Ozenoxacin: A Novel Topical Quinolone for Impetigo.

OBJECTIVE: To review the data supporting Food and Drug Administration (FDA) labeling of ozenoxacin and evaluate its place in therapy for impetigo. DATA SOURCES: A literature search was conducted using PubMed (1966 to May 2018) and Google Scholar (2000 to May 2018) with the search terms ozenoxacin, T-3912, and GF-001001-00. Other resources included clinicaltrials.gov , the manufacturing product label, and the FDA website. STUDY SELECTION AND DATA EXTRACTION: All relevant English-language data from abstracts, phase 1 to 4 studies, and review articles were included. DATA SYNTHESIS: FDA labeling of ozenoxacin was based on 2 phase 3 studies conducted in patients 2 months of age and older. Ozenoxacin demonstrated efficacy and safety for use in bullous or nonbullous impetigo from Staphylococcus aureus or Streptococcus pyogenes as compared with placebo. The lack of systemic absorption results in minimal adverse drug reactions. Studies did not detect possible adverse events commonly associated with other quinolone antibiotics. Relevance to Patient Care and Clinical Practice: This topical quinolone has bactericidal activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus. Ozenoxacin may have an expanded clinical role for the treatment of localized impetigo if resistance to current therapies increases significantly. However, ozenoxacin is unlikely to play a significant role in the treatment of impetigo in the foreseeable future, because of lack of direct comparative clinical efficacy data with currently recommended therapies and likely high cost. CONCLUSIONS: Ozenoxacin, the first nonfluorinated quinolone, is a safe, topical treatment for impetigo in patients 2 months of age and older. Although clinical trials demonstrate efficacy compared with placebo, comparative trials to current treatment options are needed to identify its therapeutic use.

Permanent cardiac pacing in children: choosing the optimal pacing site: a multicenter study.

BACKGROUND: We evaluated the effects of the site of ventricular pacing on left ventricular (LV) synchrony and function in children requiring permanent pacing. METHODS AND RESULTS: One hundred seventy-eight children (aged <18 years) from 21 centers with atrioventricular block and a structurally normal heart undergoing permanent pacing were studied cross-sectionally. Median age at evaluation was 11.2 (interquartile range, 6.3-15.0) years. Median pacing duration was 5.4 (interquartile range, 3.1-8.8) years. Pacing sites were the free wall of the right ventricular (RV) outflow tract (n=8), lateral RV (n=44), RV apex (n=61), RV septum (n=29), LV apex (n=12), LV midlateral wall (n=17), and LV base (n=7). LV synchrony, pump function, and contraction efficiency were significantly affected by pacing site and were superior in children paced at the LV apex/LV midlateral wall. LV dyssynchrony correlated inversely with LV ejection fraction (R=0.80, P=0.031). Pacing from the RV outflow tract/lateral RV predicted significantly decreased LV function (LV ejection fraction <45%; odds ratio, 10.72; confidence interval, 2.07-55.60; P=0.005), whereas LV apex/LV midlateral wall pacing was associated with preserved LV function (LV ejection fraction ≥55%; odds ratio, 8.26; confidence interval, 1.46-47.62; P=0.018). Presence of maternal autoantibodies, gender, age at implantation, duration of pacing, DDD mode, and QRS duration had no significant impact on LV ejection fraction. CONCLUSIONS: The site of ventricular pacing has a major impact on LV mechanical synchrony, efficiency, and pump function in children who require lifelong pacing. Of the sites studied, LV apex/LV midlateral wall pacing has the greatest potential to prevent pacing-induced reduction of cardiac pump function.

The epidemiology of arrhythmia in infants: a population-based study.

AIM: Cardiac arrhythmias are an important cause of morbidity in infants. Although the spectrum of types of arrhythmia has been reported, there has been no previous population-based study of the incidence of arrhythmias in infancy. Our aim was to define the population incidence of arrhythmia in infants. METHODS: We based this study on the Northern Region of England with a resident population of 3.1 million and an annual live birth rate of 33,000. We identified all clinically significant arrhythmias in infants in 1991-2010 from the regional cardiac database. All diagnoses were based on analysis of the electrocardiogram. Infants with only the substrate for arrhythmia (such as QT prolongation or ventricular pre-excitation) were excluded. RESULTS: In 20 years, there were 662,698 live births. We identified 162 cases of newly diagnosed arrhythmia of which 22 had associated structural cardiovascular malformations. The incidence of arrhythmia was 24.4 per 100,000 live births. The most common arrhythmia was atrioventricular re-entry tachycardia with an incidence of 16.3 per 100,000. Complete atrioventricular block and atrial flutter both occurred at 2.1 cases per 100,000 live births, and other arrhythmias were rare. CONCLUSIONS: This study is the first to report a population incidence of arrhythmia in infants.

Nonsynonymous variants in the SMAD6 gene predispose to congenital cardiovascular malformation.

Congenital cardiovascular malformation (CVM) exhibits familial predisposition, but most of the specific genetic factors involved are unknown. Postulating that rare variants in genes in critical cardiac developmental pathways predispose to CVM, we systematically surveyed three genes of the bone morphogenetic protein (BMP) signaling pathway for novel variants. Exonic, splice site, and untranslated regions of BMPR1A, BMPR2, and SMAD6 genes were sequenced in 90 unrelated sporadic cases of CVM. One nonsynonymous variant (p.C484F) with predicted functional impact was found in the MAD homology 2 domain of SMAD6, an intracellular inhibitor of BMP signaling. Sequencing this domain in an additional 346 cases of CVM yielded two further nonsynonymous variants (p.P415L and p.A325T). Functional effects of all three SMAD6 mutations were investigated using BMP signaling assays in vitro. Two SMAD6 variants (p.C484F and p.P415L) had significantly (P < 0.05) lower activity than wild-type SMAD6 in inhibiting BMP signaling in a transcriptional reporter assay. In addition, the p.C484F variant had a significantly (P < 0.05) lower capacity to inhibit an osteogenic response to BMP signaling. We conclude that low-frequency deleterious variants in SMAD6 predispose to CVM. This is the first report of a human disease phenotype related to genetic variation in SMAD6.

Mortality in infants with cardiovascular malformations.

UNLABELLED: Cardiovascular malformations are an important cause of infant death and the major cause of death due to malformation. Our aims were to analyse and categorise all deaths in infants with cardiovascular malformations, and to analyse trends in mortality over time and influences on mortality. We obtained details of infant deaths and cardiovascular malformations from the population of one health region for 1987-2006. We categorised deaths by cause and by presence of additional chromosomal or genetic abnormalities or non-cardiac malformations. In 676,927 live births the total infant mortality was 4,402 (6.5 per 1,000). A total of 4,437 infants had cardiovascular malformations (6.6 per 1000) of whom 458 (10.3%) died before 1 year of age. Of this number, 151 (33%) deaths had non-cardiac causes, 128 (28%) were cardiac without surgery and 179 (39%) occurred from cardiac causes after surgery. Death was unrelated to the cardiovascular malformation in 57% of infants with an additional chromosomal or genetic abnormality, in 76% of infants with a major non-cardiac malformation and in 16% of infants with an isolated cardiovascular malformation. Terminations of pregnancies affected by cardiovascular malformations increased from 20 per 100,000 registered births in the first 5 years to 78 per 100,000 in the last 5 years. A total of 2,067 infants (47%) underwent surgery and of these 216 (10%) died before 1 year of age. CONCLUSIONS: A total of 10.4% of infants who died had a cardiovascular malformation and two-thirds of deaths were due to the malformation or its treatment. Mortality declined due to increasing termination of pregnancy and improved survival after operation.

Atrioventricular block in an infant with an atrioventricular septal aneurysm.

A case of atrioventricular (AV) septal aneurysm presenting in late fetal life with AV block is reported. In the neonatal period, second-degree AV block occurred, which progressed during infancy to complete block. This report includes ante- and postnatal echocardiograms demonstrating the anatomy. Only three other reports of AV septal aneurysm are found in the literature, none of which describe heart rhythm disturbance.

Asymptomatic anomalous origin of the left coronary artery from the pulmonary artery.

Anomalous origin of the left coronary artery from the pulmonary artery is a rare congenital anomaly of the coronary arteries which usually presents with heart failure in early infancy. We describe the unusual occurrence of this in an older child with no signs of cardiac ischemia.

Twenty-year trends in prevalence and survival of Down syndrome.

The aims of this study were (1) to determine trends in total prevalence and live birth prevalence of Down syndrome, (2) to analyse trends in factors likely to influence this prevalence and (3) to determine 1-year survival in Down syndrome. A retrospective review was made of prospectively collected data on all cases of Down syndrome within a malformation registry born in 1985-2004. Down syndrome affected 1188 pregnancies among 690 215 live births (1.72 per 1000 total births). The proportion increased over 20 years from 1.3 to 2.5 per 1000 total births (P<0.0001). There were 389 terminations for Down syndrome and 51 stillbirths. There were 748 live births with Down syndrome (1.08 per 1000 live births). The live birth prevalence declined in 1985-1994 and increased in 1995-2004 with no overall change. Total live births in the population declined by 20% over 20 years. Mothers delivering at 35 years of age or above increased from 6 to 15%. The uptake of maternal serum screening increased from zero in 1987 to 35% in 1993 but then plateaued. One-year survival of live births with Down syndrome increased, especially in babies with cardiovascular malformations, reaching almost 100%. The prevalence of pregnancies affected by Down syndrome has increased significantly, but there has been no overall change in live birth prevalence. Increasing maternal age and improved survival of children with Down syndrome have offset the effects of prenatal diagnosis followed by the termination of pregnancy and declining general birth rate.

The use of a standardized order set reduces systemic corticosteroid dose and length of stay for individuals hospitalized with acute exacerbations of COPD: a cohort study.

Background: Systemic corticosteroids (SC) are an integral part of managing acute exacerbations of COPD (AECOPD). However, the optimal dose and duration vary widely in clinical practice. We hypothesized that the use of a "PowerPlan" order set in the electronic health system (EHS) that includes a 5-day SC order would be associated with a reduced steroid dose and length of stay (LOS) for individuals hospitalized with AECOPD. Patients and methods: We conducted a retrospective cohort study of Medicare recipients discharged with an AECOPD diagnosis from our University Hospital from 2014 to 2016. Our EHS-based "COPD PowerPlan" order set included admission, laboratory, pharmacy, and radiology orders for managing AECOPD. The default SC option included intravenous methyl-prednisolone for 24 hours followed by oral prednisone for 4 days. The primary endpoint was the difference in cumulative steroid dose between the PowerPlan and the usual care group. Secondary endpoints included hospital LOS and readmission rates. Results: The 250 patients included for analysis were 62±11 years old, 58% male, with an FEV1 55.1%±23.6% predicted. The PowerPlan was used in 72 (29%) patients. Cumulative steroid use was decreased by 31% in the PowerPlan group (420±224 vs 611±462 mg, P<0.001) when compared with usual care. PowerPlan use was independently associated with decreased LOS (3 days; IQR 2-4 days vs 4 days; IQR 3-6 days, P=0.022) without affecting 30- and 90-day readmission rates. Conclusion: Use of a standardized EHS-based order set to manage AECOPD was associated with a reduction in steroid dose and hospital LOS.

Visualizing the history of living spaces.

The technology available to building designers now makes it possible to monitor buildings on a very large scale. Video cameras and motion sensors are commonplace in practically every office space, and are slowly making their way into living spaces. The application of such technologies, in particular video cameras, while improving security, also violates privacy. On the other hand, motion sensors, while being privacy-conscious, typically do not provide enough information for a human operator to maintain the same degree of awareness about the space that can be achieved by using video cameras. We propose a novel approach in which we use a large number of simple motion sensors and a small set of video cameras to monitor a large office space. In our system we deployed 215 motion sensors and six video cameras to monitor the 3,000-square-meter office space occupied by 80 people for a period of about one year. The main problem in operating such systems is finding a way to present this highly multidimensional data, which includes both spatial and temporal components, to a human operator to allow browsing and searching recorded data in an efficient and intuitive way. In this paper we present our experiences and the solutions that we have developed in the course of our work on the system. We consider this work to be the first step in helping designers and managers of building systems gain access to information about occupants' behavior in the context of an entire building in a way that is only minimally intrusive to the occupants' privacy.

Cardiac arrhythmias in the fetus and newborn.

Arrhythmias are potentially life-threatening problems in the fetus and newborn. Appropriate management depends on accurate diagnosis. Atrioventricular re-entry is the most common type of supraventricular tachycardia in both the fetus and newborn. It should be distinguished from other types of tachycardia - such as atrial flutter, atrial ectopic tachycardia, permanent junctional re-entry tachycardia, and ventricular tachycardia. Neonatal and fetal bradycardias are less common clinical problems. Sustained bradycardia is most often caused by complete atrioventricular block. It can be mimicked by the more common but benign occurrence of non-conducted atrial premature beats.

The single-ventricle patient population: a current and future concern a population-based study in the North of England.

OBJECTIVE: To estimate the size and characteristics of the UK population with single-ventricle physiology, and predict future population growth. METHODS: The surviving population with single-ventricle physiology in Northern England (resident population 2.9 million) was identified from our clinical database and the Northern Congenital Abnormality Survey (NorCAS). Conditions included double inlet ventricle, tricuspid atresia, mitral atresia, hypoplastic left heart syndrome and other unbalanced defects. Fetal diagnoses, terminations of pregnancy and surgical interventions were reviewed. Childhood and adult prevalence of single-ventricle physiology were calculated. Current and future National population figures were estimated using expected mortality derived from literature. RESULTS: 80 children and 48 adults with single-ventricle physiology were identified in the NorCAS region. The most frequent underlying condition in childhood was hypoplastic left heart, and among adults was double inlet ventricle. All children over 5 years of age had completed a Fontan repair (89%) or had a Glenn anastomosis. Seven adults had not undergone a Glenn shunt or Fontan procedure. Of those patients over 30 years of age (n=12), 50% were New York Heart Association (NYHA) functional class 3, compared to 3% of those under 30 years (p=0.001). Regional childhood and adult prevalence of single-ventricle physiology was 16 and 2 per 100 000, respectively. CONCLUSIONS: The current UK single-ventricle population is composed of around 1040 adults and 1700 children. Adult numbers will increase by over 60% in the next decade with the proportion in NHYA functional class 3 set to double.

Patient-reported quality of life outcomes for children with serious congenital heart defects.

OBJECTIVE: To compare patient-reported, health-related quality of life (QoL) for children with serious congenital heart defects (CHDs) and unaffected classmates and to investigate the demographic and clinical factors influencing QoL. DESIGN: Retrospective cohort study. SETTING: UK National Health Service. PATIENTS: UK-wide cohort of children with serious CHDs aged 10-14 years requiring cardiac intervention in the first year of life in one of 17 UK paediatric cardiac surgical centres operating during 1992-1995. A comparison group of classmates of similar age and sex was recruited. MAIN OUTCOME MEASURES: Child self-report of health-related QoL scores (Pediatric Quality of Life Inventory, PedsQL) and parental report of schooling and social activities. RESULTS: Questionnaires were completed by 477 children with CHDs (56% boys; mean age 12.1 (SD 1.0) years) and 464 classmates (55%; 12.0 (SD 1.1) years). Children with CHDs rated QoL significantly lower than classmates (CHDs: median 78.3 (IQR 65.0-88.6); classmates: 88.0 (80.2-94.6)) and scored lower on physical (CHDs: 84.4; classmates: 93.8; difference 9.4 (7.8 to 10.9)) and psychosocial functioning subscales (CHDs: 76.7, classmates: 85.0; difference 8.3 (6.0 to 10.6)). Cardiac interventions, school absence, regular medications and non-cardiac comorbidities were independently associated with reduced QoL. Participation in sport positively influenced QoL and was associated with higher psychosocial functioning scores. CONCLUSIONS: Children with serious CHDs experience lower QoL than unaffected classmates. This appears related to the burden of clinical intervention rather than underlying cardiac diagnosis. Participation in sports activities is positively associated with increased emotional well-being. Child self-report measures of QoL would be a valuable addition to clinical outcome audit in this age group.

Modelling survival and mortality risk to 15 years of age for a national cohort of children with serious congenital heart defects diagnosed in infancy.

BACKGROUND: Congenital heart defects (CHDs) are a significant cause of death in infancy. Although contemporary management ensures that 80% of affected children reach adulthood, post-infant mortality and factors associated with death during childhood are not well-characterised. Using data from a UK-wide multicentre birth cohort of children with serious CHDs, we observed survival and investigated independent predictors of mortality up to age 15 years. METHODS: Data were extracted retrospectively from hospital records and death certificates of 3,897 children (57% boys) in a prospectively identified cohort, born 1992-1995 with CHDs requiring intervention or resulting in death before age one year. A discrete-time survival model accounted for time-varying predictors; hazards ratios were estimated for mortality. Incomplete data were addressed through multilevel multiple imputation. FINDINGS: By age 15 years, 932 children had died; 144 died without any procedure. Survival to one year was 79.8% (95% confidence intervals [CI] 78.5, 81.1%) and to 15 years was 71.7% (63.9, 73.4%), with variation by cardiac diagnosis. Importantly, 20% of cohort deaths occurred after age one year. Models using imputed data (including all children from birth) demonstrated higher mortality risk as independently associated with cardiac diagnosis, female sex, preterm birth, having additional cardiac defects or non-cardiac malformations. In models excluding children who had no procedure, additional predictors of higher mortality were younger age at first procedure, lower weight or height, longer cardiopulmonary bypass or circulatory arrest duration, and peri-procedural complications; non-cardiac malformations were no longer significant. INTERPRETATION: We confirm the high mortality risk associated with CHDs in the first year of life and demonstrate an important persisting risk of death throughout childhood. Late mortality may be underestimated by procedure-based audit focusing on shorter-term surgical outcomes. National monitoring systems should emphasise the importance of routinely capturing longer-term survival and exploring the mechanisms of mortality risk in children with serious CHDs.

Neonatal screening for critical cardiovascular anomalies using pulse oximetry.

INTRODUCTION: Babies with cardiac anomalies are often asymptomatic at birth, and many remain undetected despite routine newborn examination. We retrospectively assessed the effect of routine pulse oximetry in detection of such anomalies from a hospital birth population of 31 946 babies born between 1 April 1999 and 31 March 2009. METHOD: 29 925 babies who were not admitted to the neonatal unit at birth underwent postductal oxygen saturation measurement before discharge. If saturation was below 95% an examination was performed. If this was abnormal or saturation remained low, an echocardiogram was performed. All babies with cardiac anomaly diagnosed before 1-year were identified from the region's fetal abnormality database. RESULTS: Critical anomalies affected 27 infants (1 in 1180); 10 identified prenatally, 2 after echocardiogram was performed because of other anomalies, 2 in preterm infants, 2 when symptomatic before screening, 5 by oximetry screening, 1 when symptomatic in hospital after a normal screen and 5 after discharge home. Serious anomalies affected 50 infants (1 in 640); 8 identified antenatally, 7 because of other anomalies, 3 in the neonatal unit, 5 by pulse oximetry screening, 11 by routine newborn examination, and 16 after discharge home. CONCLUSIONS: Routine pulse oximetry aided detection of 5/27 of critical and 5/50 of serious anomalies in this sample, but did not prevent five babies with critical and 15 with serious anomalies being discharged undiagnosed. Results from screening over 250 000 babies have now been published, but this total includes only 49 babies with transposition, and even smaller numbers of rarer anomalies.

Tetralogy of Fallot with absent pulmonary valve syndrome, right aortic arch, and disconnected left pulmonary artery.

We present a rare case of a two-week-old infant with tetralogy of Fallot , absent pulmonary valve syndrome , right aortic arch, and disconnected left pulmonary artery (LPA) whose origin was from ductal ligament adjacent to the left subclavian artery. One-stage surgical correction, including closure of ventricular septal defect (VSD), LPA reconstruction and reconnection to the pulmonary trunk, reduction in size of the right pulmonary artery (RPA), and right ventricular outflow tract reconstruction with valved conduit, was successfully performed with good clinical mid-term outcome.

Mortality with congenital heart defects in England and Wales, 1959-2009: exploring technological change through period and birth cohort analysis.

BACKGROUND: Technological advances in surgery, intensive care and medical support have led to substantial decrease in mortality for children with congenital heart defects (CHDs) over the last 50 years. METHODS: Using routinely-collected mortality and population data for England and Wales from 1959 to 2009, the authors investigated age, period and birth cohort trends in child mortality attributable to CHDs. RESULTS: The total number of deaths with CHDs at all ages between 1959 and 2009 was 61 903 (33 929 (55%) males). Absolute numbers of CHD-related deaths in children (under age 15 years) fell from 1460 in 1959 to 154 in 2009. Infants (aged under 1 year) comprised over 60% of all deaths due to CHD during the 5-year period 1959-1963, but this fell to 22% by 2004-2008. Age-standardised death rates have declined for both sexes but, despite narrowing sex differences, males continue to have higher death rates. Successive birth cohorts have experienced improved death rates in the first year of life; however, declining mortality across all age-groups has only been observed for birth cohorts originating after 1989. Poisson regression modelling predicts continuing generational decline in mortality. CONCLUSIONS: Death rates attributable to CHDs have fallen dramatically with advances in paediatric cardiac surgery and intensive care, largely due to decreased mortality in infants aged under 1 year. Initially, mortality in later childhood rose as infant deaths fell, suggesting death was delayed beyond infancy. Children born within the last 20 years experienced lower mortality throughout childhood.

Accuracy of algorithms to predict accessory pathway location in children with Wolff-Parkinson-White syndrome.

OBJECTIVE: The aim of this study was to examine the accuracy in predicting pathway location in children with Wolff-Parkinson-White syndrome for each of seven published algorithms. PATIENTS AND INTERVENTIONS: ECGs from 100 consecutive children with Wolff-Parkinson-White syndrome undergoing electrophysiological study were analysed by six investigators using seven published algorithms, six of which had been developed in adult patients. MAIN OUTCOME MEASURES: Accuracy and concordance of predictions were adjusted for the number of pathway locations. RESULTS: Accessory pathways were left-sided in 49, septal in 20 and right-sided in 31 children. Overall accuracy of prediction was 30-49% for the exact location and 61-68% including adjacent locations. Concordance between investigators varied between 41% and 86%. No algorithm was better at predicting septal pathways (accuracy 5-35%, improving to 40-78% including adjacent locations), but one was significantly worse. Predictive accuracy was 24-53% for the exact location of right-sided pathways (50-71% including adjacent locations) and 32-55% for the exact location of left-sided pathways (58-73% including adjacent locations). CONCLUSIONS: All algorithms were less accurate in our hands than in other authors' own assessment. None performed well in identifying midseptal or right anteroseptal accessory pathway locations.

Ethics, governance and consent in the UK: implications for research into the longer-term outcomes of congenital heart defects.

OBJECTIVE: To explore the effect of research ethics, governance and consent requirements and recent reforms on UK-wide follow-up of children with congenital heart defects (CHD). DESIGN: Prospective cohort study. SETTING: UK National Health Service. PATIENTS: 3897 children with CHD requiring intervention, or resulting in death, before they were 1-year-old (1993-1995). MAIN OUTCOMES: Impact on study protocol, timeliness and findings of a multicentre study of survival and quality of life. RESULTS: The peer-reviewed study protocol was altered to accommodate ethics committee stipulations that researchers should not approach families directly with a request to participate and that the general practitioner's (GP) permission be sought before the local clinician could do so. Individual consent was required to confirm the vital status of participants and for future tracing of public death registrations. Local study registration took a median of 40 weeks (IQR 25-57). 180 (24%) of 739 surviving children (five centres) could not be contacted because their GP was untraceable (32), had changed (128) or considered contact inappropriate (20). Invitations could not be sent to 31% from the most deprived compared with 17% from the least deprived areas. CONCLUSIONS: Decision making concerning childhood interventions should be influenced by evidence on long-term outcomes. However, current UK research regulations hinder follow-up in multicentre studies. Stipulations preventing researchers contacting families directly with research invitations appear disproportionate to the risks, impede equitable access to research opportunities and introduce bias. The requirement for an individual's consent to confirm whether they are alive and monitor survival precludes effective long-term follow-up.