postrandomization exclusions, 2740 in the rapid diagnosis arm and 2810 in the conventional arm were included in the mortality analysis. There was no significant difference in 28-day survival (81.5% 2233/2740 rapid vs. 82.3% 2313/2810 conventional; hazard ratio 1.05, 95% confidence interval 0.93-1.19, p 0.42). Microbial identification was quicker in the rapid diagnosis group (median (interquartile range) 38.5 (26.7-50.3) hours after blood sampling vs. 50.3 (47.1-72.9) hours after blood sampling, p < 0.01), but times to effective antimicrobial therapy were no shorter (respectively median (interquartile range) 24 (2-78) hours vs. 13 (2-69) hours). There were no significant differences in 7-day mortality or total antibiotic consumption; times to resolution of fever, discharge from hospital or de-escalation of broad-spectrum therapy or 28-day Clostridioides difficile incidence. CONCLUSIONS: Rapid identification of bloodstream pathogens by MALDI-TOF MS in this trial did not reduce patient mortality despite delivering laboratory data to clinicians sooner.

Feasibility and effectiveness of nurses and clinical officers in implementing the WHO mhGAP intervention guide: Pilot study in Makueni County, Kenya.

OBJECTIVES: (1) To determine the feasibility and effectiveness of nurses and clinical officers in using the mental health Global Action Programme Intervention Guide (mhGAP-IG) as an intervention tool in reducing disability, improving quality of life in the clinical outcomes in patients with the mhGAP-IG priority mental disorders in a Kenyan rural setting. (2) To identify any gaps that can be contributed towards future research. METHODS: This study was conducted in 20 healthcare facilities across Makueni County in the South East of Kenya. This county had a population of approximately one million people, with no psychiatrist or clinical psychologist. We recruited 2306 participants from the healthcare facilities in the catchment areas that had previously been exposed to the community mental health awareness campaigns, while being subjected to screening for the mhGAP-IG disorders. We used the Mini-International Neuropsychiatric Interview for adults (MINI-Plus) for DSM-IV confirmatory diagnosis on those who screened positive on the mhGAP-IG. We measured disability using WHO-Disability Assessment Schedule II (DAS II), Quality of Life (QoL) using the WHO QoL-BREF, depression using Patient Health Questionnaire (PHQ-9), suicidality using The Beck Suicide Scale (BSS), psychosis using the Washington Early Recognition Center Affectivity and Psychosis (WERCAP), epilepsy using a seizure questionnaire and alcohol and substance abuse using The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). These measurements were at the baseline, followed by the training for the health professionals on using the WHO mhGAP-IG as an interventional tool. The measurements were repeated at 3 and 6 months post-intervention. RESULTS: Of the 2306 participants enrolled in the study, we followed 1718 at 3 months and 1371 at 6 months a follow-up rate of 74.5% and 59.4% respectively. All participants received psycho-education and most depending on condition also received medication. Overall, there was significant decline in disabilities, improvement in seizure control and improvement in clinical outcomes on the identified mental disorders. CONCLUSIONS: Trained, supervised and supported nurses and clinical officers can produce good outcomes using the mhGAP-IG for mental health.

Feasibility of WHO mhGAP-intervention guide in reducing experienced discrimination in people with mental disorders: a pilot study in a rural Kenyan setting.

AimsStigma can have a negative impact on help-seeking behaviour, treatment adherence and recovery of people with mental disorders. This study aimed to determine the feasibility of the WHO Mental Health Treatment Gap Interventions Guidelines (mhGAP-IG) to reduce stigma in face-to-face contacts during interventions for specific DSM-IV/ICD 10 diagnoses over a 6-month period. METHODS: This study was conducted in 20 health facilities across Makueni County in southeast Kenya which has one of the poorest economies in the country and has no psychiatrist or clinical psychologist. We recruited 2305 participants from the health facilities catchment areas that had already been exposed to community mental health services. We measured stigma using DISC-12 at baseline, followed by training to the health professionals on intervention using the WHO mhGAP-IG and then conducted a follow-up DISC-12 assessment after 6 months. Proper management of the patients by the trained professionals would contribute to the reduction of stigma in the patients. RESULTS: There was 59.5% follow-up at 6 months. Overall, there was a significant decline in 'reported/experienced discrimination' following the interventions. A multivariate linear mixed model regression indicated that better outcomes of 'unfair treatment' scores were associated with: being married, low education, being young, being self-employed, higher wealth index and being diagnosed with depression. For 'stopping self' domain, better outcomes were associated with being female, married, employed, young, lower wealth index and a depression diagnosis. In regards to 'overcoming stigma' domain; being male, being educated, employed, higher wealth index and being diagnosed with depression was associated with better outcomes. CONCLUSIONS: The statistically significant (p < 0.05) reduction of discrimination following the interventions by trained health professionals suggest that the mhGAP-IG may be a useful tool for reduction of discrimination in rural settings in low-income countries.

Changing patterns of mental health knowledge in rural Kenya after intervention using the WHO mhGAP-Intervention Guide.

BACKGROUND: Despite the high prevalence of mental disorders, mental health literacy has been comparatively neglected. People's symptom-management strategies will be influenced by their mental health literacy. This study sought to determine the feasibility of using the World Health Organization mhGAP-Intervention Guide (IG) as an educational tool for one-on-one contact in a clinical setting to increase literacy on the specified mental disorders. METHODS: This study was conducted in 20 health facilities in Makueni County, southeast Kenya which has one of the poorest economies in Kenya. It has no psychiatrist or clinical psychologist. We recruited 3267 participants from a community that had already been exposed to community mental health services. We used Mental Health Knowledge Schedule to measure the changing patterns of mental health knowledge after a period of 3 months, following a training intervention using the WHO mhGAP-IG. RESULTS: Overall, there was a significant increase in mental health related knowledge [mean range 22.4-23.5 for both post-test and pre-test scores (p < 0.001)]. This increase varied with various socio-demographic characteristics such as sex, marital status, level of education, employment status and wealth index. CONCLUSIONS: mhGAP-IG is a feasible tool to increase mental health literacy in low-resource settings where there are no mental health specialists. Our study lends evidence that the WHO Mental Health Action Plan 2013-2020 and reduction of the treatment gap may be accelerated by the use of mhGAP-IG through improving knowledge about mental illness and potentially subsequent help seeking for early diagnosis and treatment.

Fear of Negative Evaluation and Weight/Shape Concerns among Adolescents: The Moderating Effects of Gender and Weight Status.

Fear of negative evaluation has been linked with weight/shape concerns among adults, however, similar research among adolescents is lacking. We investigated the relationship between fear of negative evaluation and weight/shape concerns, including the moderating roles of gender and body mass index (BMI) in adolescents. Participant were 4045 Australian adolescents (53.7% girls) aged 11-19 years (Mage = 14 years 11 months), who completed a self-report questionnaire about weight/shape concerns, fear of negative evaluation, and weight and height. Results showed a positive association between fear of negative evaluation and weight/shape concerns, with the association being stronger among girls. Furthermore, the association between fear of negative evaluation and weight/shape concerns was stronger among adolescents with higher BMIs, especially so for boys. These results highlight the role of fear of negative evaluation in weight/shape concerns and suggest potential avenues for prevention programs.

TC-PTP regulates the IL-7 transcriptional response during murine early T cell development.

Cytokines play a critical role in directing the discrete and gradual transcriptional changes that define T cell development. The interleukin-7 receptor (IL-7R), via its activation of the JAK-STAT pathway, promotes gene programs that change dynamically as cells progress through T cell differentiation. The molecular mechanism(s) directing differential gene expression downstream of the IL-7R are not fully elucidated. Here, we have identified T cell protein tyrosine phosphatase (TC-PTP), also known as PTPN2, as a negative regulator of IL-7R-STAT signaling in T cell progenitors, contributing to both the quantitative and qualitative nature of STAT-gene targeting. Novel genetic strategies used to modulate TC-PTP expression demonstrate that depletion of TC-PTP expression heightens the phosphorylation of STAT family members, causing aberrant expression of an interferon-response gene profile. Such molecular re-programming results in deregulation of early development checkpoints culminating in inefficient differentiation of CD4+CD8+ double positive cells. TC-PTP is therefore shown to be required to safeguard the dynamic transcriptome necessary for efficient T cell differentiation.

Mixed evidence for the erosion of intertactical genetic correlations through intralocus tactical conflict.

Alternative reproductive tactics, whereby members of the same sex use different tactics to secure matings, are often associated with conditional intrasexual dimorphisms. Given the different selective pressures on males adopting each mating tactic, intrasexual dimorphism is more likely to arise if phenotypes are genetically uncoupled and free to evolve towards their phenotypic optima. However, in this context, genetic correlations between male morphs could result in intralocus tactical conflict (ITC). We investigated the genetic architecture of male dimorphism in bulb mites (Rhizoglyphus echinopus) and earwigs (Forficula auricularia). We used half-sibling breeding designs to assess the heritability and intra/intersexual genetic correlations of dimorphic and monomorphic traits in each species. We found two contrasting patterns; F. auricularia exhibited low intrasexual genetic correlations for the dimorphic trait, suggesting that the ITC is moving towards a resolution. Meanwhile, R. echinopus exhibited high and significant intrasexual genetic correlations for most traits, suggesting that morphs in the bulb mite may be limited in evolving to their optima. This also shows that intrasexual dimorphisms can evolve despite strong genetic constraints, contrary to current predictions. We discuss the implications of this genetic constraint and emphasize the potential importance of ITC for our understanding of intrasexual dimorphisms.

Are lower levels of red blood cell transfusion more cost-effective than liberal levels after cardiac surgery? Findings from the TITRe2 randomised controlled trial.

OBJECTIVE: To assess the incremental cost and cost-effectiveness of a restrictive versus a liberal red blood cell transfusion threshold after cardiac surgery. DESIGN: A within-trial cost-effectiveness analysis with a 3-month time horizon, based on a multicentre superiority randomised controlled trial from the perspective of the National Health Service (NHS) and personal social services in the UK. SETTING: 17 specialist cardiac surgery centres in UK NHS hospitals. PARTICIPANTS: 2003 patients aged >16 years undergoing non-emergency cardiac surgery with a postoperative haemoglobin of <9 g/dL. INTERVENTIONS: Restrictive (transfuse if haemoglobin <7.5 g/dL) or liberal (transfuse if haemoglobin <9 g/dL) threshold during hospitalisation after surgery. MAIN OUTCOME MEASURES: Health-related quality of life measured using the EQ-5D-3L to calculate quality-adjusted life years (QALYs). RESULTS: The total costs from surgery up to 3 months were £17 945 and £18 127 in the restrictive and liberal groups (mean difference is -£182, 95% CI -£1108 to £744). The cost difference was largely attributable to the difference in the cost of red blood cells. Mean QALYs to 3 months were 0.18 in both groups (restrictive minus liberal difference is 0.0004, 95% CI -0.0037 to 0.0045). The point estimate for the base-case cost-effectiveness analysis suggested that the restrictive group was slightly more effective and slightly less costly than the liberal group and, therefore, cost-effective. However, there is great uncertainty around these results partly due to the negligible differences in QALYs gained. CONCLUSIONS: We conclude that there is no clear difference in the cost-effectiveness of restrictive and liberal thresholds for red blood cell transfusion after cardiac surgery. TRIAL REGISTRATION NUMBER: ISRCTN70923932; Results.

Effect of early grain feeding of beef steers on postabsorptive metabolism.

The objective of this study was to determine the effect of early weaning followed by a period of high-grain feeding on plasma acetate kinetics and signaling protein phosphorylation in LM tissue of growing steers. We hypothesized that early grain feeding would result in altered cell signaling and acetate use to support observed improvements in carcass gain and marbling. Fall-born Angus × Simmental steers were weaned at 106 ± 4 d of age (early weaned [EW]; n = 6) and fed a high-grain diet for 148 d or remained with their dams (normal weaned [NW]; n = 6) on pasture until weaning at 251 ± 5 d of age. Both treatments were subsequently combined and grazed on mixed summer pasture to 394 ± 5 d of age followed by a feedlot ration until harvest at 513 ± 5 d of age. Longissimus muscle tissue biopsies were collected at 253 ± 5 and 394 ± 5 d of age and at harvest. Total and phosphorylated forms of 5' adenosine monophosphate-activated protein kinase (AMPK) and downstream proteins of the mammalian target of rapamycin signaling pathway were determined by western blotting. Eight steers were used to assess acetate clearance at different age points via a bolus infusion of acetate (4 mmol/kg of BW). Early weaned steers had greater (P < 0.05) ADG than NW steers during the early grain feeding period. Phosphorylated to total ratios of ribosomal protein S6 (rpS6) and ribosomal protein S6 kinase 1 (S6K1) were significantly different during the early grain feeding period. Phosphorylated to total ratios of S6K1, rpS6, acetyl-CoA carboxylase, and 4E binding protein 1 and the absolute amount of phosphorylated AMPK were correlated with ADG, explaining 46% of the variance. Acetate clearance rates were less (P < 0.05) and synthesis rates were greater (P = 0.06) in EW steers during early grain feeding. Acetate synthesis rates were also greater (P < 0.05) in NW steers at harvest, suggesting a permanent shift in the gut microflora or gut function in response to the treatment. Neither treatment nor acetate infusion significantly affected plasma glucose or insulin concentrations. Plasma ß-hydroxybutyric acid concentrations increased with acetate infusion (P < 0.05). Based on these results, altered cell signaling during the early grain feeding period likely mediated increased protein deposition, leading to increased carcass weights, but observed changes in acetate appearance and clearance rates do not appear to explain the observed differences in intramuscular fat deposition during the terminal feeding period.

Associations between gonadotropins, testosterone and ß amyloid in men at risk of Alzheimer's disease.

Testosterone and gonadotropins have been associated with cognitive decline in men and the modulation of ß amyloid (Aß) metabolism. The relatively few studies that have investigated whether changes in one or a combination of these hormones influence Aß levels have focused primarily on plasma Aß(1-40) and not on the more pathogenic Aß(1-42). Currently, no study has investigated whether these hormones are associated with an increase in brain amyloid deposition, ante mortem. Through the highly characterised Australian imaging, biomarkers and lifestyle study, we have determined the impact of these hormones on plasma Aß levels and brain amyloid burden (Pittsburgh compound B (PiB) retention). Spearman's rank correlation and linear regression analysis was carried out across the cohort and within subclassifications. Luteinizing hormone (LH) was the only variable shown, in the total cohort, to have a significant impact on plasma Aß(1-40) and Aß(1-42) levels (beta=0.163, P<0.001; beta=0.446, P<0.001). This held in subjective memory complainers (SMC) (Aß(1-40); beta=0.208, P=0.017; Aß(1-42); beta=0.215, P=0.017) but was absent in mild cognitive impairment (MCI) and Alzheimer's disease (AD) groups. In SMC, increased frequency of the APOE-ɛ4 allele (beta=0.536, P<0.001) and increasing serum LH levels (beta=0.421, P=0.004) had a significant impact on PiB retention. Whereas in MCI, PiB retention was associated with increased APOE-ɛ4 allele copy number (beta=0.674, P<0.001) and decreasing calculated free testosterone (beta=-0.303, P=0.043). These findings suggest a potential progressive involvement of LH and testosterone in the early preclinical stages of AD. Furthermore, these hormones should be considered while attempting to predict AD at these earliest stages of the disease.

Treating severe and enduring anorexia nervosa: a randomized controlled trial.

BACKGROUND: There are no evidence-based treatments for severe and enduring anorexia nervosa (SE-AN). This study evaluated the relative efficacy of cognitive behavioral therapy (CBT-AN) and specialist supportive clinical management (SSCM) for adults with SE-AN. METHOD: Sixty-three participants with a diagnosis of AN, who had at least a 7-year illness history, were treated in a multi-site randomized controlled trial (RCT). During 30 out-patient visits spread over 8 months, they received either CBT-AN or SSCM, both modified for SE-AN. Participants were assessed at baseline, end of treatment (EOT), and at 6- and 12-month post-treatment follow-ups. The main outcome measures were quality of life, mood disorder symptoms and social adjustment. Weight, eating disorder (ED) psychopathology, motivation for change and health-care burden were secondary outcomes. RESULTS: Thirty-one participants were randomized to CBT-AN and 32 to SSCM with a retention rate of 85% achieved at the end of the study. At EOT and follow-up, both groups showed significant improvement. There were no differences between treatment groups at EOT. At the 6-month follow-up, CBT-AN participants had higher scores on the Weissman Social Adjustment Scale (WSAS; p = 0.038) and at 12 months they had lower Eating Disorder Examination (EDE) global scores (p = 0.004) and higher readiness for recovery (p = 0.013) compared to SSCM. CONCLUSIONS: Patients with SE-AN can make meaningful improvements with both therapies. Both treatments were acceptable and high retention rates at follow-up were achieved. Between-group differences at follow-up were consistent with the nature of the treatments given.

Dimensions of physical frailty and cognitive function in older adults with amnestic mild cognitive impairment.

OBJECTIVE: The objective of this study was to examine relationships between dimensions of physical frailty and severity of cognitive impairment in older adults with amnestic mild cognitive impairment (aMCI). PATIENTS AND METHODS: The prevalence of physical frailty dimensions including slow gait speed, low physical activity, and low grip strength was examined among 201 sedentary older adults with aMCI. Associations between dimensions of physical frailty and severity of cognitive impairment, as measured with the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and individual dimensions of cognitive function were examined using multiple linear regression models. RESULTS: Greater than 50% of participants met physical frailty criteria on dimensions of slow gait speed, low physical activity and low grip strength. Slower gait speed was associated with elevated severity of cognitive impairment. Both gait speed and physical activity were associated with individual dimensions cognitive function. CONCLUSIONS: Dimensions of physical frailty, particularly gait speed, were associated with severity of cognitive impairment, after adjusting for age, sex and age-related factors. Further studies are needed to investigate mechanisms and early intervention strategies that assist older adults with aMCI to maintain function and independence.

The relationship between infant lung function and the risk of wheeze in the preschool years.

RATIONALE: There is evidence that perinatal lung development predicts childhood wheeze. However, very few studies have examined whether preschool wheeze is associated with lower premorbid lung function in early infancy, and as yet there is no information relating atopic and non-atopic preschool wheeze to early lung development. OBJECTIVE: To examine the association between premorbid infant lung function and preschool wheeze, and to explore associations with atopic and non-atopic wheeze phenotypes. METHODS: Infant lung function was measured in 147 healthy term infants aged 5-14 weeks. Rapid thoracoabdominal compression was performed during tidal breathing and at raised volume to measure maximal expiratory flow at functional residual capacity (V' max FRC) and forced expiratory volume in 0.4 sec (FEV(0.4)). Atopic status was determined by skin prick testing at 3 years and wheeze ascertained from parental questionnaires (1 and 3 years). MEASUREMENTS AND MAIN RESULTS: Lower early infancy V' max FRC was associated with wheeze in both the first and third years of life (P=0.002 and 0.006, respectively). Lower early infancy FEV(0.4) was associated with wheeze in the first year (P=0.03). Compared to non-atopic children who did not wheeze, non-atopic children who wheezed in their third year of life had lower FEV(0.4) (P=0.02), while FEV(0.4) values of atopic children who wheezed were not significantly different (P=0.4). CONCLUSIONS: Lower premorbid infant lung function was present in infants who subsequently wheezed during the first and third years of life. Lower FEV(0.4) in early infancy was associated with non-atopic wheeze but not atopic wheeze at 3 years of age.