Combination protein biomarkers predict multiple sclerosis diagnosis and outcomes.

Establishing biomarkers to predict multiple sclerosis diagnosis and prognosis has been challenging using a single biomarker approach. We hypothesised that a combination of biomarkers would increase the accuracy of prediction models to differentiate multiple sclerosis from other neurological disorders and enhance prognostication for people with multiple sclerosis. We measured 24 fluid biomarkers in the blood and cerebrospinal fluid of 77 people with multiple sclerosis and 80 people with other neurological disorders, using ELISA or Single Molecule Array assays. Primary outcomes were multiple sclerosis versus any other diagnosis, time to first relapse, and time to disability milestone (Expanded Disability Status Scale 6), adjusted for age and sex. Multivariate prediction models were calculated using the area under the curve value for diagnostic prediction, and concordance statistics (the percentage of each pair of events that are correctly ordered in time for each of the Cox regression models) for prognostic predictions. Predictions using combinations of biomarkers were considerably better than single biomarker predictions. The combination of cerebrospinal fluid [chitinase-3-like-1 + TNF-receptor-1 + CD27] and serum [osteopontin + MCP-1] had an area under the curve of 0.97 for diagnosis of multiple sclerosis, compared to the best discriminative single marker in blood (osteopontin: area under the curve 0.84) and in cerebrospinal fluid (chitinase-3-like-1 area under the curve 0.84). Prediction for time to next relapse was optimal with a combination of cerebrospinal fluid[vitamin D binding protein + Factor I + C1inhibitor] + serum[Factor B + Interleukin-4 + C1inhibitor] (concordance 0.80), and time to Expanded Disability Status Scale 6 with cerebrospinal fluid [C9 + Neurofilament-light] + serum[chitinase-3-like-1 + CCL27 + vitamin D binding protein + C1inhibitor] (concordance 0.98). A combination of fluid biomarkers has a higher accuracy to differentiate multiple sclerosis from other neurological disorders and significantly improved the prediction of the development of sustained disability in multiple sclerosis. Serum models rivalled those of cerebrospinal fluid, holding promise for a non-invasive approach. The utility of our biomarker models can only be established by robust validation in different and varied cohorts.

Image Phenotyping of Preterm-Born Children Using Hyperpolarized 129Xe Lung Magnetic Resonance Imaging and Multiple-Breath Washout.

Rationale: Preterm birth is associated with low lung function in childhood, but little is known about the lung microstructure in childhood. Objectives: We assessed the differential associations between the historical diagnosis of bronchopulmonary dysplasia (BPD) and current lung function phenotypes on lung ventilation and microstructure in preterm-born children using hyperpolarized 129Xe ventilation and diffusion-weighted magnetic resonance imaging (MRI) and multiple-breath washout (MBW). Methods: Data were available from 63 children (aged 9-13 yr), including 44 born preterm (⩽34 weeks' gestation) and 19 term-born control subjects (⩾37 weeks' gestation). Preterm-born children were classified, using spirometry, as prematurity-associated obstructive lung disease (POLD; FEV1 < lower limit of normal [LLN] and FEV1/FVC < LLN), prematurity-associated preserved ratio of impaired spirometry (FEV1 < LLN and FEV1/FVC ⩾ LLN), preterm-(FEV1 ⩾ LLN) and term-born control subjects, and those with and without BPD. Ventilation heterogeneity metrics were derived from 129Xe ventilation MRI and SF6 MBW. Alveolar microstructural dimensions were derived from 129Xe diffusion-weighted MRI. Measurements and Main Results: 129Xe ventilation defect percentage and ventilation heterogeneity index were significantly increased in preterm-born children with POLD. In contrast, mean 129Xe apparent diffusion coefficient, 129Xe apparent diffusion coefficient interquartile range, and 129Xe mean alveolar dimension interquartile range were significantly increased in preterm-born children with BPD, suggesting changes of alveolar dimensions. MBW metrics were all significantly increased in the POLD group compared with preterm- and term-born control subjects. Linear regression confirmed the differential effects of obstructive disease on ventilation defects and BPD on lung microstructure. Conclusion: We show that ventilation abnormalities are associated with POLD, and BPD in infancy is associated with abnormal lung microstructure.

Genomic Insights Into the Mechanism of Carbapenem Resistance Dissemination in Enterobacterales From a Tertiary Public Heath Setting in South Asia.

SUMMARY: 10.6% patients were CRE positive. Only 27% patients were prescribed at least 1 antibiotic to which infecting pathogen was susceptible. Burn and ICU admission and antibiotics exposures facilitate CRE acquisition. Escherichia coli ST167 was the dominant CRE clone. BACKGROUND: Given the high prevalence of multidrug resistance (MDR) across South Asian (SA) hospitals, we documented the epidemiology of carbapenem-resistant Enterobacterales (CRE) infections at Dhaka Medical College Hospital between October 2016 and September 2017. METHODS: We enrolled patients and collected epidemiology and outcome data. All Enterobacterales were characterized phenotypically and by whole-genome sequencing. Risk assessment for the patients with CRE was performed compared with patients with carbapenem-susceptible Enterobacterales (CSE). RESULTS: 10.6% of all 1831 patients with a clinical specimen collected had CRE. In-hospital 30-day mortality was significantly higher with CRE [50/180 (27.8%)] than CSE [42/312 (13.5%)] (P = .001); however, for bloodstream infections, this was nonsignificant. Of 643 Enterobacterales isolated, 210 were CRE; blaNDM was present in 180 isolates, blaOXA-232 in 26, blaOXA-181 in 24, and blaKPC-2 in 5. Despite this, ceftriaxone was the most commonly prescribed empirical antibiotic and only 27% of patients were prescribed at least 1 antibiotic to which their infecting pathogen was susceptible. Significant risk factors for CRE isolation included burns unit and intensive care unit admission, and prior exposure to levofloxacin, amikacin, clindamycin, and meropenem. Escherichia coli ST167 was the dominant CRE clone. Clustering suggested clonal transmission of Klebsiella pneumoniae ST15 and the MDR hypervirulent clone, ST23. The major trajectories involved in horizontal gene transfer were IncFII and IncX3, IS26, and Tn3. CONCLUSIONS: This is the largest study from an SA public hospital combining outcome, microbiology, and genomics. The findings indicate the urgent implementation of targeted diagnostics, appropriate antibiotic use, and infection-control interventions in SA public institutions.

Characterising airway obstructive, dysanaptic and PRISm phenotypes of prematurity-associated lung disease.

INTRODUCTION: Although obstructive airway disease has been shown to be associated with prematurity, other spirometry phenotypes are less well described. OBJECTIVES: We characterised abnormal spirometry phenotypes in preterm-born children, including prematurity-associated obstructive lung disease (POLD, forced expiratory volume in 1 s (FEV1)

Association of Gestation and Fetal Growth Restriction on Cardiovascular Health in Preterm-Born Children.

OBJECTIVES: To prospectively evaluate the associations of early and current life factors, including gestational age and fetal growth restriction in preterm-born subjects, on cardiovascular health including measures of central and peripheral blood pressure and arterial stiffness and assess cardiovascular changes before and after acute exercise in preterm- and term-born school-aged children. STUDY DESIGN: From 240 children, aged 7-12 years, 204 (141 preterm-born and 63 term-born) had satisfactory data. An oscillometric device recorded cardiovascular measures before and after cycle ergometer exercise testing. Data were analyzed with multivariable linear regression and mediation. RESULTS: Central systolic blood pressure (SBP) was 6.4 mmHg (95% CI, 1.2, 11.6) higher in preterm-born children with fetal growth restriction and 3.4 mmHg (0.02, 6.8) higher in those without fetal growth restriction when compared with term controls. Augmentation index was 4.1% (0.7, 7.4) higher in the preterm fetal growth restriction group when compared with those without fetal growth restriction but was similar between the latter group and term controls. Regression modelling showed gestational age, female sex, and antenatal smoking, but not fetal growth restriction, were significantly associated with SBP. In contrast, fetal growth restriction and fat mass index, but not gestation, were significantly associated with augmentation index. Cardiovascular exercise responses were similar between all 3 groups studied. CONCLUSIONS: Our data show the differential associations of prematurity and fetal growth restriction on central SBP and augmentation index. Cardiovascular responses to exercise were similar in all 3 groups. Preterm-born children with and without fetal growth restriction are at an increased risk of cardiovascular disease in adult life. TRIAL REGISTRATION: URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-003712-20/GB: RHiNO, EudraCT: 2015-003712-20.

Characterizing the urinary proteome of prematurity-associated lung disease in school-aged children.

INTRODUCTION: Although different phenotypes of lung disease after preterm birth have recently been described, the underlying mechanisms associated with each phenotype are poorly understood. We, therefore, compared the urinary proteome for different spirometry phenotypes in preterm-born children with preterm- and term-born controls. METHODS: Preterm and term-born children aged 7-12 years, from the Respiratory Health Outcomes in Neonates (RHiNO) cohort, underwent spirometry and urine collection. Urine was analysed by Nano-LC Mass-Spectrometry with Tandem-Mass Tag labelling. The preterm-born children were classified into phenotypes of prematurity-associated preserved ratio impaired spirometry (pPRISm, FEV1 < lower limit of normal (LLN), FEV1/FVC ≥ LLN), prematurity-associated obstructive lung disease (POLD, FEV1 < LLN, FEV1/FVC < LLN) and preterm controls (FEV1 ≥ LLN,). Biological relationships between significantly altered protein abundances were analysed using Ingenuity Pathways Analysis software, and receiver operator characteristic curves were calculated. RESULTS: Urine was analysed from 160 preterm-born children and 44 term controls. 27 and 21 were classified into the pPRISm and POLD groups, respectively. A total of 785 proteins were detected. Compared to preterm-born controls, sixteen significantly altered proteins in the pPRISm group were linked to six biological processes related to upregulation of inflammation and T-cell biology. In contrast, four significantly altered proteins in the POLD group were linked with neutrophil accumulation. Four proteins (DNASE1, PGLYRP1, B2M, SERPINA3) in combination had an area under the curve of 0.73 for pPRISm and three combined proteins (S100A8, MMP9 and CTSC) had AUC of 0.76 for POLD. CONCLUSIONS: In this exploratory study, we demonstrate differential associations of the urinary proteome with pPRISm and POLD. TRIAL REGISTRATION: EudraCT: 2015-003712-20.

Association of early-life factors with prematurity-associated lung disease: prospective cohort study.

BACKGROUND: Although bronchopulmonary dysplasia (BPD) is associated with lung function deficits in childhood, many who develop BPD have normal lung function in childhood and many without BPD, including those born at 33-34 weeks of gestation, have lung dysfunction in childhood. Since the predictability of BPD for future lung deficits is increasingly doubted, we prospectively recruited preterm-born children to identify early-life factors associated with lung function deficits after preterm birth. METHODS: From 767 children aged 7-12 years who had their respiratory symptoms assessed, and had spirometry before and after a bronchodilator in our Respiratory Health Outcomes in Neonates (RHiNO) study, 739 (544 preterm-born at ≤34 weeks of gestation and 195 term-born) had satisfactory lung function. Data were analysed using multivariable logistic regression and mediation. RESULTS: When preterm-born children were classified according to their lung function, low lung function (prematurity-associated lung disease (PLD)) was associated with BPD, gestation and intra-uterine growth restriction (IUGR) on univariable logistic regression analyses. However, on multivariable logistic regression analyses, gestation (ß= -0.153, se 0.051; p=0.003) and IUGR (OR 1.783, 95% CI 1.06-3.00; p=0.029) remained significantly associated with later deficits of lung function, but BPD (OR 0.99, 95% CI 0.52-1.89; p=0.974) did not. Mediation analyses confirmed these results. CONCLUSIONS: Although traditionally BPD has been associated with low lung function in later life, the data show that gestation and IUGR are significantly associated with PLD in childhood, but BPD is not. By identifying children with PLD, we can better understand the underlying mechanisms and develop optimal therapies.

Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity.

Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease with high mortality and limited treatment options. How blood lipids regulate AAA development is unknown. Here lipidomics and genetic models demonstrate a central role for procoagulant enzymatically oxidized phospholipids (eoxPL) in regulating AAA. Specifically, through activating coagulation, eoxPL either promoted or inhibited AAA depending on tissue localization. Ang II administration to ApoE-/- mice increased intravascular coagulation during AAA development. Lipidomics revealed large numbers of eoxPL formed within mouse and human AAA lesions. Deletion of eoxPL-generating enzymes (Alox12 or Alox15) or administration of the factor Xa inhibitor rivaroxaban significantly reduced AAA. Alox-deficient mice displayed constitutively dysregulated hemostasis, including a consumptive coagulopathy, characterized by compensatory increase in prothrombotic aminophospholipids (aPL) in circulating cell membranes. Intravenously administered procoagulant PL caused clotting factor activation and depletion, induced a bleeding defect, and significantly reduced AAA development. These data suggest that Alox deletion reduces AAA through diverting coagulation away from the vessel wall due to eoxPL deficiency, instead activating clotting factor consumption and depletion in the circulation. In mouse whole blood, ∼44 eoxPL molecular species formed within minutes of clot initiation. These were significantly elevated with ApoE-/- deletion, and many were absent in Alox-/- mice, identifying specific eoxPL that modulate AAA. Correlation networks demonstrated eoxPL belonged to subfamilies defined by oxylipin composition. Thus, procoagulant PL regulate AAA development through complex interactions with clotting factors. Modulation of the delicate balance between bleeding and thrombosis within either the vessel wall or circulation was revealed that can either drive or prevent disease development.

Differential association of air pollution exposure with neonatal and postneonatal mortality in England and Wales: A cohort study.

BACKGROUND: Many but not all studies suggest an association between air pollution exposure and infant mortality. We sought to investigate whether pollution exposure is differentially associated with all-cause neonatal or postneonatal mortality, or specific causes of infant mortality. METHODS AND FINDINGS: We separately investigated the associations of exposure to particulate matter with aerodynamic diameter ≤ 10 µm (PM10), nitrogen dioxide (NO2), and sulphur dioxide (SO2) with all-cause infant, neonatal, and postneonatal mortality, and with specific causes of infant deaths in 7,984,366 live births between 2001 and 2012 in England and Wales. Overall, 51.3% of the live births were male, and there were 36,485 infant deaths (25,110 neonatal deaths and 11,375 postneonatal deaths). We adjusted for the following major confounders: deprivation, birthweight, maternal age, sex, and multiple birth. Adjusted odds ratios (95% CI; p-value) for infant deaths were significantly increased for NO2, PM10, and SO2 (1.066 [1.027, 1.107; p = 0.001], 1.044 [1.007, 1.082; p = 0.017], and 1.190 [1.146, 1.235; p < 0.001], respectively) when highest and lowest pollutant quintiles were compared; however, neonatal mortality was significantly associated with SO2 (1.207 [1.154, 1.262; p < 0.001]) but not significantly associated with NO2 and PM10 (1.044 [0.998, 1.092; p = 0.059] and 1.008 [0.966, 1.052; p = 0.702], respectively). Postneonatal mortality was significantly associated with all pollutants: NO2, 1.108 (1.038, 1.182; p < 0.001); PM10, 1.117 (1.050, 1.188; p < 0.001); and SO2, 1.147 (1.076, 1.224; p < 0.001). Whilst all were similarly associated with endocrine causes of infant deaths (NO2, 2.167 [1.539, 3.052; p < 0.001]; PM10, 1.433 [1.066, 1.926; p = 0.017]; and SO2, 1.558 [1.147, 2.116; p = 0.005]), they were differentially associated with other specific causes: NO2 and PM10 were associated with an increase in infant deaths from congenital malformations of the nervous (NO2, 1.525 [1.179, 1.974; p = 0.001]; PM10, 1.457 [1.150, 1.846; p = 0.002]) and gastrointestinal systems (NO2, 1.214 [1.006, 1.466; p = 0.043]; PM10, 1.312 [1.096, 1.571; p = 0.003]), and NO2 was also associated with deaths from malformations of the respiratory system (1.306 [1.019, 1.675; p = 0.035]). In contrast, SO2 was associated with an increase in infant deaths from perinatal causes (1.214 [1.156, 1.275; p < 0.001]) and from malformations of the circulatory system (1.172 [1.011, 1.358; p = 0.035]). A limitation of this study was that we were not able to study associations of air pollution exposure and infant mortality during the different trimesters of pregnancy. In addition, we were not able to control for all confounding factors such as maternal smoking. CONCLUSIONS: In this study, we found that NO2, PM10, and SO2 were differentially associated with all-cause mortality and with specific causes of infant, neonatal, and postneonatal mortality.

Outbreak of Hypervirulent Multidrug-resistant Klebsiella variicola Causing High Mortality in Neonates in Bangladesh.

We report a clonal outbreak of multidrug-resistant (MDR) Klebsiella variicola (sequence type [ST] 771) in a Bangladeshi neonatal unit from October 2016 to January 2017, associated with high mortality (54.5%). During the outbreak, K. variicola ST771 acquired an MDR plasmid harboring blaNDM-1, linked to high exposure to ceftriaxone and amikacin.

Comparison of the Associations of Early-Life Factors on Wheezing Phenotypes in Preterm-Born Children and Term-Born Children.

Although respiratory symptoms, including wheezing, are common in preterm-born subjects, the natural history of the wheezing phenotypes and the influence of early-life factors and characteristics on phenotypes are unclear. Participants from the Millennium Cohort Study who were born between 2000 and 2002 were studied at 9 months and at 3, 5, 7, and 11 years. We used data-driven methods to define wheezing phenotypes in preterm-born children and investigated whether the association of early-life factors and characteristics with wheezing phenotypes was similar between preterm- and term-born children. A total of 1,049/1,502 (70%) preterm-born children and 12,307/17,063 (72%) term-born children had recent wheeze data for 3 or 4 time points. Recent wheeze was more common at all time points in the preterm-born group than in term-born group. Four wheezing phenotypes were defined for both groups: no/infrequent, early, persistent, and late. Early-life factors and characteristics, especially antenatal maternal smoking, atopy, and male sex, were associated with increased rates for all phenotypes in both groups, and breastfeeding was protective in both groups, except late wheeze in the preterm group. Preterm-born children had similar phenotypes to term-born children. Although early-life factors and characteristics were similarly associated with the wheezing phenotypes in both groups, the preterm-born group had higher rates of early and persistent wheeze. However, a large proportion of preterm-born children had early wheeze that resolved with time.

All-Cause Mortality of Low Birthweight Infants in Infancy, Childhood, and Adolescence: Population Study of England and Wales.

BACKGROUND: Low birthweight (LBW) is associated with increased mortality in infancy, but its association with mortality in later childhood and adolescence is less clear. We investigated the association between birthweight and all-cause mortality and identified major causes of mortality for different birthweight groups. METHODS AND FINDINGS: We conducted a population study of all live births occurring in England and Wales between 1 January 1993 and 31 December 2011. Following exclusions, the 12,355,251 live births were classified by birthweight: 500-1,499 g (very LBW [VLBW], n = 139,608), 1,500-2,499 g (LBW, n = 759,283), 2,500-3,499 g (n = 6,511,411), and ≥3,500 g (n = 4,944,949). The association of birthweight group with mortality in infancy (<1 y of age) and childhood/adolescence (1-18 y of age) was quantified, with and without covariates, through hazard ratios using Cox regression. International Classification of Diseases codes identified causes of death. In all, 74,890 (0.61%) individuals died between birth and 18 y of age, with 23% of deaths occurring after infancy. Adjusted hazard ratios for infant deaths were 145 (95% CI 141, 149) and 9.8 (95% CI 9.5, 10.1) for the VLBW and LBW groups, respectively, compared to the ≥3,500 g group. The respective hazard ratios for death occurring at age 1-18 y were 6.6 (95% CI 6.1, 7.1) and 2.9 (95% CI 2.8, 3.1). Male gender, the youngest and oldest maternal age bands, multiple births, and deprivation (Index of Multiple Deprivation score) also contributed to increased deaths in the VLBW and LBW groups in both age ranges. In infancy, perinatal factors, particularly respiratory issues and infections, explained 84% and 31% of deaths in the VLBW and LBW groups, respectively; congenital malformations explained 36% and 23% in the LBW group and ≥2,500 g groups (2,500-3,499 g and ≥3,500 g groups combined), respectively. Central nervous system conditions explained 20% of deaths in childhood/adolescence in the VLBW group, with deaths from neoplasms and external conditions increasingly prevalent in the 1,500-2,499 g and ≥2,500 g birthweight groups. The study would have benefited had we had access to information on gestational age and maternal smoking, but since the former is highly correlated with birthweight and the latter with deprivation, we believe that our findings remain robust despite these shortcomings. CONCLUSIONS: LBW is associated with infant and later child and adolescent mortality, with perinatal factors and congenital malformations explaining many of the deaths. By understanding and ameliorating the influences of upstream exposures such as maternal smoking and deprivation, later mortality can be decreased by reducing the delivery of vulnerable infants with LBW.

Early-term birth is a risk factor for wheezing in childhood: A cross-sectional population study.

BACKGROUND: Early term-born (37-38 weeks' gestation) infants have increased respiratory morbidity during the neonatal period compared with full term-born (39-42 weeks' gestation) infants, but longer-term respiratory morbidity remains unclear. OBJECTIVE: We assessed whether early term-born children have greater respiratory symptoms and health care use in childhood compared with full term-born children. METHODS: We surveyed 1- to 10-year-old term-born children (n = 13,361). Questionnaires assessed respiratory outcomes with additional data gathered from national health databases. RESULTS: Of 2,845 eligible participants, 545 were early term-born and 2,300 were full term-born. Early term-born children had higher rates of admission to the neonatal unit (odds ratio [OR], 1.7; 95% CI, 1.2-2.5) and admission to the hospital during their first year of life (OR, 1.6; 95% CI, 1.2-2.1). Forty-eight percent of early term-born children less than 5 years old reported wheeze ever compared with 39% of full term-born children (OR, 1.5; 95% CI, 1.1-1.9), and 26% versus 17% reported recent wheezing (OR, 1.7; 95% CI, 1.3-2.4). Early term-born children older than 5 years reported higher rates of wheeze ever (OR, 1.4; 95% CI, 1.05-1.8) and recent wheezing over the last 12 months than full-term control subjects (OR, 1.4; 95% CI, 1.02-2.0). Increased rates of respiratory symptoms in early term-born children persisted when family history of atopy and delivery by means of cesarean sections were included in logistic regression models. CONCLUSION: Early term-born children had significantly increased respiratory morbidity and use of health care services when compared with full term-born children, even when stratified by mode of delivery and family history of atopy.

The effect of birth weight on lung spirometry in white, school-aged children and adolescents born at term: a longitudinal population based observational cohort study.

OBJECTIVE: To evaluate how birth weight affects lung function measurements in childhood and adolescence in term-born children. STUDY DESIGN: We used data for white, term-born, singletons, from the Avon Longitudinal Study of Parents and Children to determine the association between birth weight and lung function at age 8-9 (n=4086) and 14-17 (n=2582) years. z-scores for lung function measures, adjusted for sex, height, and age, were modeled in terms of birth weight z-score adjusted for sex. In addition, gestation and head circumference then confounders (maternal smoking during pregnancy and social class) were added to the model. RESULTS: At age 8-9 years, birth weight z-scores were significantly associated with lung function z-scores (forced expiratory volume in 1 second, forced vital capacity [FVC], and forced mid-expiratory flow between 25% and 75% of FVC). These relationships essentially were unchanged when birth weight z-scores were further adjusted for gestation, head circumference, and confounders, except for forced mid-expiratory flow between 25% and 75% of FVC, which was no longer significant after we adjusted for head circumference and confounders. At age 14-17 years, the associations between adjusted birth-weight z-scores and spirometry z-scores were in general not significant. Estimated differences for forced expiratory volume in 1 second were 30 mL at ages 8-9 years and 33 mL at 14-17 years for 1 kg change in birth-weight standardized for gestation and sex. CONCLUSIONS: Birth weight is associated with lung function in term-born children at 8-9 years, but less so at 14-17 years, suggesting that birth weight influences lung function in early childhood but has lesser effect later in life.

Physical activity in school-age children born preterm.

OBJECTIVES: To compare objectively measured physical activity in 11- and 15-year-old children who were born preterm with term-born controls and related physical activity measures to lung function measures. STUDY DESIGN: We used data from the Avon Longitudinal Study of Parents and Children. We compared total physical activity, moderate-to-vigorous physical activity, and sedentary behavior between children born at 25-32, 33-34, 35-36, and 37-43 weeks' gestation at ages 11 and 15 years. At age 11 years, physical activity measures were correlated with lung spirometry recorded at age 7-9 years. RESULTS: Valid physical activity data at age 11 years were available for 5025, 197, 57, and 48 children born at 37-43, 35-36, 33-34, and 25-32 weeks' gestation, respectively. At age 15 years, valid physical activity data were available for 1829, 62, 32, and 24 children born at 37-43, 35-36, 33-34, and 25-32 weeks' gestation. Boys were more physically active than girls at both ages. There were no differences in total physical activity, moderate-to-vigorous physical activity, or sedentary behavior in children between the different gestation groups. Physical activity at age 11 years did not correlate with spirometry measures at age 7-9 years. CONCLUSIONS: Physical activity was similar for the different gestational groups and did not correlate with lung spirometry. Physical activity does not appear to be limited in preterm-born children despite lung function deficits noted in childhood.

Perinatal outcomes and travel time from home to hospital: Welsh data from 1995 to 2009.

AIM: To study the association between travel time from home to hospital and birth outcomes. METHODS: For all registrable births to women resident in Wales (1995-2009), we calculated the travel time between the mother's residence and the postcode-based location for both the birth hospital and all hospitals with maternity services that were open. Using logistic regression, we obtained odds ratios for the association between travel time and each birth outcome, adjusted for confounders. RESULTS: In our analysis of 412 827 singleton births, for every 15-min increase in travel time to the birth hospital, there was an increased risk of early (n = 609; OR: 1.13; 95%CI: 1.07, 1.20) and late neonatal death (n = 251; OR: 1.15; 95%CI: 1.05, 1.26). Results for intrapartum stillbirth were inconclusive (n = 135; OR: 1.13; 95%CI: 0.98, 1.30). For the above-combined (n = 995) results, we get OR: 1.15, 95%CI: 1.09, 1.20. No association was found with travel time to the nearest hospital (OR: 1.01; 95%CI: 0.90, 1.13 per 15-min increase in travel time) for the composite outcome of intrapartum stillbirth and neonatal deaths. CONCLUSION: Longer travel time to the birth hospital was associated with increased risk of neonatal deaths, but there was no strong evidence of association with the geographical location of maternity services.

The incidence, clinical features, and management of essential infantile esotropia in the United Kingdom. A British Ophthalmology Surveillance Unit (BOSU) study.

BACKGROUND/OBJECTIVES: A national study was undertaken through the British ophthalmology surveillance unit (BOSU) to determine the incidence, presenting features and management of essential infantile esotropia (EIE) in the UK. METHODS: Data from a prospective national observational study of newly diagnosed EIE presenting to clinicians in the United Kingdom over a 12-month period were collected. Cases with a confirmed diagnosis by a clinician of a constant, non-accommodative esotropia ≥20 prism dioptres (PD), presenting at ≤12 months, with no neurological or ocular abnormalities were identified through BOSU. Follow-up data were collected at 12 months. RESULTS: A total of 57 cases were reported giving an incidence of EIE of 1 in 12,828 live births. The mean age of diagnosis and intervention were 7.05 ± 2.6 months (range 2-12) and 14.7 ± 4.9 months (range 6.5-28.1), respectively. Management was surgical in 59.6%, botulinum toxin alone in 22.8%, and 17.5% were observed. The preoperative angle of esotropia was smaller in the observation group (P = 0.04). The postoperative angle of esotropia was not statistically significant between botulinum toxin or surgery (P = 0.3), although the age of intervention was earlier in the botulinum group (P = 0.007). Early intervention (before 12 months of age) did not influence the post-intervention motor outcomes between 0 and 10 prism dioptres of esotropia (P = 0.78). CONCLUSIONS: The incidence of EIE in the UK is considerably lower than reported in other population-based studies. The preferred method of treatment was surgical with earlier intervention in those treated with botulinum toxin. An early age of intervention (<12 months) did not influence motor outcomes.

Similarities of metabolomic disturbances in prematurity-associated obstructive lung disease to chronic obstructive pulmonary disease.

Prematurity-associated lung disease (PLD) is a long-term consequence of preterm-birth. Since the underlying mechanisms of PLD remain poorly characterised, we compared the urinary metabolome between recently described spirometry phenotypes of PLD. Preterm- and term-born children aged 7-12 years, from the Respiratory Health Outcomes in Neonates (RHiNO) cohort, underwent spirometry and urine collection. The urinary metabolome was analysed by gas chromatography time-of-flight mass spectrometry. Preterm-born children were classified into phenotypes of prematurity-associated obstructive lung disease (POLD, Forced expiratory volume in 1 s (FEV1) < lower limit of normal (LLN), FEV1/Forced Vital Capacity (FVC) < LLN), prematurity-associated preserved ratio impaired spirometry (pPRISm, FEV1 < LLN, FEV1/FVC ≥ LLN) and Preterm/Term controls (FEV1 ≥ LLN). Metabolite set enrichment analysis was used to link significantly altered metabolites between the groups with metabolic pathways. Univariable and multivariable linear regression models examined associations between early and current life factors and significantly altered metabolites of interest. Urine from 197 preterm- and 94 term-born children was analysed. 23 and 25 were classified into POLD and pPRISm groups respectively. Of 242 identified metabolites, 49 metabolites were significantly altered in the POLD group compared with Preterm controls. Decreased capric acid (log2 fold change - 0.23; p = 0.003), caprylic acid (- 0.18; 0.003) and ceratinic acid (- 0.64; 0.014) in the POLD group, when compared to preterm controls, were linked with reduced ß-oxidation of very long chain fatty acids (p = 0.004). Reduced alanine (log2 fold change - 0.21; p = 0.046), glutamic acid (- 0.24; 0.023), and pyroglutamic acid (- 0.17; 0.035) were linked with decreased glutathione metabolism (p = 0.008). These metabolites remained significantly associated with POLD in multivariable models adjusting for early/current life factors. The pPRISm urinary metabolome was minimally changed when compared with preterm-born controls. When compared to term-born subjects, alterations in tryptophan metabolism were implicated (p = 0.01). The urinary metabolome in POLD showed significantly altered ß-oxidation of fatty acids and glutathione metabolism, implying alterations in cellular metabolism and oxidative stress. Similar findings have been noted in adults with chronic obstructive pulmonary disease. Given the similarity of findings between the POLD group and those reported for COPD, the POLD group should be considered at future risk of developing COPD.

Low circulatory levels of total cholesterol, HDL-C and LDL-C are associated with death of patients with sepsis and critical illness: systematic review, meta-analysis, and perspective of observational studies.

BACKGROUND: Mechanistic studies have established a biological role of sterol metabolism in infection and immunity with clinical data linking deranged cholesterol metabolism during sepsis with poorer outcomes. In this systematic review we assess the relationship between biomarkers of cholesterol homeostasis and mortality in critical illness. METHODS: We identified articles by searching a total of seven electronic databases from inception to October 2023. Prospective observational cohort studies included those subjects who had systemic cholesterol (Total Cholesterol (TC), HDL-C or LDL-C) levels assessed on the first day of ICU admission and short-term mortality recorded. Meta-analysis and meta-regression were used to evaluate overall mean differences in serum cholesterol levels between survivors and non-survivors. Study quality was assessed using the Newcastle-Ottawa Scale. FINDINGS: From 6469 studies identified by searches, 24 studies with 2542 participants were included in meta-analysis. Non-survivors had distinctly lower HDL-C at ICU admission -7.06 mg/dL (95% CI -9.21 to -4.91, p < 0.0001) in comparison with survivors. Corresponding differences were also seen less robustly for TC -21.86 mg/dL (95% CI -31.23 to -12.49, p < 0.0001) and LDL-C -8.79 mg/dL (95% CI, -13.74 to -3.83, p = 0.0005). INTERPRETATION: Systemic cholesterol levels (TC, HDL-C and LDL-C) on admission to critical care are inversely related to mortality. This finding is consistent with the notion that inflammatory and metabolic setpoints are coupled, such that the maladaptive-setpoint changes of cholesterol in critical illness are related to underlying inflammatory processes. We highlight the potential of HDL-biomarkers as early predictors of severity of illness and emphasise that future research should consider the metabolic and functional heterogeneity of HDLs. FUNDING: EU-ERDF-Welsh Government Ser Cymru programme, BBSRC, and EU-FP7 ClouDx-i project (PG).