Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans.

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

Association between exposure to household cigarette smoking behavior and cigarette smoking in Hispanic adults: Findings from the Hispanic Community Health Study/Study of Latinos.

BACKGROUND: Cigarette smoking behavior is highly determined by social influences during childhood and adolescence. This phenomenon has not been fully evaluated in the Hispanic/Latino population. PURPOSE: To examine the association between exposure to household cigarette smoking behavior (HCSB) and adult cigarette smoking among a diverse Hispanic/Latino population living in four US urban centers. The effect of acculturation on cigarette smoking was also evaluated. METHODS: Data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) (n=13,231, ages 18-74years, collected between March 2008 and June 2011) were analyzed using logistic regression. RESULTS: HCSB exposure was an independent risk factor for adult current cigarette smoking in Hispanic/Latinos (OR 1.7; 95% CI 1.4, 2.1) after controlling for relevant confounders including socio-demographic and cultural factors. Cubans and Puerto Ricans had the highest prevalence of HCSB exposure (59% and 47% respectively) and highest prevalence of current cigarette smoking (26% and 32%) compared with other Hispanic/Latino groups, (p<.01). CONCLUSIONS: Our data suggest that exposure to HCSB in Hispanics/Latinos living in the US is an independent predictor of adult cigarette smoking, and this association appears to be strongest in Cubans and Puerto Ricans.

Adhesion molecules, endothelin-1 and lung function in seven population-based cohorts.

CONTEXT: Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothelial dysfunction causes COPD is unknown. OBJECTIVE: Test associations of endothelial biomarkers with FEV1 using instrumental variables. METHODS: Among 26 907 participants with spirometry, ICAM-1, P-selectin, E-selectin and endothelin-1 were measured in subsets. RESULTS: ICAM-1 and P-selectin were inversely associated with FEV1 among European-Americans (-29 mL and -34 mL per standard deviation of log-transformed biomarker, p < 0.001), as was endothelin-1 among African-Americans (-22 mL, p = 0.008). Genetically-estimated ICAM-1 and P-selectin were not significantly associated with FEV1. The instrumental variable for endothelin-1 was non-informative. CONCLUSION: Although ICAM-1, P-selectin and endothelin-1 were inversely associated with FEV1, associations for ICAM-1 and P-selectin do not appear causal.

Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver--update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS.

Initially, a set of guidelines for the use of ultrasound contrast agents was published in 2004 dealing only with liver applications. A second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some non-liver applications. Time has moved on, and the need for international guidelines on the use of CEUS in the liver has become apparent. The present document describes the third iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS) using contrast specific imaging techniques. This joint WFUMB-EFSUMB initiative has implicated experts from major leading ultrasound societies worldwide. These liver CEUS guidelines are simultaneously published in the official journals of both organizing federations (i.e., Ultrasound in Medicine and Biology for WFUMB and Ultraschall in der Medizin/European Journal of Ultrasound for EFSUMB). These guidelines and recommendations provide general advice on the use of all currently clinically available ultrasound contrast agents (UCA). They are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis and improve the management of patients worldwide.

Subclinical atherosclerosis, airflow obstruction and emphysema: the MESA Lung Study.

Airflow obstruction is an independent risk factor for cardiovascular events in the general population. The affected vascular bed and contribution of emphysema to cardiovascular risk are unclear. We examined whether an obstructive pattern of spirometry and quantitatively defined emphysema were associated with subclinical atherosclerosis in the carotid, peripheral and coronary circulations. The Multi-Ethnic Study of Atherosclerosis recruited participants aged 45-84 yrs without clinical cardiovascular disease. Spirometry, carotid intima-media thickness (IMT), ankle-brachial index (ABI) and coronary artery calcium (CAC) were measured using standard protocols. Percentage of emphysema-like lung was measured in the lung windows of cardiac computed tomography scans among 3,642 participants. Multiple linear regression was used to adjust for cardiac risk factors, including C-reactive protein. Decrements in forced expiratory volume in 1 s (FEV(1)) and FEV(1)/forced vital capacity ratio were associated with greater internal carotid IMT, particularly among smokers (p=0.03 and p<0.001, respectively) whereas percentage emphysema was associated with reduced ABI regardless of smoking history (p=0.004). CAC was associated with neither lung function (prevalence ratio for the presence of CAC in severe airflow obstruction 0.99, 95% CI 0.91-1.07) nor percentage emphysema. An obstructive pattern of spirometry and emphysema were associated distinctly and independently with subclinical atherosclerosis in the carotid arteries and peripheral circulation, respectively, and were not independently related to CAC.

Pulmonary Arterial Pruning and Longitudinal Change in Percent Emphysema and Lung Function: The Genetic Epidemiology of COPD Study.

BACKGROUND: Pulmonary endothelial damage has been shown to precede the development of emphysema in animals, and vascular changes in humans have been observed in COPD and emphysema. RESEARCH QUESTION: Is intraparenchymal vascular pruning associated with longitudinal progression of emphysema on CT imaging or decline in lung function over 5 years? STUDY DESIGN AND METHODS: The Genetic Epidemiology of COPD Study enrolled ever smokers with and without COPD from 2008 through 2011. The percentage of emphysema-like lung, or "percent emphysema," was assessed at baseline and after 5 years on noncontrast CT imaging as the percentage of lung voxels < -950 Hounsfield units. An automated CT imaging-based tool assessed and classified intrapulmonary arteries and veins. Spirometry measures are postbronchodilator. Pulmonary arterial pruning was defined as a lower ratio of small artery volume (< 5 mm2 cross-sectional area) to total lung artery volume. Mixed linear models included demographics, anthropomorphics, smoking, and COPD, with emphysema models also adjusting for CT imaging scanner and lung function models adjusting for clinical center and baseline percent emphysema. RESULTS: At baseline, the 4,227 participants were 60 ± 9 years of age, 50% were women, 28% were Black, 47% were current smokers, and 41% had COPD. Median percent emphysema was 2.1 (interquartile range, 0.6-6.3) and progressed 0.24 percentage points/y (95% CI, 0.22-0.26 percentage points/y) over 5.6 years. Mean FEV1 to FVC ratio was 68.5 ± 14.2% and declined 0.26%/y (95% CI, -0.30 to -0.23%/y). Greater pulmonary arterial pruning was associated with more rapid progression of percent emphysema (0.11 percentage points/y per 1-SD increase in arterial pruning; 95% CI, 0.09-0.16 percentage points/y), including after adjusting for baseline percent emphysema and FEV1. Arterial pruning also was associated with a faster decline in FEV1 to FVC ratio (-0.04%/y per 1-SD increase in arterial pruning; 95% CI, -0.008 to -0.001%/y). INTERPRETATION: Pulmonary arterial pruning was associated with faster progression of percent emphysema and more rapid decline in FEV1 to FVC ratio over 5 years in ever smokers, suggesting that pulmonary vascular differences may be relevant in disease progression. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.

Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function.

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV1. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

Randomised aspirin assignment and risk of adult-onset asthma in the Women's Health Study.

BACKGROUND: Randomised data in men show a small but significant reduction in the risk of adult-onset asthma among those given aspirin. The results from an observational study in women suggest that frequent use of aspirin decreases the risk of adult-onset asthma, but randomised data in women are lacking. A study was undertaken to test the effect of 100 mg aspirin or placebo on alternate days on the risk of adult-onset asthma in the Women's Health Study. METHODS: A randomised, double-blind, placebo-controlled clinical trial of aspirin and vitamin E was performed in apparently healthy women with no indication or contraindication to aspirin therapy and no history of asthma at study entry. Female health professionals self-reported an asthma diagnosis on yearly questionnaires. RESULTS: Among 37 270 women with no reported history of asthma prior to randomisation and during 10 years of follow-up, there were 872 new cases diagnosed with asthma in the aspirin group and 963 in the placebo group (hazard ratio 0.90; 95% CI 0.82 to 0.99; p = 0.027). This apparent 10% lower relative risk of incident adult-onset asthma among those assigned to aspirin was significantly modified by body mass index, with no effect in women with a body mass index of >/=30 kg/m2. The effect of aspirin on adult-onset asthma was not significantly modified by age, smoking status, exercise levels, postmenopausal hormone use or randomised vitamin E assignment. CONCLUSIONS: In this large randomised clinical trial of apparently healthy adult women, administration of 100 mg aspirin on alternate days reduced the relative risk of a newly reported diagnosis of asthma.

Plasma hemostatic factors and endothelial markers in four racial/ethnic groups: the MESA study.

BACKGROUND: Hemostatic factors and endothelial markers may play some role in racial/ethnic differences in cardiovascular disease (CVD) rates. However, little information exists on hemostatic factors and endothelial markers across racial/ethnic groups. OBJECTIVES: To describe, in four American racial/ethnic groups (Caucasian, Black, Hispanic, and Chinese), mean levels of selected hemostatic factors and endothelial markers. PATIENTS AND METHODS: Multi-ethnic Study of Atherosclerosis baseline data were used (participant age: 45-84 years). Sex-specific analysis of covariance models, and t-tests for pairwise comparisons, were used to compare means of factors and markers. Adjustments were made for demographics and traditional CVD risk factors. Differences were significant at P < 0.05. RESULTS: Blacks had the highest levels of factor VIII, D-Dimer, plasmin-antiplasmin (PAP), and von Willebrand factor, among the highest levels of fibrinogen and E-selectin (women only), but among the lowest levels of intercellular adhesion molecule 1 (ICAM-1), and, in men, the lowest levels of plasminogen activator inhibitor-1 (PAI-1). Whites and Hispanics tended to have intermediate levels of factors and markers, although they had the highest levels of ICAM-1, and Hispanics had the highest mean levels of fibrinogen and E-selectin (women only). Chinese participants had among the highest levels of PAI-1, but the lowest, or among the lowest, of all other factors and markers. No soluble thrombomodulin differences were observed. CONCLUSIONS: In this large cohort, hemostatic factor and endothelial marker mean levels varied by race/ethnicity, even after adjustment for traditional CVD risk factors.

A controlled statistical study to assess measurement variability as a function of test object position and configuration for automated surveillance in a multicenter longitudinal COPD study (SPIROMICS).

PURPOSE: A test object (phantom) is an important tool to evaluate comparability and stability of CT scanners used in multicenter and longitudinal studies. However, there are many sources of error that can interfere with the test object-derived quantitative measurements. Here the authors investigated three major possible sources of operator error in the use of a test object employed to assess pulmonary density-related as well as airway-related metrics. METHODS: Two kinds of experiments were carried out to assess measurement variability caused by imperfect scanning status. The first one consisted of three experiments. A COPDGene test object was scanned using a dual source multidetector computed tomographic scanner (Siemens Somatom Flash) with the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) inspiration protocol (120 kV, 110 mAs, pitch = 1, slice thickness = 0.75 mm, slice spacing = 0.5 mm) to evaluate the effects of tilt angle, water bottle offset, and air bubble size. After analysis of these results, a guideline was reached in order to achieve more reliable results for this test object. Next the authors applied the above findings to 2272 test object scans collected over 4 years as part of the SPIROMICS study. The authors compared changes of the data consistency before and after excluding the scans that failed to pass the guideline. RESULTS: This study established the following limits for the test object: tilt index ≤0.3, water bottle offset limits of [-6.6 mm, 7.4 mm], and no air bubble within the water bottle, where tilt index is a measure incorporating two tilt angles around x- and y-axis. With 95% confidence, the density measurement variation for all five interested materials in the test object (acrylic, water, lung, inside air, and outside air) resulting from all three error sources can be limited to ±0.9 HU (summed in quadrature), when all the requirements are satisfied. The authors applied these criteria to 2272 SPIROMICS scans and demonstrated a significant reduction in measurement variation associated with the test object. CONCLUSIONS: Three operator errors were identified which significantly affected the usability of the acquired scan images of the test object used for monitoring scanner stability in a multicenter study. The authors' results demonstrated that at the time of test object scan receipt at a radiology core laboratory, quality control procedures should include an assessment of tilt index, water bottle offset, and air bubble size within the water bottle. Application of this methodology to 2272 SPIROMICS scans indicated that their findings were not limited to the scanner make and model used for the initial test but was generalizable to both Siemens and GE scanners which comprise the scanner types used within the SPIROMICS study.

Insight into Best Variables for COPD Case Identification: A Random Forests Analysis.

RATIONALE: This study is part of a larger, multi-method project to develop a questionnaire for identifying undiagnosed cases of chronic obstructive pulmonary disease (COPD) in primary care settings, with specific interest in the detection of patients with moderate to severe airway obstruction or risk of exacerbation. OBJECTIVES: To examine 3 existing datasets for insight into key features of COPD that could be useful in the identification of undiagnosed COPD. METHODS: Random forests analyses were applied to the following databases: COPD Foundation Peak Flow Study Cohort (N=5761), Burden of Obstructive Lung Disease (BOLD) Kentucky site (N=508), and COPDGene® (N=10,214). Four scenarios were examined to find the best, smallest sets of variables that distinguished cases and controls:(1) moderate to severe COPD (forced expiratory volume in 1 second [FEV1] <50% predicted) versus no COPD; (2) undiagnosed versus diagnosed COPD; (3) COPD with and without exacerbation history; and (4) clinically significant COPD (FEV1<60% predicted or history of acute exacerbation) versus all others. RESULTS: From 4 to 8 variables were able to differentiate cases from controls, with sensitivity ≥73 (range: 73-90) and specificity >68 (range: 68-93). Across scenarios, the best models included age, smoking status or history, symptoms (cough, wheeze, phlegm), general or breathing-related activity limitation, episodes of acute bronchitis, and/or missed work days and non-work activities due to breathing or health. CONCLUSIONS: Results provide insight into variables that should be considered during the development of candidate items for a new questionnaire to identify undiagnosed cases of clinically significant COPD.

Inhaled tiotropium for stable chronic obstructive pulmonary disease.

BACKGROUND: Tiotropium is a new anticholinergic therapy for chronic obstructive pulmonary disease (COPD) that differs from ipratropium by its functional relative selectivity for muscarinic receptor subtypes and which allows once-per-day dosing. OBJECTIVES: To determine the efficacy of tiotropium on clinical endpoints such exacerbations and hospitalisations, symptom scales and pulmonary function compared to placebo and other bronchodilators used for stable COPD. SEARCH STRATEGY: Randomised controlled trials (RCTs) were identified from the Cochrane Airways Review Group Specialised Register, a compilation of systematic searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL, and hand searching of 20 respiratory journals. Bibliographies from included studies and reviews were searched. The date of the last search was October 2004. SELECTION CRITERIA: Randomised clinical trials comparing tiotropium with placebo, ipratropium bromide, or long-acting ss2-agonists for greater than, or equal to, one month's duration. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data. Missing data were obtained from authors or the manufacturer of tiotropium. The data were analysed using the Cochrane Review Manager RevMan 4.2. Studies were pooled to yield weighted mean differences (WMD) or odds ratios (OR) and reported using 95% confidence intervals (CI). MAIN RESULTS: From 69 identified references, nine RCTs (6,584 patients) met inclusion criteria. Tiotropium reduced the odds of a COPD exacerbation (OR 0.74; 95% CI 0.66 to 0.83) and related hospitalisations (OR 0.64; 95% CI 0.51 to 0.82) compared to placebo or ipratropium. When applied to an annual baseline risk of 45% for exacerbations and 10% for hospitalisation, the number of patients needed to treat with tiotropium for one year were 14 (95% CI 11 to 22) to prevent one exacerbation and 30 (95% CI 22 to 61) to prevent one hospitalisation compared to placebo and ipratropium. Reductions in these endpoints compared to long-acting ss2-agonists were not statistically significant. Similar patterns were evident for quality-of-life and symptom scales. Increases in FEV1 and FVC from baseline were significantly larger with tiotropium than with placebo, ipratropium and long-acting ss2-agonists over 6 to 12 months. The decline in trough FEV1 from steady state was 30 ml (95% CI 7 to 53 ml) less with tiotropium than with placebo or ipratropium over one year; no data on decline in FEV1 from steady state were available for long-acting ss2-agonists. Dry mouth was increased by tiotropium. AUTHORS' CONCLUSIONS: Tiotropium reduced COPD exacerbations and related hospitalisations compared to placebo and ipratropium. It also improved health-related quality-of-life and symptom scores among patients with moderate and severe disease, and may have slowed decline in FEV1. Additional long-term studies are required to evaluate its effect on mortality and change in FEV1 to clarify its role in comparison to, or in combination with, long-acting ss2-agonists and to assess its effectiveness in mild and very severe COPD.

Identifying Patients with Undiagnosed COPD in Primary Care Settings: Insight from Screening Tools and Epidemiologic Studies.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, yet research suggests this disease is greatly underdiagnosed. This literature review sought to summarize the most common and significant variables associated with case-finding or missed cases of COPD to inform more effective and efficient detection of high-risk COPD patients in primary care. METHODS: PubMed and EMBASE were searched for articles describing case-finding and epidemiologic research to detect or characterize new cases of COPD. International studies in primary and non-primary care settings, published in English from 2002-2014, were eligible for inclusion. Studies related to risk factors for development of COPD were excluded. RESULTS: Of the 33 studies identified and reviewed, 21 were case-finding or screening and 12 were epidemiological, including cross-sectional, longitudinal, and retrospective designs. A range of variables were identified within and across studies. Variables common to both screening and epidemiological studies included age, smoking status, and respiratory symptoms. Seven significant predictors from epidemiologic studies did not appear in screening tools. No studies targeted discovery of higher risk patients such as those with reduced lung function or risks for exacerbations. CONCLUSION: Variables used to identify new cases of COPD or differentiate COPD cases and non-cases are wide- ranging, (from sociodemographic to self-reported health or health history variables), providing insight into important factors for case identification. Further research is underway to develop and test the best, smallest variable set that can be used as a screening tool to identify people with undiagnosed, high-risk COPD in primary care.

Nonadherence in tuberculosis treatment: predictors and consequences in New York City.

BACKGROUND: Poor adherence to antituberculosis treatment is the most important obstacle to tuberculosis control. PURPOSE: To identify and analyze predictors and consequences of nonadherence to antituberculosis treatment. PATIENTS AND METHODS: Retrospective study of a citywide cohort of 184 patients with tuberculosis in New York City, newly diagnosed by culture in April 1991-before the strengthening of its control program-and followed up through 1994. Follow-up information was collected through the New York City tuberculosis registry. Nonadherence was defined as treatment default for at least 2 months. RESULTS: Eighty-eight of the 184 (48%) patients were nonadherent. Greater nonadherence was noted among blacks (unadjusted relative risk [RR] 3.0, 95% confidence interval [CI] 1.1 to 8.6, compared with whites), injection drug users (RR 1.5, 95% CI 1.1 to 2.0), homeless (RR 1.4, 95% CI 1.0 to 1.8), alcoholics (RR 1.4, 95% CI 1.0 to 1.9), and HIV-infected patients (RR 1.4, 95% CI 1.1 to 1.9); also, census-derived estimates of household income were lower among nonadherent patients (P = 0.018). In multivariate analysis, only injection drug use and homelessness predicted nonadherence, yet 46 (39%) of 117 patients who were neither homeless nor drug users were nonadherent. Nonadherent patients took longer to convert to negative culture (254 versus 64 days, P < 0.001), were more likely to acquire drug resistance (RR 5.6, 95% CI 0.7 to 44.2), required longer treatment regimens (560 versus 324 days, P < 0.0001), and were less likely to complete treatment (RR 0.5, 95% CI 0.4 to 0.7). There was no association between treatment adherence and all-cause mortality. CONCLUSIONS: In the absence of public health intervention, half the patients defaulted treatment for 2 months or longer. Although common among the homeless and injection drug users, the problem occurred frequently and unpredictably in other patients. Nonadherence may contribute to the spread of tuberculosis and the emergence of drug resistance, and may increase the cost of treatment. These data lend support to directly observed therapy in tuberculosis.

Nursing interval and maternal responsivity: effect on early infant crying.

In industrialized societies, the unique pattern of crying in the first three months is "unexplained" but thought to be due to different biobehavioral factors from later crying behavior. To increase the range of the feeding and caretaking behaviors hypothesized to be relevant determinants of early crying, home observations and diary records were analyzed from samples of two subcultures of American middle-class women (La Leche League and "standard care" mothers; each n = 16) differing primarily in such practices. Both during and after the early crying stage, frequently fed infants cried or fretted less often (8.1 v 15.8 episodes per hour at 2 months of age; 10.7 v 16.6 episodes per hour at 4 months of age), and fewer of them exhibited rhythmic crying behavior (four v 11 at 2 months; eight v 13 at 4 months) during observations. However, only during the early crying period at 2 months were interval between feedings and maternal response latency shown to be independent determinants of cry/fret frequency (overall r2 = .35, P = .01), each factor accounting for approximately half of the explained individual variance. Furthermore, feeding interval was the only variable associated with rhythmic crying behavior at 2 months of age (r2 = .20;P = .01). In similar analyses at 4 months, there were no significant relationships with later crying or fretting. The results suggest that, in the presence of variation in feeding practice greater than that which is typical for our society, feeding interval may be a significant factor in early (but not later) crying behavior; furthermore, this effect is independent of and additive to the soothing effect of short response latency.

Increased carrying reduces infant crying: a randomized controlled trial.

The crying pattern of normal infants in industrialized societies is characterized by an overall increase until 6 weeks of age followed by a decline until 4 months of age with a preponderance of evening crying. We hypothesized that this "normal" crying could be reduced by supplemental carrying, that is, increased carrying throughout the day in addition to that which occurs during feeding and in response to crying. In a randomized controlled trial, 99 mother-infant pairs were assigned to an increased carrying or control group. At the time of peak crying (6 weeks of age), infants who received supplemental carrying cried and fussed 43% less (1.23 v 2.16 h/d) overall, and 51% less (0.63 v 1.28 hours) during the evening hours (4 PM to midnight). Similar but smaller decreases occurred at 4, 8, and 12 weeks of age. Decreased crying and fussing were associated with increased contentment and feeding frequency but no change in feeding duration or sleep. We conclude that supplemental carrying modifies "normal" crying by reducing the duration and altering the typical pattern of crying and fussing in the first 3 months of life. The relative lack of carrying in our society may predispose to crying and colic in normal infants.

Temperament and the psychobiology of childhood stress.

This paper provides a conceptual overview of recent research on the developmental psychobiology of childhood stress. We propose that the construct of temperament can be regarded as an organizing principle in children's responses to environmental adversity, and we review three physiologic "windows" through which such responses can be usefully examined. It is concluded that individual differences between children in their psychobiologic reactivity to stressors may constitute an important and novel point of departure for future studies of stress and childhood morbidity.

Crying and motor behavior of six-week-old infants and postpartum maternal mood.

OBJECTIVE: To determine whether prepartum and postpartum emotional distress in first-time mothers is associated with crying and fussing behavior and activity level in 6-week-old infants, after eliminating potential biases. DESIGN: Observational study examining predictive and concurrent associations between maternal emotions and infant behaviors. SETTING: General community. PARTICIPANTS: Expectant primiparas attending obstetricians' offices for routine prenatal care were recruited in the third trimester. Mothers and babies were required to be free of medical complications to complete the study. Of 113 mothers who enrolled, complete crying/fussing data were obtained in 88 dyads. Activity data were obtained in a designated subgroup of 50 infants. MEASUREMENTS: Mothers completed a self-report scale of emotional distress, the 28-item General Health Questionnaire, at 34 weeks of gestation and at 6 weeks postpartum. Crying/fussing data were obtained using a previously validated parent diary of infant behavior during the sixth week of life. Motor activity was measured objectively in the home setting with actometers. RESULTS: Third-trimester distress was not related to either infant crying/fussing or activity. Postpartum distress was significantly related to crying/fussing duration and bout frequency (r[88] = .45 and .28, respectively; both P < .01). These relations were not diminished after controlling statistically for background and/or potential mediating variables, nor could they be accounted for by different diary-recording styles in the mothers. Postpartum distress was not, however, related to activity level (r[50] = -.09; not significant). Furthermore, the pattern of maternal distress was associated differentially with crying levels. Distress levels increased from prepartum to postpartum among mothers of infants who met predefined clinical criteria for "colic," while decreasing in the others ("colic" status x period interaction: F(1,86) = 8.2; P < .01). Also, infant crying varied among four groups of mothers who differed according to presence and timing of clinically significant emotional disturbance (one-way analysis of variance, F (3,86) = 9.4; P < .001). Infants of mothers who became significantly distressed postpartum ("reactive") cried more than those in the other groups, even mothers who had been distressed both prepartum and postpartum ("depressed") (3.7 vs 2.7 h/d; P = .05, post hoc Tukey). CONCLUSIONS: Maternal emotional distress and infant crying behavior are associated in the postpartum period independent of reporting or referral biases. Clinically significant levels of crying (or "colic") are differentially associated with different patterns of clinically significant maternal distress. Reported concern about either maternal mood or infant crying behavior should be taken seriously as a possible indicator of a stressed mother-infant relationship.

Mucosal function and breath hydrogen excretion: comparative studies in the clinical evaluation of children with nonspecific abdominal complaints.

To evaluate the role of the lactose breath hydrogen test for the detection of lactose malabsorption in children with chronic nonspecific abdominal complaints, breath hydrogen excretion was measured in 131 children with recurrent abdominal pain (n = 75) or chronic nonspecific diarrhea (n = 56) following a lactose load (2 gm/kg; maximum 50 gm). The data were compared to those obtained from lactose tolerance tests (n = 113) and symptom response following a lactose load (n = 109) performed simultaneously with the lactose breath hydrogen test, and with results from small bowel biopsies obtained in 31 children to determine dissacharidase activity and mucosal histology. The results indicate that an increase in breath hydrogen of greater than 10 ppm above base line values (delta ppm) by 120 minutes ("early increase" response) completely discriminates between biopsy-proven isolated lactase-insufficient and lactase-sufficient children. A similar increase after 120 minutes ("late increase" response) is consistent both with normal mucosal function and partial lactase insufficiency due to mucosal injury. Breath hydrogen responses predicted assayed lactase activity in all patients with isolated lactase insufficiency, but were "falsely negative" in four of ten children whose lactase insufficiency was secondary to mucosal injury. In both clinical groups, lactose malabsorbers report significantly more symptoms than absorbers (P less than .001), but neither symptom reports nor tolerance tests are accurate methods for distinguishing lactose malabsorbers from absorbers. Although the lactose breath hydrogen test provides objective documentation of lactose malabsorption, it is equally predictive of assayed lactase activity in all clinical groups.

Supplementary carrying compared with advice to increase responsive parenting as interventions to prevent persistent infant crying.

OBJECTIVE: To compare two interventions (supplementary carrying, increased parental responsiveness) introduced from birth for their effectiveness in reducing the amounts of crying in general community infants at 2, 6, and 12 weeks age. DESIGN AND PARTICIPANTS: Mothers and infants in newborn wards of maternity hospitals were assigned to carrying intervention, responsiveness intervention, or control groups. Follow-up measures were used to confirm that the interventions were implemented and to determine their effects on infant crying. SETTING AND MEASUREMENTS: Diary measurements completed in the home were employed to measure the aspects of parental behavior targeted by the interventions. Audio recordings, diaries, and questionnaires assessed the amounts the infants cried and the impact of the crying on their mothers and the health services. Sample sizes at 6 weeks of age were 59 (carrying intervention), 57 (responsiveness intervention), and 94 infants (control group). RESULTS: The carrying intervention successfully increased the amounts the infants were carried, particularly while settled, to the target levels. The responsiveness intervention led to more limited increases in carrying and to a modest increase in feeding frequency, but did not affect measures of parental interactiveness and play. No differences in amounts of crying and fussing were found between the three groups of infants on any of the measures. Subsidiary analyses confirmed that the dependent variable (infant fuss/crying) and main independent variable (carrying while settled) were not significantly correlated. CONCLUSION: It is not, at present, possible to recommend either supplementary carrying or increased parental responsiveness as primary, preventative interventions to reduce infant crying.